Hormonal control of cardiac ion channels and transporters

Progress in Biophysics & Molecular Biology 72 (1999) 67±108

Review

Hormonal control of cardiac ion channels and transporters Y. Shimoni* Department of Physiology and Biophysics, Health Sciences Centre, Faculty of Medicine, University of Calgary, 3330 Hospital Dr. N.W., Calgary, Alta., Canada T2N 4N1

Contents 1.

Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 1.1. De®ning parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

3.

General considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

4.

Adrenaline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. b-Adrenergic e€ects . . . . . . . . . . . . . . . . . . . . 4.1.1. Calcium currents . . . . . . . . . . . . . . . . 4.1.2. Potassium currents . . . . . . . . . . . . . . 4.1.3. Sodium current . . . . . . . . . . . . . . . . . 4.1.4. Chloride currents . . . . . . . . . . . . . . . 4.1.5. Hyperpolarization-activated current If 4.1.6. Pumps and exchangers. . . . . . . . . . . . 4.2. a-Adrenergic e€ects . . . . . . . . . . . . . . . . . . . . 4.3. Pathophysiology . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

71 72 72 73 74 74 74 75 75 77

5.

Angiotensin II. . . . . . . . . . . . . . . . . . 5.1. Calcium currents . . . . . . . . . . . 5.2. Sodium and potassium currents 5.3. Chloride current . . . . . . . . . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

79 80 80 81

6.

Aldosterone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

7.

Antidiuretic hormone (arginine-vasopressin) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

* Fax: +1-403-270-0313. E-mail address: [email protected] (Y. Shimoni) 0079-6107/99/$ - see front matter # 1999 Elsevier Science Ltd. All rights reserved. PII: S 0 0 7 9 - 6 1 0 7 ( 9 9 ) 0 0 0 0 5 - X

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

68

8.

Atrial 8.1. 8.2. 8.3.

9.

Thyroid hormones . . . . . . . . 9.1. Calcium currents . . . . 9.2. Potassium currents . . 9.3. Sodium currents . . . . 9.4. Na+/K+ pump . . . . . 9.5. Na+±Ca2+ exchanger

10.

natriuretic peptides (ANP) Calcium currents . . . . . . . Potassium currents . . . . . Sodium current . . . . . . . .

Insulin . . . . . . . . . . . . . . . 10.1. Calcium currents . . . 10.2. Potassium currents . 10.3. Na+/K+ pump . . . . 10.4. Na+/H+ exchange . 10.5. Na+/Ca2+ exchange 10.6. Modi®cations . . . . .

. . . . . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

83 83 84 84

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

84 85 86 88 88 88

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

89 90 90 92 92 92 92

11.

Glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

12.

Glucagon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

13.

Ovarian hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 13.1. Calcium currents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 13.2. Potassium currents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

14.

Growth hormone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

15.

Parathyroid hormone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

16.

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

1. Foreword 1.1. De®ning parameters In reviewing the hormonal regulation of cardiac ion channels and transporters, several arbitrary decisions had to be made, relating mainly to criteria of inclusion and exclusion. The ®rst issue was which hormones to include: if a strict traditional de®nition of a hormone is a substance released into the bloodstream by a gland, adrenaline should, but atrial natriuretic peptides should not be included. However, adrenaline e€ects overlap to a great extent with those of the neurotransmitter noradrenaline, released by the sympathetic nerve endings, which is not a hormone. The e€ects of the sympathetic and parasympathetic transmitters were

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

69

reviewed extensively by Harztell in 1988 and the cellular events related to the activation of aadrenergic receptors were reviewed by Fedida et al. (1993) and by Terzic et al. (1993). However, in view of recent developments in methodology and in light of many new ®ndings relating to the modulation of adrenergic e€ects, it was decided to include adrenaline in the present review. A further point is that the formal distinction of hormones has become blurred, with the realization, for example that a variety of hormones such as angiotensin, are also produced locally by several tissues, including the heart (Baker et al., 1992). A cardiac steroidogenic system has also been proposed recently (Silvestre et al., 1998), as has a cardiac vasopressin system (Hupf et al., 1999). Thus, criteria of inclusion are inherently `fuzzy'. In this context, the abundance of vasoactive peptides also necessitated some selection, bearing in mind that in many cases not much is known about direct e€ects on cardiac currents or transport mechanisms. Thus, this review does cover atrial natriuretic peptides, released by cardiac cells themselves, but not VIP, CGRP, substance P or endothelin. The second issue related to the question of whether to restrict the survey to e€ects of hormones on channels, or whether to include pumps and exchangers. Since the latter have a direct bearing on cardiac electrical function (Noble, 1992), it was decided to include these, wherever data is available. The function of the cardiovascular system as a whole depends critically on the blood vessels themselves. There is an ever-increasing wealth of information regarding e€ects of hormones on ion channels in vascular smooth muscle cells, as well as the key role played by endothelial cells. Unfortunately, these remain outside the scope of this review. Also excluded are the e€ects of hormones on intracardiac neurons.

2. Introduction Although the heart is not the primary target of many hormones, most hormones have been found to a€ect cardiac function, partly by a€ecting ion channels and transporters. This modulation a€ects the electric activity of the heart and can lead to either bene®cial or detrimental e€ects. A tonic modulatory role of hormones on action potentials in many regions of the heart is therefore a (sometimes unrecognized) part of the multitude of diverse factors which contribute to the action potential con®guration. This hormonal modulation may a€ect heart rate, conduction of the action potential and contractility. Since levels of hormones in the bloodstream ¯uctuate, with possibly di€erent, superimposed periodicities (Shannaho€-Khalsa et al., 1998), their impact on electrical parameters will also vary. The study of acute e€ects of hormones on ion channels may be relevant to short-term ¯uctuations. However, it should be recognized that although the study of acute e€ects of hormones on ion channels and transporters is necessary for understanding hormonal regulation, the overall impact on cardiac function will be determined by an integrated response to all the simultaneous factors at work at a given moment, including the chronic, background level of each hormone. Long-term, chronic changes in hormone levels are known to a€ect the heart. It is wellestablished that cardiac complications are among the more serious outcomes of imbalance in the levels of several hormones, such as insulin (Fein and Sonnenblick, 1985; Shehadeh and

70

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

Regan, 1994) or thyroid hormone (Morkin et al., 1983). Some complications are indirect, resulting from, for example, coronary disease, whereas other complications are known to result from direct e€ects on the myocardium, independently of other factors. Some of these complications involve changes in ion transfer mechanisms, which may result in changes in heart rate, contractility or normal propagation of the action potential. Conversely, as discussed in following sections, primary heart disease often results in changes in the normal e€ects of hormones on the heart. The present review will present the evidence available at present regarding the e€ects of several hormones on ion channels and transporters. Where known, the mechanisms of hormone action will be discussed, as well as the possible implications of hormone action for cardiac activity. In some studies, the e€ects of acute application of hormones on ion channels are reported, whereas in others long-term e€ects of hormonal imbalance are described. Modulatory in¯uences which alter the basic actions of di€erent hormones, as well as changes following heart disease, will be described, where data is available. The distinction between acute, chronic and pathophysiological e€ects of hormones has important implications for a comprehensive understanding of the role these hormones play. As will become apparent, there is an imbalance in the literature, with the actions of a few hormones being a major target of intense investigation, whereas other hormones have been studied only minimally, or not at all. The investigation of the e€ects of hormones on channels and transporters and the associated intracellular mechanisms, has taken on new dimensions in recent years. The development of techniques for heterologous expression of cloned channels and receptors, as well as methods for the overexpression or knockout of speci®c cellular components, have greatly advanced the understanding of the complex regulation processes which occur normally and in disease. An attempt has been made here to cover many of the new ®ndings, although the rapidly increasing abundance of reports appearing in the literature must have led to many omissions. Hopefully, no key ®ndings have been missed.

3. General considerations The action of hormones depends on their binding to speci®c receptors. Many hormones have several receptor subtypes, so that di€erent responses can be elicited, depending on the receptor subtype which is activated. The e€ects of a hormone binding to its receptor are brought about by a complex transduction process which involves a cascade of events terminating in the ®nal action on the channel or transporter. There are several cellular transduction pathways that have been described in detail and some of them are shared by di€erent hormones (with speci®city deriving from the receptors involved or from the participation of di€erent combinations of components of the cascade). A very brief and general description of some of the characteristics of these transduction pathways is given below. A more complete description can be found in Gilman (1987) and in McDonald et al. (1994). The transduction cascade usually involves activation of GTP-binding (G-) proteins, which are heterotrimeric membrane proteins, consisting of a and bg subunits (Gilman, 1987). There are many types of G-proteins (e.g. Gs, Gi, etc.), several of which have been cloned and expressed in heterologous systems. In addition, recent results with overexpression of G proteins

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

71

have also been reported (Lader et al., 1998). It is known that more than one type of G-protein can be activated by the binding of a hormone to its receptor (McDonald et al., 1994). In the absence of agonists, the subunits of G-proteins are associated, with GDP bound to the a subunit. Agonist binding to receptors displaces GDP, leading to GTP binding. This dissociates the trimer, with both the a and the bg subunits a€ecting downstream e€ectors (Gilman, 1987). Some e€ects have been found to be membrane delimited, with direct actions on channel proteins. In most cases, there is an activation of second messenger systems. These actions are mediated by the activation of membrane-bound enzymes such as adenylyl cyclase, which elevates intracellular cyclic AMP (cAMP), guanylyl cyclase (which can also be found in the cytosol) which elevates cyclic GMP (cGMP), phospholipase C, which leads to the breakdown of phosphoinositides, leading to elevation of diacylglycerol and inositol triphosphaste or others (see McDonald et al., 1994 for further details). Many of these second messengers lead to activation or deactivation of protein kinases and/or phosphatases, which change the phosphorylation level (and thus the activity) of target channels or transporters. Some of the protein kinases a€ecting channels are protein kinase A, activated by cAMP, protein kinase C, activated by diacylglycerol and protein kinase G, which is activated by cGMP. The activation of guanylyl cyclase leading to CGMP formation is in many cases caused by the second messenger nitric oxide (Schmidt et al., 1993). The levels of cyclic nucleotides (cAMP and cGMP) are in turn regulated by a balance between their formation by agonists and their breakdown by several di€erent phosphodiesterases (Beavo, 1995). Hormone actions have been found to a€ect all of these components, as well as additional ones (e.g. calcium± calmodulin kinase; tyrosine kinase/phosphatase systems, etc.). This very brief sketch of the intracellular modulators of hormone action can serve only as a very minimal basis for understanding the mode of action of hormones. In reality, increasing levels of the complexity associated with hormone action are becoming apparent. For example, there are many interesting recent ®ndings concerning interactions between the di€erent pathways, di€erential localized e€ects due to subcellular compartmentalization and more. Some of these will be described below, as the e€ects of di€erent hormones are outlined. Rather than proceeding with a survey of the known e€ects of the di€erent hormones in a random fashion, some attempt at a logical grouping has been made. Thus, the ®rst sections deal with hormones that target the cardiovascular system as one of their main functions. These include adrenaline, angiotensin, antidiuretic hormone (vasopressin), atrial natriuretic peptides and aldosterone. These hormones can control the cardiovascular system by regulating cardiac output, through e€ects on stroke volume (contractility) and/or on heart rate. In addition (or in parallel) cardiac output is controlled through e€ects on vascular tone, blood volume and kidney function (water and salt balance), etc. The second group of hormones discussed are those involved in metabolic regulation, such as thyroid hormones, insulin, glucagon and glucocorticoids. The third group includes gonadal hormones and other hormones serving di€erent regulatory functions.

4. Adrenaline The e€ects of circulating adrenaline are mediated by binding to both a and b receptors. The

72

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

e€ects on cardiac ion currents were reviewed several years ago (Hartzell, 1988; Fedida et al., 1993; Terzic et al., 1993). Several major developments have taken place in recent years, which have greatly enhanced our understanding of the details of adrenergic regulation of cardiac ionic currents. These include ®ndings relating to adrenergic modulation of additional currents, the elucidation of receptor subtypes involved and a better understanding of the transduction pathways involved. An additional important development has been the realization that these regulatory mechanisms are dynamic, and are subject to alterations under a wide variety of conditions, some of which are outlined below. Following is a brief summary of the e€ects of b and a-adrenergic activation on the major cardiac currents and transporters, including some of the more recent developments. In the subsequent section, an account of some of the changes which occur in this modulation in di€erent pathologies is given. 4.1. b-Adrenergic e€ects 4.1.1. Calcium currents Early work showed that activation of b receptors enhances the L-type calcium current (Trautwein and Cavalie, 1985), through a complex transduction pathway involving activation of a G-protein (Gs), which activates adenylyl cyclase. The ensuing elevation in cAMP levels in turn activates protein kinase A (Trautwein and Osterrieder, 1986), which leads to phosphorylation of the channel (Trautwein and Hescheler, 1990). The a1 subunit of the channel is the main target for phosphorylation, although the beta subunit, and possibly other accessory proteins are also phosphorylated in order to enhance the current through this channel (Charnet et al., 1995). The degree of channel phosphorylation which determines current magnitude is ultimately determined by a balance between the actions of kinases and phosphatases which dephosphorylate the channel. Activation of a phosphatase associated with the L-type calcium channel was found to attenuate the current (Singer-Lahat et al., 1994). There is some evidence that a-adrenergic agonists activate a phosphatase inhibitor protein, which would tip the kinase/phosphatase balance towards current enhancement (Neumann et al., 1991). Early work, partly based on co-expression of Ca2+ channels and b receptors suggested that b1 receptors mediate the e€ect (Yatani et al., 1995), possibly exclusively in guinea pig ventricle (Hool and Harvey, 1997). More recent evidence suggests that the b2 receptor can also mediate e€ects on calcium channels in frog, rat and human atrial myocytes (Skeberdis et al., 1997). In recent work using transgenic mice overexpressing the b2 receptor, it was found that the receptor is also concurrently linked to the Gi protein, which must be inhibited in order for the stimulatory response to be evident (Xiao et al., 1999). It was further shown in this model that the overexpression of the b2 receptor can speci®cally modulate the calcium current, without a€ecting a delayed recti®er K+ current, which is normally also modulated by adrenergic stimulation (An et al., 1999). This suggests a compartmentalization of the b-adrenergiccontrolled cAMP, with a distinct separate localization of the Ca2+ and K+ channels. Such a localized functional coupling of b-adrenergic receptors to adjacent Ca2+ channels was also shown in frog ventricular cells, in elegant experiments using microperfusion of two cell halves (Jurevicius and Fischmeister, 1996). A b-adrenergic e€ect on Ca2+ channels has been found in ventricular, atrial and pacemaker

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

73

tissues (Hartzell, 1988) and contributes to an elevated action potential plateau, as well as to the enhanced heart rate. This e€ect is more prominent in adult, as opposed to neonatal rabbit ventricular myocytes, probably due to a reduction in tonic inhibition by Gi (Osaka and Joyneer, 1992). However, as mentioned above, subtle complexities exist in this (and any hormonal) modulation. For example, the in¯ux of calcium is partly governed by calciumdependent inactivation of the channel. This is determined (in ventricular cells) to a large extent by calcium release from the sarcoplasmic reticulum (SR). However, SR calcium uptake and release are also key targets of b-adrenergic stimulation, so that modulation of the in¯ux through the L-type calcium channel may also be in¯uenced indirectly. This has been suggested in recent work (Sako et al., 1997) with transgenic mice missing phospholamban, a key component of the SR. In this model there is no enhanced b-adrenergic-dependent uptake and release of calcium from the SR. Sako et al. (1997) suggest that a normal slowing of Ca2+ current inactivation by b-adrenergic agonists is o€set by SR calcium release, due to calciumdependent inactivation of the current. In the transgenic mice the rate of current inactivation is dramatically slowed, due to the reduced SR calcium release. This ®nding emphasizes the fact that hormone e€ects on ion currents consist of a variety of interacting factors. In addition to the cAMP-mediated regulation of Ca2+ channels by b-adrenergic agonists, there is a membrane-delimited direct e€ect on the channels, mediated by the a subunit of the Gs protein (Brown and Birnbaumer, 1988). Although this has not been found in frog myocytes and is still disputed in mammalian ventricular cells as well (Hartzell et al., 1991), there is further supportive evidence for this in recent work using stem-cell derived myocytes, in which the early development of the di€erent components of the b-adrenergic modulation is carefully monitored (Maltsev et al., 1999). Such a membrane-delimited pathway could contribute to a fast action of b-adrenergic activation on the current, as well as providing a means for bypassing (over-riding) the adenylyl cyclase pathway, which can be inhibited by other agonists. The b-adrenergic e€ects on T-type calcium currents are somewhat controversial. Although most reports indicate a lack of e€ect of b-adrenergic stimulation of this current in both canine atrial and in rabbit sinoatrial cells (Bean, 1985; Hagiwara et al., 1988) there are other results indicating that the current is augmented in (canine and guinea pig) ventricular cells (Tseng and Boyden, 1991; McDonald et al., 1994; Vassort and Alvarez, 1994). It is possible that there are real tissue-related di€erences, but this issue is not yet clear. The stimulatory e€ect may be due to a direct membrane-delimited action of Gs on the channel Vassort. 4.1.2. Potassium currents A delayed recti®er potassium current was found to be augmented by b-adrenergic stimulation (Walsh and Kass, 1988), by a G-protein-dependent mechanism (Harvey and Hume, 1989a). More recent work showed that of the two components of the delayed recti®er (Sanguinetti and Jurkiewicz, 1990), b-adrenergic stimulation augments IKs and not IKr (Sanguinetti et al., 1991). In contrast, there is evidence showing that the inwardly-rectifying current IK1 is suppressed by b-adrenergic stimulation (Koumi et al., 1995). A recently-identi®ed ultrarapid delayed recti®er K+ current in human atrial myocytes has also been found to be enhanced by b-adrenergic stimulation (Li et al., 1996). The enhanced K+ currents will contribute to the shortening of the action potential, which is essential when the heart rate increases in response to adrenaline.

74

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

4.1.3. Sodium current The e€ects of b-adrenergic stimulation on the fast sodium current seems to be more controversial (Fozzard and Hanck, 1996). Although initial work indicated an inhibition of INa by b agonists in guinea pig myocytes (Schubert et al., 1989), later reports showed an enhanced INa in rabbit or rat myocytes (Kirstein et al., 1996). These contradictory e€ects may be due to species di€erences or to recording methods (Gintant and Liu, 1992). An alteration of ion channel selectivity by b-adrenergic agonists, allowing calcium in¯ux through the sodium channel, has also been suggested recently (Santana et al., 1998). Results obtained by measuring b-adrenergic e€ects on conduction velocity show an augmentation in well-polarized cells, but a reduction in depolarized cells (Munger et al., 1994). This voltage-dependence may underlie some of the con¯icting results obtained by direct measurements of INa. Another possibility is that in some cases the inhibitory action of PKA stimulation is superimposed on a preceding PKC activation (Fozzard and Hanck, 1996). Further complications in analyzing the actions of b-adrenergic stimulation may arise from changes in channel kinetics which may occur during PKA activation, or spontaneously during some types of recording (Fozzard and Hanck, 1996). If enhancement of the sodium current does occur, it will enable a more rapid propagation of the action potential, which is also of importance at higher heart rates. 4.1.4. Chloride currents An additional current which has been found to be activated by b-adrenergic stimulation is a cAMP-dependent chloride channel (Harvey and Hume, 1989b; Harvey et al., 1990). This current was originally proposed to be a background sodium current, based on the fact that removal of extracellular sodium abolished it (Egan et al., 1987, 1988). It is now known that sodium has a modulatory role on this cAMP-dependent chloride current (Hume and Harvey, 1991). The role of this current, which may be species-dependent (Pelzer et al., 1997a) is not completely understood. Recent evidence suggests that a beta-adrenergic activation of a Clcurrent participates in volume regulation of cardiac myocytes (Wang et al., 1997a,b). Whatever its role, activation of such a current by b-adrenergic stimulation would a€ect the balance of currents during the action potential plateau, and participate in determining the timing of the repolarization of the membrane. The activation or enhancement of this current by b receptor activation will also assist in abbreviating the action potential, as the heart accelerates under the adrenergic in¯uence. A calcium-activated chloride current has been identi®ed as contributing to the transient outward current in atrial (Zygmunt and Gibbons, 1992) and ventricular cells (Zygmunt, 1994). This current is enhanced by b-adrenergic stimulation (Zygmunt and Gibbons, 1991), although this is an indirect e€ect caused by elevation of intracellular calcium. 4.1.5. Hyperpolarization-activated current If It has long been known that b-adrenergic stimulation enhances the hyperpolarizationactivated current If , formerly labeled IK2, in Purkinje ®bres and SA node cells (Tsien, 1974; Brown et al., 1979; Zaza et al., 1996). This action, mediated by a direct activation of the channel by cAMP (DiFrancesco and Tortora, 1991), involves a shift in the activation range of the current (Tsien, 1974). A similar e€ect of b-adrenergic stimulation was recorded in sheep (Earm et al., 1983) and human (Porciatti et al., 1997) atrial tissue. The b-adrenergic regulation

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

75

of this current remains unmodi®ed from neonate to adult stages (Accili et al., 1997a,b), as well as during pathologies such as hypertension (Cerbai et al., 1996) or heart failure (Hoppe et al., 1998). It has recently been shown that phosphatase inhibition potentiates the b-adrenergic e€ects on this current (Accili et al., 1997a,b), with the conclusion that b-adrenergic modulation of this current involves both a phopshorylation and a non-phosphorylation mechanism. 4.1.6. Pumps and exchangers An additional e€ect of b-adrenergic activation is the enhancement of Na+/K+ pump activity (Gao et al., 1994; Stimers and Dobretsov, 1998). This would assist cells in maintaining normal internal Na+ and K+ concentrations, to partly compensate for the potential accumulation of intracellular sodium and loss of potassium, accompanying the enhanced heart rate during exposure to adrenaline. However, the presence of this e€ect is still controversial, since Main et al. (1997) ®nd no direct e€ect of b-adrenergic stimulation on the Na+/K+ pump. The e€ects on the Na+/Ca2+ exchange are also controversial. While Main et al. (1997) ®nd no direct e€ect of isoprenaline on the exchanger in guinea pig ventricular cells, Zhou and Lipsius (1993) ®nd that isoprenaline enhances the magnitude and accelerates the decay of the current carried by the exchanger in cat atrial pacemaker cells. Recently, a molecular determinant was identi®ed for the cAMP regulation of the Na+/Ca2+ exchanger in frog, but not in mammalian heart (Shuba et al., 1998). Since the exchanger is activated by increases in intracellular calcium, isoprenaline can also a€ect the current indirectly, by elevating resting or systolic calcium. This has been suggested to occur under conditions of excess b-adrenergic stimulation (Volders et al., 1997), contributing to the appearance of arrhythmogenic early after-depolarizations. In catecholamine-induced cardiomyopathy, Makino et al. (1985) ®nd a depressed activity of the exchanger. 4.2. a-Adrenergic e€ects The multiple cardiac e€ects of stimulating the a1-adrenergic pathway were reviewed by Fedida et al. (1993) and by Terzic et al. (1993). These include positive inotropic and chronotropic e€ects which are mediated by both a1A and a1B receptors (Williamson et al., 1994; Hattori and Kanno, 1997). Many of these e€ects are caused by changes in some of the ionic currents which are activated during the action potential. The transduction pathway subsequent to activation of a-adrenergic receptors involves both pertussis toxin (PTX)-sensitive and insensitive G-proteins (Terzic et al., 1993), which may change as a function of post-natal development (Han et al., 1989). The PTX-insensitive G-proteins involved in a-adrenergic e€ects are the Gq or Gh subtypes. Alpha-adrenergic activation generally involves activation of phospholipase C (e.g. Viamonte et al., 1990), breakdown of phosphatidylinositides, formation of 1,4,5 inositol triphosphate (Steinberg et al., 1989) and diacylglycerol, all of which lead to the release of intracellular calcium and activation of protein kinase C (Deng et al., 1997; Woo and Lee, 1999), respectively. Other phospholipases may also be activated by a-adrenergic receptors, such as phospholipase A2 and D (Fedida et al., 1993; Terzic et al., 1993). In addition to PKC, activation of phosphodiesterases and calmodulin-dependent kinase may play a role in some aadrenergic actions (Terzic et al., 1993). One of the major e€ects of activating this pathway is to attenuate several potassium

76

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

currents. These include a transient outward current (Apkon and Nerbonne, 1988; Fedida et al., 1989), a delayed recti®er current (Apkon and Nerbonne, 1988), the background inward recti®er current (Fedida et al., 1991) and the acetylcholine-activated current (Braun et al., 1992). However, an a-adrenergic-mediated stimulation of the muscarinic K+ channel has also been reported, mediated by arachidonate metabolites (Kurachi et al., 1989). Recently, the coexpression of di€erent K+ channels and a1C receptors in Xenopus oocytes has demonstrated a complex selective modulation of di€erent channels by receptor activation (Tseng et al., 1997). These authors ®nd an a-adrenergic-mediated increase in a slow delayed recti®er K+ current, which is calcium and PKC-dependent. A rapidly activating delayed recti®er K+ current and a transient outward K+ current are inhibited by activation of the co-expressed a-adrenergic receptor, also through an involvement of PKC. Interestingly, an attempt to de®ne the intracellular mediator of a-adrenergic attenuation of the transient outward current in rabbit atrial cells suggested that PKC was not involved (Braun et al., 1990). However, a di€usible second messenger was shown to be involved (Braun et al., 1990), ruling out a membrane-delimited pathway (Fedida et al., 1993). Over the last few years little progress has been made in determining the nature of the intracellular mediators linking receptor activation to the attenuation of this current. Among the main new ®ndings regarding e€ects of a-adrenergic stimulation on ionic currents is the demonstration that IK1 in human, as well as in rabbit atrial myocytes is attenuated by methoxamine, by a mechanism suggested to be PKC-dependent (Sato and Koumi, 1995). In addition, a newly identi®ed ultrarapid delayed recti®er, IKur, which corresponds to the cloned Kv1.5 channel (Feng et al., 1997), is attenuated by phenylephrine (Li et al., 1996). Overall, attenuation of potassium currents will broaden the action potential, and thus have a positive inotropic e€ect. This may be of importance in situations where the b-adrenergic pathways are compromised, in which the aadrenergic pathways can assume a more dominant role in regulating contractile force. The sodium current was generally considered to be una€ected by a-adrenergic agonists. However, new evidence suggests an attenuation of INa by methoxamine (Weight et al., 1997). This attenuation of INa is probably mediated by PKC, since direct PKC activation has also been shown to attenuate this current (Murray et al., 1997). The e€ects on the L-type Ca2+ current are more controversial. Several earlier studies showed no signi®cant e€ect in rabbit atrial cells. In rat ventricular cells Liu et al. (1994a,b) found no e€ect in adult cells, but an enhancing e€ect of phenylephrine on the L-type calcium current in neonatal rat ventricular cells. This e€ect was shown to be dependent on a PTX-insensitive G protein and mediated by PKC (Liu et al., 1994c). It was later shown that a-adrenergic activation can attenuate the b-adrenergic stimulated unitary calcium current in rat ventricular cells (Chen et al., 1996). It has recently been shown that by using perforated patch-clamp recordings, in which dialysis of intracellular modulators is prevented, it was possible to show that a-adrenergic agonists produce an enhancement (sometimes preceded by a transient decrease) of the L-type Ca2+ current (Liu and Kennedy, 1998; Zhang et al., 1998) even in adult cells. The later work con®rmed that the e€ect on the L-type Ca2+ current is mediated through the PKC pathway (Chen et al., 1996; Zhang et al., 1998). Furthermore, it was possible to use a speci®c inhibitor of PKC translocation to show that it is the C2-containing conventional PKC isozymes (a and b) that are involved in current attenuation (Zhang et al., 1997). Interestingly, an a-adrenergic-mediated inotropic response was shown to be mediated by

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

77

the novel (calcium-independent) PKC isoforms (Deng et al., 1997), highlighting the complexity of these e€ects. The T-type calcium current was also reported to be enhanced by a-adrenergic stimulation (Tseng and Boyden, 1989). Much of the more recent work relating to a-adrenergic modulation of currents in cardiac cells involves the activation of a chloride current, considered to play a role in volume regulation of cells. However, the results reported are con¯icting, possibly due to use of a agonists in some studies, as opposed to direct PKC stimulators, such as phorbol esters, in others. The latter may have additional or di€erent e€ects. Thus, Duan et al. (1995) found a PKC-dependent a-adrenergic inhibition of a basal Cl current, as well as of a current induced by swelling, in rabbit atrial myocytes. Walsh and Long (1994) found that PKC activates a Cl current in guinea pig ventricular cells, while Middleton and Harvey (1998) reported no e€ect of a phorbol ester given alone, but a potentiation of the PKA (b-receptor activated)-dependent Cl current, which is blocked by PKC inhibitors. An interesting additional e€ect of adrenergic stimulation is produced by changes in the junctional conductance, which depends on gap junction channels. The conductance of these channels has been found to be augmented by b-adrenergic stimulation, and diminished by aadrenergic stimulation (De Mello, 1997). This can have an impact on action potential propagation and the synchronization of ventricular activation. Many of the membrane transporting systems which participate in cellular ionic and pH homeostasis are also a€ected by a-adrenergic activation. In early studies, indirect measurements of the Na+/K+ pump activity showed an enhancement by a-adrenergic agonists (Shah et al., 1988). More recently, direct measurements of the electrogenic pump current have shown a direct enhancement of this outward current (Wang et al., 1998). The ensuing hyperpolarization may underlie the a-adrenergic-mediated decrease in automaticity of sheep and canine Purkinje ®bres (Fedida et al., 1993). Recent work has also provided evidence for a PKC-dependent a-adrenergic stimulation of the inward current generated by the Na+/Ca2+ exchanger in rat ventricular myocytes (Stengl et al., 1998). This e€ect may also have direct consequences for the action potential con®guration, since an enhanced inward current will tend to prolong the action potential plateau. Alpha-adrenergic stimulation is also known to cause intracellular alkalinization (Fedida et al., 1993), due to stimulation of the electroneutral Na+/H+ exchanger (Terzic et al., 1992). This was recently shown to be due to stimulation of the a1A adrenergic receptors (Yokoyama et al., 1998). The Na±K±2Cl cotransporter is also activated by a-adrenergic agonists (Andersen et al., 1998). The latter two e€ects will only a€ect the electric activity of the heart indirectly, if at all. 4.3. Pathophysiology The dynamic nature of the adrenergic regulation of currents is evident on many levels. For example, Osaka and Joyneer (1992) show a post-natal enhancement of b-adrenergic e€ects on the L-type calcium current in the rabbit, although the converse may be true in the rat (Katsube et al., 1996). Developmental changes in the modulation of cardiac repolarization by a and b adrenergic activation can lead to di€erences in the susceptibility to arrhythmias (Cua et al., 1997). In addition, under many pathological conditions and in heart failure there is a

78

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

diminution in the e€ectiveness of the b-adrenergic pathway, due to changes in receptors (Brodde, 1993) and/or in receptor coupling to intracellular e€ectors, leading to a reduced transduction ecacy (Bristow et al., 1990; Homcy et al., 1991; Ouadid et al., 1995; Ohyanagi and Iwasaki, 1996; Mukherjee et al., 1998; Richard et al., 1998). These changes are associated with increases in Gi protein and a decrease in responsiveness of Gs-coupled receptors (Brodde et al., 1998). These have been shown to be translated into changes in the b-adrenergic activation of several currents. Thus, heart failure and myocardial infarction are associated with a reduced augmentation of L-type calcium channels (Ouadid et al., 1995; Zhang et al., 1995; Aggarwal and Boyden, 1996; Spinale et al., 1997; Leclerq et al., 1998; Mukherjee et al., 1998). Furthermore, during cardiac hypertrophy, calcium channels may be uncoupled from the b receptors (Meszaros and Levai, 1992). A decreased sensitivity of L-type calcium channels to badrenergic stimulation is also found in myocytes from spontaneously hypertensive rats (Habuchi et al., 1995a,b). The enhancement of INa by isoprenaline is also attenuated in myocytes from failing, infarcted hearts (Kirstein et al., 1995). Interestingly, although the response of ICa-L to b-adrenergic stimulation diminishes with age, the modulation of If by badrenergic stimulation is not age-dependent (Accili et al., 1997a,b), nor does it change in heart failure or in hypertension (Cerbai et al., 1996; Hoppe et al., 1998). It has recently been shown that when Gs expression is increased by adenovirus infection, b-adrenergic activation by isoprenaline leads to release of excess bg subunits. This paradoxically activates the muscarinic K+ channel, which is normally activated by acetylcholine (Sorota et al., 1999). There is also evidence suggesting that during hormonal imbalance, such as in non-insulindependent (type II) diabetes (Tsuchida et al., 1994) and in hyperthyroidism (Mager et al., 1992), there is a reduction in the responsiveness of the L-type calcium current to b-adrenergic stimulation, even when there is no change in the basal current amplitude (Tsuchida et al., 1994). Recently, an enhancement of the sensitivity of the L-type calcium current, the delayed recti®er and the chloride current to b-adrenergic stimulation was found to be induced by inhibiting tyrosine kinase (Hool et al., 1998). Interleukin-1 was also found to enhance the badrenergic responsiveness of L-type calcium currents, possibly by indirect actions on protein kinase C (Rozanski and Witt, 1994). This may have implications for the adrenergic modulation of the heart under in¯ammatory conditions, although this has not yet been addressed. These results suggest that more subtle modi®cations of the adrenergic regulation of these currents are present, the details of which remain to be elucidated. An important consideration is that in addition to acute e€ects on ion channels, chronic changes in catecholamine levels have e€ects on the expression of ion channels. Thus, neonatal myocytes exposed for 24 h to the b agonist isoprenaline show an increase in L-type calcium channel density, whereas an a agonist decreases the density (Maki et al., 1996). In a rat model of hypertrophy induced by isoprenaline, the transient outward current was found to be diminished, although the b-adrenergic e€ects may be indirect in this case. a-Adrenergic e€ects: much less is known about changes in the a-adrenergic modulation of ionic currents under pathological conditions, although there is much evidence for a generally enhanced role of a-adrenergic e€ects under pathological conditions, such as ischemia (Corr and Cra€ord, 1981). There is evidence showing that during ischemia a-adrenergic stimulation results in abnormal automaticity in Purkinje ®bers (Anyukhovsky et al., 1994). Altered hormonal status can also a€ect a-adrenergic mechanisms. In type I (insulin-de®cient) diabetes,

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

79

in which there is an enhanced contractile responsiveness to a-adrenergic agonists (Tomlinson et al., 1992), there is also evidence showing an enhanced attenuation of potassium currents (Shimoni et al., 1995a). In contrast, under hyperthyroid conditions, in which a adrenergicmediated contractile e€ects are diminished (MacLeod and McNeill, 1981), the attenuation of potassium currents was also found to be diminished (Shimoni and Banno, 1993a).

5. Angiotensin II The renin±angiotensin system is a major modulator of cardiovascular homeostasis, with the octapeptide angiotensin II (AT-II) being the major e€ector (Baker et al., 1992). Interest in the cardiovascular actions of AT-II has grown in recent years due to several new developments. AT-II levels are known to increase during chronic congestive heart failure or in response to mechanical stress (Sadoshima and Izumo, 1997; Francis, 1998; Nicholls et al., 1998). Chronically elevated angiotensin II levels may be detrimental, leading to electrophysiological and morphological abnormalities (De Mello et al., 1997). Indeed, the inhibition of angiotensinconverting enzyme (ACE), which mediates the ®nal stage of AT-II formation, is now known to have many bene®cial cardiac e€ects (Borghi and Ambrosioni, 1998). Furthermore, in addition to its traditional role as a classic hormone, originating in the liver and activated by renin which is released by cells in the kidney, it is now recognized that a localized cardiac renin±angiotensin system is also present, allowing a paracrine local action of AT-II (Baker et al., 1992; Sadoshima and Izumo, 1997). Thus, stretch of ventricular tissue leads to release of AT-II which is stored in ventricular cells (Dostal and Baker, 1998). This may allow direct and selective cardiac actions, independent of the vascular actions of circulating AT-II (Liang and Gardner, 1998; Mazzolai et al., 1998). Thus, although the major action of AT-II is to augment blood pressure by increasing vascular tone (Cody, 1997), direct actions on cardiac muscle have long been identi®ed as well, leading to positive chronotropic and inotropic e€ects (Kobayashi et al., 1978; Chen et al., 1991; Lambert et al., 1991; Baker et al., 1992; Watanabe and Endoh, 1998). These e€ects will usually increase cardiac output, and thus contribute to maintenance of adequate blood pressure. These actions are aided by an apparent increase in intercellular coupling, and hence of conduction velocity (Hermsmeyer, 1980; De Mel lo et al., 1993), which will aid the synchronic activation of ventricular contraction. Despite the general agreement regarding the positive inotropic and chronotropic e€ects of AT-II, there seem to be species di€erences, with guinea pig showing less sensitivity than other species (Freer et al., 1976). In addition, the direct e€ects on ionic currents seem to be complex, with con¯icting results reported by di€erent groups. In addition, although most physiological actions of AT-II are ascribed to the type 1 AT-II receptor, the type 2 receptor is also present in cardiac tissue, with the relative distribution of the receptor subtypes changing under pathological conditions (van Bilsen, 1997). Only one report describes e€ects of activation of the type 2 receptor on ion channels (see below). The following results relate predominantly to activation of the AT-II type 1 receptor.

80

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

5.1. Calcium currents It is generally agreed that L-type calcium currents are augmented by acute addition of ATII, in ventricular and pacemaker (sinoatrial and Purkinje ®bre) cells (Kass and Blair, 1981; Allen et al., 1988; Kaibara et al., 1994). Long-term (6 days) treatment has also been reported to increase L-type calcium channel number (measured in binding assays) as well as increasing the mRNA levels for the a-subunit of the channel (Krizanova et al., 1997). However, there are also reports showing a reduction in this current (Habuchi et al., 1995a,b, in SA node cells) as well as reports showing no e€ect on basal currents, with a decrease of the b-agonist-augmented current (Ai et al., 1998, in guinea pig ventricular cells). These con¯icting results may be partly due to a rapid desensitization which occurs (Abdellatif et al., 1991), possibly with di€ering time courses in di€erent conditions. Another clue may lie in the sensitivity of the e€ects of AT-II to intracellular pH (Kaibara et al., 1994), which may have been dissimilar in the di€erent studies, thus leading to the con¯icting results. Di€erences may also arise from the activation of di€erent transduction pathways. The major mechanism for AT-II action has traditionally been considered to involve a Gprotein-mediated phospholipase C (PLC) activation leading to phosphoinositide breakdown and protein kinase C (PKC) activation (Dostal et al., 1997). Indeed, activating PKC by phorbol esters was found to mimic the action of AT-II (Dosemeci et al., 1988). Consistent with these results, cAMP levels were found to be una€ected by AT-II in cells where the current is enhanced (Allen et al., 1988). However, other transduction pathways have also been suggested to be involved in AT-II action including the inhibition of adenylate cyclase (Ohnishi et al., 1992). Activation of this pathway may explain the reduction in L-type calcium currents found in SA node cells. Kaibara et al. (1994), as well as Talukder and Endoh (1997) suggest that activation of a Na+/H+ antiporter is involved in calcium current augmentation by AT-II, since the e€ect is blocked by inhibition of Na+/H+ counter-transport by amiloride analogues and by sodium de®ciency. There has only been one report indicating an enhancement of the T-type calcium current in cardiac cells by activation of the AT-II type 1 receptor (Ertel et al., 1997), although this has also been found in adrenal cells (Lu et al., 1996). Activating the AT-II type 2 receptor attenuates the current (Ertel et al., 1997). 5.2. Sodium and potassium currents Very few studies have addressed the e€ects of AT-II on other currents. Three studies concur in ®nding an activation of sodium channels by AT-II (Moorman et al., 1989; Nilius et al., 1989; Benz et al., 1992). Although the overall e€ects are similar, there is disagreement regarding the mechanism of action. Moorman et al. (1989) and Nilius et al. (1989) provide evidence for the involvement of a second messenger, and for mediation by protein kinase C. Benz et al. (1992) ®nd direct activation of sodium channels by (very high concentrations of) AT-II and conclude that PKC is not involved. A single report suggests a di€erential e€ect of AT-II on potassium currents in guinea pig ventricular myocytes (Daleau and Turgeon, 1994). These results suggest an increase in the rapid component (IKr) and a decrease in the slow component (IKs). This should prolong the

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

81

action potential plateau and assist in the positive inotropic e€ect of AT-II. The inwardly rectifying current IK1 was also found to be enhanced by a large concentration (1 mM) of AT-II (Morita et al., 1995) in rabbit ventricular cells. An inhibitory action of AT-II on ATPdependent K+ channels has also been reported by Tsuchiya et al. (1997), who proposed that inhibition of adenylyl cyclase increases subsarcolemmal ATP levels, thus inhibiting these channels. A preliminary study has found that a more prolonged incubation (2±52 h) of adult canine epicardial myocytes with high AT-II concentrations changes the properties of the transient outward current Ito (Yu et al., 1997a,b). The current becomes more similar to the current measured in endocardial cells, leading the authors to suggest a tonic paracrine in¯uence of the cardiac renin±angiotensin system on this current. Such a tonic e€ect may partly underlie the normal epicardial±endocardial gradient in Ito magnitudes (Litowski and Antzelevitch, 1988) and kinetics in rat (Shimoni et al., 1995b) and human (Wettwer et al., 1994) ventricle. AT-II has also been found (Enous et al., 1992) to attenuate the arrhythmogenic transient inward current (Lederer and Tsien, 1976), which arises following intracellular calcium overload. This action may serve as a safeguard mechanism, ensuring that if the actions of ATII lead to calcium overload, there will be a smaller likelihood for the development of transient depolarizations (TD's) with ensuing arrhythmias. Since the arrhythmogenic transient inward current is (at least partly) mediated by the sodium±calcium exchanger (Giles and Shimoni, 1989), the above results concur with the ®nding that AT-II can downregulate the sodium± calcium exchanger in cultured neonatal rat cells (Ju et al., 1996). 5.3. Chloride current Angiotensin II has been reported to activate a chloride current in rabbit ventricular myocytes, dependent on intracellular calcium (Morita et al., 1995). In rabbit sino-atrial cells AT-II also activates a chloride current (Bescond et al., 1994). This action can be blocked by PKC inhibitors, suggesting that AT-II actions are PKC-mediated. However, another transduction pathway may also be involved, since AT-II can inhibit the protein kinase Adependent chloride current in guinea pig ventricular cells, presumably by inhibiting adenylyl cyclase (Obayashi et al., 1997). Angiotensin II also plays a major role in regulating intracellular pH in cardiac cells, by activating proton-extruding transporters in the sarcolemma. These include the Na+/H+ exchanger, activated by the AT1 receptor, the Na+/HCOÿ 3 exchanger, activated by the AT2 receptor (Dostal and Baker, 1998). and the Na+-independent Clÿ/HCOÿ 3 exchanger (Camilion de Hurtado et al., 1998). The latter was shown to be mediated by PKC, and linked to the AT1 receptor. Angiotensin II was found to increase intracellular pH in the absence of external bicarbonate, due to stimulation of the sodium±hydrogen exchanger. This e€ect was absent in the presence of a physiological bicarbonate bu€er (Camilion de Hurtado et al., 1998). However, even when pH is unchanged, a rise in intracellular sodium can indirectly increase intracellular calcium and (partly) mediate the inotropic e€ect of AT-II. Finally, AT-II was also found to enhance the expression of gap junction channels in neonatal rat ventricular myocytes (Dodge et al., 1998), which may a€ect conduction pathways. In view of this variety of often con¯icting reported actions of AT-II on cardiac cells it is

82

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

dicult to integrate the results obtained by various groups. The net e€ect on the action potential seems to be a prolongation with an enhanced plateau (Kass and Blair, 1981), although De Mello and Crespo (1995) ®nd that AT-II reduces rat papillary muscle action potential duration. A shortened action potential is also seen in SA nodal cells (Habuchi et al., 1995a,b). The e€ect on action potential may also be biphasic (Morita et al., 1995) and may vary as the heart rate changes due to AT-II action. Interestingly, long term treatment with ACE inhibitors shortens the Q-T interval and reduces Q-T dispersion (Gonzalez-Juanatey et al., 1998), implying that a chronic elevation of AT-II levels prolongs the action potential in human ventricle. This e€ect is countered by ACE inhibition, which lowers AT-II levels. To further complicate matters, angiotensin is reported to decrease b-adrenergic responsiveness in rat heart, following both acutely (Schwartz and Na€, 1996) or chronically (Henegar and Janicki, 1996) added AT-II. One possible reason for such varied responses may be inferred from the work of Yu et al. (1997a,b) , who proposed a regional-speci®c e€ect of AT-II. Thus, cells in di€erent regions may respond di€erently, based on variations in receptors and/or transduction pathways linking the hormone to the various ion channels and transporters.

6. Aldosterone This hormone is often activated in conjunction with the renin±angiotensin system. Its main target is the kidney, and its e€ects on the cardiovascular system are obtained through regulation of salt/water balance. However, there are identi®ed myocardial receptors for aldosterone (Korichneva et al., 1995) and, interestingly, there is a recent study showing that there is a localized cardiac synthesis of aldosterone (Silvestre et al., 1998). This would allow a localized regulatory mechanism to operate, independently of changes in circulating hormone levels. However, there are to date no studies (known to us) on aldosterone e€ects on cardiac ion channels. However, some e€ects on ion transport have been reported. Thus, in rabbit ventricular cells, aldosterone has been found to stimulate the electrogenic Na+/K+ pump, with an enhanced Ipump. (Mihailidou et al., 1998). This e€ect is suggested to be mediated by an enhancement of the Na+/K+/2Clÿ cotransporter. In aldosterone-induced hypertension, there are enhanced levels of mRNA encoding the a2 and a3 subunits of the Na+/K+ ATPase, as well as reduced mRNA levels for the Na+/Ca2+ exchanger (Ramirez-Gil et al., 1998). An e€ect on acid±base balance in cultured neonatal ventricular cells has also been reported, with + + transporters (Korichneva aldosterone enhancing the activity of both Clÿ/HCOÿ 3 and Na /H et al., 1995). The mechanisms of these actions are unclear, but a study showing a repression of calcium-dependent and -independent PKC by aldosterone in neonatal rat cardiac myocytes (Sato et al., 1997) may hold some clues, which could serve as a basis for further investigations. In a DOCA (deoxycorticosterone acetate) model of cardiac hypertrophy, action potential amplitude and duration are increased, with a decrease in the transient outward current, in rat ventricle (Coulombe et al., 1994; Momtaz et al., 1996). The sustained K+ current, as well as the L-type calcium current and a current attributed to the Na+/Ca2+ exchanger are unaltered. These e€ects, however, may be indirect and not necessarily attributable to a direct e€ect of DOCA.

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

83

7. Antidiuretic hormone (arginine-vasopressin) Vasopressin (ADH) is a key player in cardiovascular homeostasis, through its actions on the vasculature and the kidneys, attained by binding to two classes of receptors. Thus, its major e€ects on cardiac output are indirect, mediated by changes in blood volume and total peripheral resistance. This may underlie the paucity of studies of direct e€ects on cardiac ion channels. In one study, vasopressin was found to activate L-type calcium channels, through V1 receptor stimulation (Zhang et al., 1995a,b). This e€ect is probably mediated by PKC activation. Thus, there may be a direct cardiac e€ect leading to enhanced contractility and cardiac output, which can contribute to maintenance of blood pressure. In congestive heart failure, circulating levels of ADH levels are increased (Pool, 1998) and this has been implicated as contributing to a worsening of cardiac function (Middlekau€ and Mark, 1998). It is unknown if other ionic currents are modulated by ADH, or if this modulation changes in pathological conditions. It is possible that indirect e€ects are present, since ADH may regulate secretion of other hormones, such as atrial natriuretic peptides (Zongazo et al., 1991). Very recently, a cardiac origin of vasopressin has been identi®ed in pressure-overloaded or NO-stimulated hearts (Hupf et al., 1999). The ADH is synthesized in non-myocyte cells and can be released into the coronaries.

8. Atrial natriuretic peptides (ANP) This family of peptides is released by atrial (and brain) cells in response to stretch and volume overload. Their main actions are to cause vasodilation, diuresis and natriuresis, partly by repressing the renin±angiotensin±aldosterone system (Stein and Levin, 1998). The circulating levels of these peptides are known to be elevated by a-adrenergic stimulation (Schiebinger et al., 1992) and in early-stage heart failure ( Fukai et al., 1998). In addition to their actions on vascular smooth muscle and kidney cells, direct actions on cardiac cells have also been found. The action potential duration and amplitude was found to be reduced by ANP in atrial and ventricular muscles from several species, including human (Kecskemeti et al., 1996). 8.1. Calcium currents The major ®nding is that these peptides inhibit the L-type calcium channels, in rabbit, rat and guinea pig ventricular cells (Sorbera and Morad, 1990; Tohse et al., 1995), in chick embryonic and human fetal cells (Bkaily et al., 1993) and in adult human atrial cells (Le Grand et al., 1992). This e€ect persists when the calcium current is prestimulated by b-adrenergic stimulation (Le Grand et al., 1992; Bkaily et al., 1993). In frog ventricle, these peptides have no e€ect on the basal current, but the b-adrenergic stimulated current is attenuated (Gisbert and Fischmeister, 1988). This e€ect was found to depend on formation of cGMP (Le Grand et al., 1992; Bkaily et al., 1993; Tohse et al., 1995), leading presumably to the activation of protein kinase G (Tohse et al., 1995), although in frog ventricle a stimulation of adenylyl

84

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

cyclase may be involved (Gisbert and Fischmeister, 1988). This attenuating e€ect on the L-type calcium current presumably contributes to the overall role of these peptides in reducing blood pressure, since cardiac output will be decreased when contractility is attenuated. This is supported by the work of Tei et al. (1990) who found that ANP's reduce cytosolic free calcium in guinea pig ventricular cells, an e€ect attributed to a cGMP-mediated activation of a sarcolemmal calcium pump. The T-type calcium current was found to be una€ected (Bkaily et al., 1993), although Ertel et al. (1997) reported an attenuation of this current by ANP. 8.2. Potassium currents Very few studies address the e€ects of ANP on K+ currents. Bkaily et al. (1993) found an increase in delayed outward K+ currents, not dependent on cGMP. Le Grand et al. (1992) found a reduction in the transient outward K+ current, not dependent on cGMP, but mediated by a GTP-binding protein. 8.3. Sodium current The two studies available give con¯icting results. Whereas Bkaily et al. (1993) found no e€ects in human fetal cells, Sorbera and Morad (1990) found an attenuation of INa by ANP in guinea pig ventricular cells. The e€ects on this current could thus be both species and agedependent, although this has not yet been investigated. Sorbera and Morad (1990) suggested that there is a ANP-dependent change in the selectivity of the fast sodium channels, which become calcium-conducting. Since ANP's produce elevated cGMP levels, these results of Sorbera and Morad (1990) are of interest, since Santana et al. (1998) recently showed the same e€ect following elevation of cAMP levels. Thus, it is possible that elevated cyclic nucleotide levels may, under some circumstances, lead to a common e€ect whereby the sodium channel changes its selectivity. In addition, a related C-type natriuretic peptide (CNP), normally produced in the brain, has been found to have positive chronotropic and inotropic e€ects in canine atrial and nodal tissues (Beaulieu et al., 1997). This may turn out to be important in ®ne tuning cardiac rate, as this peptide has been suggested to be produced in atrial tissues as well (Beaulieu et al., 1997). Finally, it should be recognized that complex interactions may exist, in which ANP levels are modi®ed by other hormones, such as ADH (Zongazo et al., 1991), or by a-adrenergic regulation (Schiebinger et al., 1992). The next group of hormones to be discussed are ones involved in di€erent aspects of metabolic regulation. The major ones, which have been the main subjects of investigation in recent years are thyroid hormones and insulin.

9. Thyroid hormones L-Thyroxine (T4) and triiodothyronine (T3) are pivotal hormones which regulate a wide variety of cellular functions, including cellular metabolism, protein synthesis and transport

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

85

mechanisms. The heart has long been known to be a major target of these hormones (Morkin et al., 1983; Dillmann, 1990), and deviations from normal levels have profound e€ects on the cardiovascular system (Buccino et al., 1967; Klein, 1990; Franklyn and Gammage, 1996). In addition, excess thyroid hormone increases the propensity for several types of (mainly supraventricular) cardiac arrhythmias (Miyazawa et al., 1989; Olshausen et al., 1989). Conversely, hypothyroidism may protect against some types of arrhythmias (Sarma et al., 1990; Venkatesh et al., 1991), and may increase the threshold for induction of ventricular ®brillation (Liu et al., 1996). However, hypothyroidism may render the heart more sensitive to other types of arrhythmias, such as torsades de pointes (Fredlund and Olsson, 1983). Advanced congestive heart failure is often found to be associated with a reduction in T3 concentration (Opasich et al., 1996; Hamilton et al., 1998), which has led to an on-going investigation of the bene®cial therapeutic e€ects of acute thyroid hormone addition in patients with this condition (Gomberg-Maitland and Frishman, 1998; Hamilton et al., 1998). In addition to marked changes in contractility in response to altered thyroid hormone levels (Buccino et al., 1967; Morkin et al., 1983), there are profound changes in action potential con®guration. Action potential duration has been found to be shortened in guinea pig, rabbit and rat ventricular tissue or in single myocytes from hyperthyroid animals (Sharp et al., 1985; Binah et al., 1987; Meo et al., 1994). In ventricular tissue or myocytes from hypothyroid animals action potentials are prolonged (Binah et al., 1987). The same results were obtained in atrial tissue as well (Freedberg et al., 1970). Johnson et al. (1973) found a steeper diastolic depolarization in pacemaker action potentials recorded in hyperthyroid rabbits. This could underlie the enhanced sinus node activity seen under hyperthyroid conditions in many mammals, including humans (Valcavi et al., 1992; Johansson and Thoren, 1997). The study of thyroid hormone e€ects on ion channels in the heart was initiated by Binah and co-workers. They showed (Binah et al., 1987; Rubinstein and Binah, 1989) that several currents are altered in ventricular myocytes from guinea pigs with altered thyroid status. 9.1. Calcium currents In ventricular myocytes from hyperthyroid guinea pigs (after 8±11 daily T3 injections), the L-type calcium currents were substantially enhanced (Rubinstein and Binah, 1989). This e€ect could be seen as early as 2 h after intraperitoneal injection of T3 to the animals, but was not observed when myocytes were superfused with the hormone for 30 min. In subsequent experiments, this group suggested that the e€ect of excess thyroid hormone is a result of adenylyl cyclase stimulation, based on the ®nding that in myocytes from hyperthyroid guinea pigs b-adrenergic stimulation or intracellular cAMP application no longer enhances the L-type calcium current (Mager et al., 1992). In contrast to these results, in ventricular myocytes from hyperthyroid rabbits, no changes were observed in the L-type calcium current, in comparison to control current amplitudes (Shimoni and Banno, 1993b). Ono et al. (1992), using single channel recordings from rabbit ventricular cells, found that acute T3 (10 nM) induces a transient enhancement of the L-type calcium current, attributed to extranuclear actions of the hormone on calcium mobilization. However, Han et al. (1994) found that in vitro exposure of normal rabbit ventricular myocytes to very high concentrations (1 mM) of T3 for 5±24 h leads to sustained enhanced L-type

86

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

currents. In addition, the sensitivity to b-adrenergic stimulation is enhanced (Han et al., 1994). This is consistent with the results of Kim et al. (1987), who found enhanced calcium channel numbers (based on a binding assay) in cultured chick ventricular cells grown in 10 nM T3, with an increased calcium uptake in response to b-adrenergic stimulation. Compatible with this result, Shannon et al. (1995) found a reduced sensitivity of L-type calcium currents to badrenergic stimulation in cultured neonatal ventricular myocytes under hypothyroid conditions. The results showing enhanced sensitivity to b-adrenergic stimulation (Kim et al., 1987; Han et al., 1994) are congruent with the overall enhanced responsiveness of the heart to badrenergic stimulation in the hyperthyroid state (Bilzekian and Loeb, 1983), as well as with the enhanced cAMP production measured by Hohl et al. (1989). However, alterations in badrenergic responsiveness under hyperthyroid conditions may be species dependent (Crozatier et al., 1991; Mager et al., 1992). An increased b-adrenergic responsiveness is consistent with changes found in GTP-binding proteins, measured in neonatal rat ventricular cells exposed to T3 (Bahouth, 1995). The increased levels of Gs in hyperthyroid conditions (measured in rat ventricle), along with the decreased levels of Gi (reported also by Michel-Reher et al., 1993) can account for the enhanced b-adrenergic responsiveness. However, Levine et al. (1990) found no decrease in Gi protein levels in hyperthyroid conditions (also in rat ventricle), although in hypothyroid conditions Gi levels were elevated. Levine et al. (1990) also found no changes in Gs protein levels following alteration of the thyroid status. It is thus dicult at present to reconcile these results with those of Mager et al. (1992) who found no b-adrenergic stimulation of the L-type calcium current in ventricular cells from hyperthyroid guinea pigs. Species di€erences may be important in this context as well. 9.2. Potassium currents Binah et al. (1987) and Rubinstein and Binah (1989) were the ®rst to describe an augmentation of a delayed recti®er K+ current in guinea pig ventricular myocytes, obtained from hyperthyroid animals. Interestingly, hypothyroid conditions did not seem to attenuate current magnitudes, compared to control values, despite the observed prolongation in action potentials. Furthermore, when animals were injected (intraperitoneally) with T3, only the calcium current, but not the delayed recti®er was enhanced after 2 h (Rubinstein and Binah, 1989), suggesting di€erent regulatory pathways (see below). In recent work, Bosch et al. (1997) found a transcriptional downregulation of the KvLQT1 subunit of IKs in ventricular cells from hypothyroid guinea pigs, which presumably underlies the prolongation of the action potential in these conditions. Shimoni et al. found that in ventricular myocytes from hyperthyroid rabbits there was a large augmentation of the transient outward current, It. The reactivation kinetics were signi®cantly faster as well. Other kinetic parameters (such as voltage-dependent inactivation) were unchanged. The temperature sensitivity of the current was also found to be reduced (Shimoni and Banno, 1993b). Single channel recordings showed that under hyperthyroid conditions there were no changes in unitary channel conductance or in open probability, suggesting that the changes in the macroscopic current were due to an increase in the number of functional channels. Interestingly, in atrial cells from the same animals, there were no changes in current magnitude, kinetics or temperature sensitivity. Under hypothyroid

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

87

conditions, no changes were seen in either ventricular or atrial cells. The attenuating e€ects of the a-adrenergic agonist methoxamine on It were smaller in hyperthyroid conditions (Shimoni and Banno, 1993a). In later work, Shimoni and Severson (1995) showed that in ventricular myocytes from hyperthyroid rats there were no changes in the transient outward current, It, but a signi®cant reduction was seen under hypothyroid conditions. A sustained delayed recti®er current in these cells, Iss, was enhanced in hyperthyroid, but unchanged in hypothyroid conditions. In a subsequent study Shimoni et al. (1995b) showed that the attenuation of It under hypothyroid conditions is region-speci®c, with a much larger e€ect in epicardial cells. This dissipates the normal transmural gradient in the density of this current and may, therefore, also dissipate the epicardial±endocardial di€erences in action potential duration. Since these di€erences underlie the upright (positive) T-wave of the ECG (Burgess, 1979), similar results in the human ventricle would help to explain the ¯attening or inversion of the T wave, which is commonly seen in hypothyroid patients (Fredlund and Olsson, 1983). This e€ect may contribute to spatial and temporal dispersion of repolarization, which predisposes the heart to potentially lethal arrhythmias (Surawicz, 1997; de Bruyne et al., 1998). In further experiments, Shimoni et al. (1997) demonstrated that T3 regulates the post-natal expression of the (calcium-independent) transient outward current. Ventricular myocytes obtained from hyperthyroid neonates had signi®cantly larger It magnitudes (compared to untreated pups). In parallel, mRNA levels of Kv4.2 and Kv4.3, the channel isoforms underlying It in rat ventricle (Fiset et al., 1997a) were also augmented. In cells from hypothyroid rat pups, It was greatly attenuated. The background inwardly rectifying IK1 current was not a€ected by thyroid status. When neonatal rat ventricular cells were cultured for 72 h with nM concentrations of T3, It and Iss densities were found to be enhanced (Guo et al., 1997). Wickenden et al. (1997) found similar e€ects on Iss in cultured neonatal rat ventricular cells. It magnitude was not signi®cantly enhanced after 72 h in 100 nM T3 in their study, although reactivation was enhanced. They also found enhanced mRNA and channel protein for Kv4.3, but not Kv4.2, following exposure to T3. Wickenden et al. (1997) also found that mRNA and protein levels of another potassium channel isoform, Kv1.4, were attenuated by T3. In addition to e€ects of chronic changes in T3, Sakaguchi et al. (1996) found that nM concentrations of T3 added acutely to guinea pig ventricular cells enhance the inward recti®er IK1. If this e€ect persists, it would partly explain the abbreviation of the action potential seen in chronic hyperthyroid conditions. These results, however, are inconsistent with results obtained by Craelius et al. (1990) who found a prolongation of the action potential following acute T3 addition. More recently, it was found that hypothyroid conditions also induce changes in the ATPdependent K+ channel in rat ventricle (Light et al., 1998). A decrease in the ATP sensitivity of the channel was demonstrated, making the channel more likely to open when ATP levels start to decrease. This may protect the heart under ischemic conditions. Consistent with these results was the ®nding that K(ATP) channel openers such as cromakalim are more e€ective in shortening the action potentials in ventricular cells from hypothyroid rats, as compared to controls (Light et al., 1998).

88

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

9.3. Sodium currents An important role for thyroid hormone may involve e€ects on sodium currents. Several groups have found acute e€ects (within minutes) of nM concentrations of T3. The major e€ect seems to be a slowing of current inactivation (Harris et al., 1991, in neonatal rat ventricular cells), in a process which probably depends on a PTX-sensitive G protein (Cui and Sen, 1992, in guinea pig ventricular cells). Dudley and Baumgarten (1993) found an increase in the bursting activity of single sodium channels (in rabbit ventricular cells), which underlies the slowing of inactivation. This slowing of inactivation may underlie the prolongation of the action potential, which is seen after acute addition of T3 (Craelius et al., 1990). A slowing of INa inactivation may lead to the development of early afterdepolarizations and arrhythmias (Boutjdir et al., 1994; Sicouri et al., 1997) and may, thus, underlie (at least partly) the propensity for arrhythmias in hyperthyroidism. 9.4. Na+/K+ pump It has long been known that thyroid hormones control the Na+/K+ ATPase activity in cardiac tissue (Philipson and Edelman, 1977), with upregulation of pump activity by excess hormone. More recently, more detailed studies, measuring changes in mRNA levels and protein expression (Orlowski and Lingrel, 1990; Kamitani et al., 1992) have revealed how T3 upregulates the di€erent isoforms of this enzyme. These studies concur in ®nding increases in the mRNA and protein levels of the a1 and a2, as well as the b isoforms of the enzyme. In neonatal rat ventricular cells cultured with thyroid hormone, Na+/K+ ATPase activity was also found to be augmented. More recently, Doohan et al. (1997) studied the electrophysiological consequences of this action, and found that there is an increase in the electrogenic pump current in rabbit ventricular myocytes under hyperthyroid conditions. Their work also indicated an enhancement of sodium in¯ux through the Na+/H+ exchanger. 9.5. Na+±Ca2+ exchanger Two studies addressing the e€ects of thyroid hormone on the sodium±calcium exchange ®nd con¯icting results. Hojo et al. (1997) found a T3-induced increase in mRNA and protein levels in neonatal rat ventricular cells, whereas Boerth and Artman (1996) found that hypothyroidism increased, and hyperthyroidism decreased mRNA and protein levels of the exchanger in immature and adult rabbit ventricular myocytes. These con¯icting results may re¯ect species and/or age related di€erences. Thyroid hormones exert most of their actions by binding to nuclear receptors, leading to alterations of gene expression (Brent et al., 1991). This underlies the length of time (hours to days) required to obtain e€ects. Thyroid hormone e€ects on some ion channels have been shown to be sensitive to cycloheximide (Felzen et al., 1989), implying synthesis of new channels following exposure to the hormone. However, extranuclear binding sites have long been recognized in many tissues, including the heart (Segal, 1989). Such receptors could mediate the acute e€ects observed on action potential duration and sodium channels. It should also be borne in mind that some of the e€ects of thyroid hormone may be indirect,

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

89

through activation of other systems. Thus, in addition to alterations in adrenergic responsiveness (Bilzekian and Loeb, 1983), elevated atrial natriuretic peptide activity is also one of the consequences of hyperthyroidism (Ladenson et al., 1988). It has also been shown recently that under hyperthyroid conditions there is an activation of the cardiac renin± angiotensin system (Kobori et al., 1997). Thus, the integrated actions of excess thyroid hormone in vivo may be more complex than previously appreciated.

10. Insulin The e€ects of insulin on the heart have been of major interest due to the high (and increasing) incidence of diabetes mellitus. Both insulin-dependent (type I) and non-insulindependent (type II) diabetes are known to lead to cardiac dysfunction (Rodrigues and McNeill, 1992; Pierce et al., 1997). Insulin itself has been shown to have direct e€ects on the heart, observed as increases in cardiac output following infusion of insulin for 2±4 h (Muscelli et al., 1998; Ter Maaten et al., 1998). Cardiac performance is enhanced by insulin treatment in diabetic rat models (Strodter et al., 1995) and resistance to insulin may contribute to cardiac deterioration in chronic heart failure (Swan et al., 1994). Interestingly, insulin has also been shown to produce vasodilation by an endothelium-dependent production of nitric oxide (Chen and Messina, 1996). Although this has not yet been shown to occur in cardiac tissue, there may be unrecognized e€ects of insulin, mediated by NO, on cardiac ion channels. Most of the research to date has focused on type I (insulin-de®cient) diabetes, due mainly to the existence of convenient animal models, either of spontaneously developing or induced diabetes (Cheta, 1998). In the latter, pancreatic b-cells are destroyed by toxins such as streptozotocin (STZ) or alloxan, leading to a reduction in circulating insulin levels (Dillmann, 1989). This leads to rapid contractile dysfunction, developing within days (Ren and Davido€, 1997) and sustained for many months (Fein et al., 1980; Ren and Davido€, 1997). It has been shown that although basal intracellular calcium levels are unchanged (Yu et al., 1997a,b), calcium handling mechanisms are altered (Lagadic-Gossmann et al., 1996; Yu et al., 1997a,b). It has also been shown that low insulin levels are responsible for many of the abnormalities (Davido€ and Ren, 1997) and that these can be reversed by insulin (Fein et al., 1986). Type II diabetes, in which circulating insulin levels are elevated, is also associated with contractile dysfunction (Ferraro et al., 1993; Pierce et al., 1997). The electric activity of the heart is also signi®cantly altered by insulin de®ciency. The spontaneous rates of isolated rat and rabbit atria are reduced (Foy and Lucas, 1978; Senges et al., 1980) and arrhythmias are more common, although other diabetes-related complications such as ischemic heart disease may contribute to the higher incidence of arrhythmias. Action potentials have been found to be prolonged in rat ventricle (Sauviat and Feuvray, 1986; Nobe et al., 1990; Magyar et al., 1992; Jourdon and Feuvray, 1993; Shimoni et al., 1994) and in rat atrial tissue (Legaye et al., 1988). This corresponds to the well-documented prolongation of the (rate-corrected) Q-T interval in ECG's of people with type I diabetes (Ewing et al., 1991; Lo et al., 1993), which is associated with a higher mortality (Ewing et al., 1991; Sawicki et al., 1996). The changes accompanying insulin-de®cient diabetic conditions are complex and varied, including changes in glucose, insulin and fatty acid levels, as well as changes in cellular

90

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

metabolism. Nevertheless, a key role for insulin de®ciency per se was identi®ed as a€ecting action potential con®guration, as ®rst described by Magyar et al. (1992). They found that insulin treatment could partially abbreviate the prolonged action potential duration which developed in diabetic rats. Direct measurements of the e€ects of changing insulin levels have been restricted mainly to L-type calcium and potassium channels. 10.1. Calcium currents In both an insulin-dependent rat model (3±4 weeks after STZ injection) and in a genetic, non-insulin-dependent rat model of diabetes (at 19 months of age), no changes were found in the density or kinetics of the L-type calcium currents (Jourdon and Feuvray, 1993; Tsuchida et al., 1994). In the genetically diabetic rats, however, there was a reduction in the response of the current to b-adrenergic stimulation (Tsuchida et al., 1994), although the enhancement of the current in response to forskolin or intracellular cAMP was similar to control. This suggests an impairment in the receptors or in the GTP-binding protein which couples the receptors to adenylyl cyclase. However, after longer durations of STZ-induced diabetes (24±30 weeks), Wang et al. (1995) found a decrease in the L-type calcium current. This corresponds to the decrease in the maximal number of nitrendipine binding sites, measured by Lee et al. (1992), after 3 and 8 weeks of STZ-induced diabetes. This decrease could be reversed by chronic (several weeks) insulin treatment. However, in contrast to these results, Gotzsche et al. (1996) and Nishio et al. (1990) found an increase in the number of binding sites, after 10 or 12 weeks of STZ treatment, which could also be reversed or prevented by chronic (several weeks) insulin treatment. 10.2. Potassium currents Magyar et al. (1992) were the ®rst to demonstrate a reduction in the magnitude of the transient outward current (with slightly accelerated inactivation) in ventricular cells from STZtreated rats. The steady state inactivation or recovery from inactivation were unaltered. They also found an attenuated delayed recti®er (sustained) current. There were no changes in the inward recti®er IK1. Jourdon and Feuvray (1993) and Shimoni et al. (1994) also found attenuated transient outward currents., with no changes in IK1. No changes in current kinetics were found, except that Shimoni et al. (1994) showed a slower recovery from inactivation. Shimoni et al. (1994), who also reported an attenuated sustained outward current, found that the attenuated currents could be measured as early as 4±5 days after STZ injection, in contrast to the other studies, in which a longer duration (several weeks) was required. This may be partly due to the higher concentration of STZ used by Shimoni et al. (1994). Wang et al. (1995) also found an attenuation in the transient and sustained K+ currents, with a slower recovery from inactivation of the transient current. Subsequently, Shimoni et al. (1995b) showed that insulin de®ciency preferentially attenuates the transient outward current in epicardial, as compared to endocardial cells. The attenuation of the sustained current appeared to be similar in both regions. This reduction in the transmural gradient of an outward current is expected to dissipate the epicardial±endocardial di€erences in action potential duration. This

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

91

may underlie the ¯attening of the T wave of the ECG, often seen in diabetic patients (Airaksinen, 1985). The role of insulin in modulating the transient outward and sustained K+ currents was elucidated by the demonstration that the addition of insulin in vitro to myocytes from diabetic rats could restore both of these currents (Magyar et al., 1995; Xu et al., 1996; Shimoni et al., 1998a). However, this e€ect was found to require several hours. This suggests that insulin, which has many actions which involve the regulation of gene expression (O'Brien and Granner, 1996; Saltiel, 1996), may also regulate the transcription and/or synthesis of these K+ channels. Consistent with this is the ®nding that inhibition of protein synthesis with cycloheximide prevents the augmentation of both K+ currents by insulin, in myocytes from diabetic rats (Shimoni et al., 1999). Also consistent with this proposed mechanism of insulin action are results showing that inhibiting the phosphorylation of MAP kinase, a key enzyme regulating transcription, can prevent the action of insulin on these currents (Shimoni et al., 1998a). Type I diabetes is characterized by a shift in the balance of substrates utilized for energy production, so that the heart uses less glucose and more free fatty acids (Rodrigues and McNeill, 1992). The compound dichloroacetate (DCA) reverses this (Nicholl et al., 1991). Xu et al. (1996) proposed that the action of insulin on K+ currents derives from its e€ects on cellular metabolism, based on their ®nding that DCA can also restore the transient K+ current in diabetic myocytes. However, this e€ect still took several hours to develop, not consistent with the rapid e€ects of DCA on cellular metabolism (Nicholl et al., 1991). Shimoni et al. (1998a) were unable to augment K+ currents in diabetic myocytes with DCA. Furthermore, they found that the inhibition of PI 3-kinase, a key enzyme which mediates the e€ects of insulin on cellular metabolism, did not prevent the e€ects of insulin on K+ currents. It would thus seem, at this point, that insulin a€ects K+ channels independently of its e€ects on metabolism, most likely by regulating channel synthesis. Both Xu et al. (1996) and Shimoni et al. (1998a) found that incubating cells from control animals with insulin did not a€ect the transient outward current. However, in control myocytes, incubation with insulin (5±10 h) enhanced the sustained, steady state delayed recti®er current, Iss (Shimoni et al., 1998a). This is of relevance to insulin-resistant type II diabetes, in which circulating insulin levels are higher than normal. A fructose-enriched diet given to rats leads to elevated glucose and (roughly 2-fold) elevated insulin levels, which by de®nition is an insulin-resistant state, similar to that in type II diabetes (Hwang et al., 1987). In this model Iss was found to be elevated, in comparison to normal current densities (Shimoni et al., 1998a). The transient outward current was unchanged. Furthermore, adding insulin in vitro to cells from these rats had a smaller (although signi®cant) augmenting e€ect on Iss, as compared to the augmentation in control cells (Ewart et al., 1998). This indicates that insulin resistance is evident in terms of insulin e€ects on ion channels, in addition to the more usual de®nition of resistance, de®ned as a reduced insulin-stimulated glucose uptake. K+ currents have also been measured in a genetic model of type II diabetes, the JCR corpulent insulin-resistant rat, in which insulin levels are much (5±10-fold) higher than normal (Pierce et al., 1997). In ventricular cells from these rats, the sustained K+ current density is not di€erent from that in lean rats from the same strain, nor is this current sensitive to insulin (Ewart et al., 1998). Thus, in type II diabetes, the

92

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

sensitivity of a delayed recti®er current to insulin is lost. The mechanism for this is unknown at present. In all the type II (hyperinsulinemic) rat models tested, the transient outward current was not signi®cantly di€erent than in normal rats (Rusznak et al., 1996; Ewart et al., 1998; Shimoni et al., 1998a). The ATP-dependent K+ current has also been found to be altered under conditions of insulin de®ciency, either as a result of changes in the outward recti®cation properties (Smith and Wahler, 1996) or as a result of an augmented sensitivity to inhibition by ATP (Shimoni et al., 1998b). However, these e€ects, which may alter the response of the diabetic heart to ischemic episodes, have not yet been demonstrated to be a direct result of insulin de®ciency. 10.3. Na+/K+ pump Several studies have shown that STZ-induced diabetes is associated with a reduction in Na+±K+ ATPase activity, associated with a reduction in ouabain binding sites and in the mRNA levels of both a and b subunits (Kjeldsen et al., 1982; Ng et al., 1993; Ver et al., 1997; Banyasz and Kovacs, 1998). This is considered to be due to the de®ciency in insulin, since insulin is known to regulate Na+±K+ ATPase, both acutely and chronically (Ewart and Klip, 1995). Limited studies have addressed the consequences for the electric activity of the heart. Thus, LaManna and Ferrier (1981) showed that acute addition of insulin in canine, feline and rat ventricular tissue resulted in a hyperpolarization of the membrane potential, which was abolished by cardiotonic steroids. The directly measured Na+/K+ pump current was also a€ected by acute addition of insulin, with changes in its voltage dependence (Hansen et al., 1995). Other e€ects of acutely added insulin may also be present. For example, Lantz et al. (1980) found a ouabain-resistant, insulin-induced hyperpolarization in embryonic chick cells. Eckel and Reinauer (1990), using a voltage-sensitive dye, also measured a hyperpolarizing e€ect of insulin in rat ventricular cells. The mechanism for this action is unknown. 10.4. Na+/H+ exchange Insulin-dependent diabetes is also associated with a reduction in the activity of the Na+/H+ exchanger (Lagadic-Gossmann et al., 1988; Pierce et al., 1990). The electric consequences are unknown, although the reduced activity of the exchanger results in altered intracellular pH regulation during ischemia (Khandoudi et al., 1990), which could indirectly a€ect several ionic currents. An altered intracellular sodium or proton concentration under diabetic conditions could have consequences for the electric activity of cardiac cells under normoxic or ischemic conditions, although this has not been studied yet. Furthermore, it is not yet known if the change in Na+/H+ exchange is directly attributable to insulin de®ciency. 10.5. Na+/Ca2+ exchange Both type I and type II diabetes are associated with disruptions in many cellular calcium homeostatic mechanisms, including an attenuated sodium±calcium exchanger (Pierce and

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

93

Russell, 1997; Scha€er et al., 1997). The exchanger is stimulated by acute addition of insulin (Ballard et al., 1994), possibly through stimulation of protein kinase C (Scha€er et al., 1997). The sodium±calcium exchanger is electrogenic, and its activation by insulin should have small, but potentially important e€ects on the cardiac action potential (Noble, 1992). However, this has not yet been demonstrated. 10.6. Modi®cations Insulin-de®cient diabetes is associated with a reduced sensitivity to b-adrenergic (Yu et al., 1994) and an enhanced sensitivity to a-adrenergic stimulation (Canga and Sterin-Borda, 1986). This is accompanied by changes in signal transduction mechanisms, with altered cAMP accumulation and G protein expression (Wichelhaus et al., 1994). Protein kinase C levels and activity are also altered (Inoguchi et al., 1992; Tanaka et al., 1992; Malhotra et al., 1997). However, the consequences of these changes for the activation of ion channels in the heart has not been studied extensively. Shimoni et al. (1995a) found a larger attenuating e€ect of aadrenergic agonists on the transient outward and sustained K+ currents in a type I diabetic rat model. Tsuchida et al. (1994) found a smaller augmentation of the L-type calcium current by isoprenaline in a type II diabetic model, consistent with the ®ndings of Scha€er et al. (1991), who described a defective response to cAMP-dependent protein kinase in a model of noninsulin dependent diabetes, in which insulin levels are high. However, none of these changes have been directly attributed to changes in insulin levels. Future studies will have to determine the role of insulin in the changes which occur in the adrenergic modulation of cardiac ion currents, as well as whether diabetes-related changes in the cardiac renin±angiotensin system (Sechi et al., 1994) a€ect the electric activity of the heart. An interesting new perspective on the modulation of ion channels by hormones has emerged from recent work done by this author (Shimoni et al., 1999). In myocytes from STZ-diabetic rats, insulin was found to restore the density of attenuated K+ currents by a mechanism dependent on MAP kinase and on protein synthesis (Shimoni et al., 1998a, 1999). Furthermore, the augmentation of both the transient and the sustained outward currents was blocked when the cytoskeleton was disrupted. Adding cytochalasin D (CD), a disrupter of the actin micro®lament system, prevented the augmenting action of insulin on these currents. This e€ect of CD was prevented by stabilizing the micro®laments with phalloidin, so that with both of these drugs present insulin could still enhance the K+ currents. Colchicine, an agent that disrupts the microtubular system, also prevented the action of insulin. In combination, these results suggest (although no direct proof is available yet) that insulin controls the synthesis of these channels, and that subsequent to their synthesis and processing, the channels translocate to the cell membrane with the aid of these elements of the cytoskeleton. The e€ects of cytoskeletal disruption on the on-going activity of ion channels has been described for several currents (Galli and DeFelice, 1994; Mazzanti et al., 1996; Maltsev and Undrovinas, 1997). However, our results with insulin suggest that the hormone controls the longer-term activity of ion channels, by controlling the synthesis of the channels. The functional expression of these channels in the membrane in turn depends on the integrity of the cytoskeleton, presumably due to a translocation of newly-formed channels to the cell membrane. This may suggest a chronic role for the cytoskeleton in hormonal action, which has

94

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

indeed been suggested (Hall, 1984). Several hormones such as angiotensin and dexamethasone have been found to alter actin micro®lament assembly (Koukouritaki et al., 1997; Aoki et al., 1998). The actions of vasopressin and aldosterone on epithelial Na channels (Smith et al., 1995) and of ACTH on cAMP production in cultured glomerulosa cells (Cote et al., 1997a) have been found to depend on interactions with the cytoskeleton. Many responses are associated with the integrity of the cytoskeleton. a1-adrenergic responsiveness (in hepatic cells) is disrupted by colchicine (Butta et al., 1996) and excess b-adrenergic stimulation can disassemble microtubules in cardiomyocytes (Hori et al., 1994). Many signal transduction elements such as tyrosine phosphorylation (Garcia et al., 1997), GTP-binding proteins (Cote et al., 1997b) or their coupling to phospholipase C (Macias-Silva and Garcia-Sainz, 1994), as well as NO action (Burgstahler and Nathanson, 1995) are associated with the cytoskeleton. Thus, it is very likely that many chronic actions of hormones on cardiac ion channels will be a€ected by such cytoskeleton-dependent interactions. Impairment of cytoskeleton integrity, such as occurs in ischemic conditions (Ganote and Armstrong, 1993) may in turn a€ect the actions of hormones on these channels. These aspects of hormonal regulation await future research.

11. Glucocorticoids These hormones have a variety of functions, some of which have long been known to involve regulation of the cardiovascular system. For example, 3 days treatment with dexamethasone was found to have a positive inotropic e€ect (Penefsky and Kahn, 1971). Action potential changes have also been documented. Thus, the perinatal shortening of the cardiac action potential in rats was prevented by glucocorticoid treatment (Legrand et al., 1981). However, only a small number of studies address the direct e€ects of these hormones on cardiac ion currents. Only one study investigated the e€ects of acute administration: cortisone was found to enhance the action potential plateau and the associated calcium current in frog atrial ®bres (Soustre, 1979). The remaining studies involved long-term administration of dexamethasone, with or without adrenalectomy. Takimoto and Leviran (1994) found that adrenalectomy leads to a decrease in message levels and protein expression of the Kv1.5 potassium channel isoform in rat ventricles. Injection of dexamethasone increased Kv1.5 mRNA levels and protein expression. Message levels of other Kv isoforms (Kv1.4 and Kv2.1) and Kv2,1 expression were una€ected by dexamethasone (Takimoto and Leviran, 1994). Interestingly, atrial Kv1.5 was una€ected by either the de®ciency or the excess of hormone. The consequences of these results remain unclear, since Kv1.5 has been implicated in repolarization in both atrial (Wang et al., 1993a,b) and ventricular cells (Fiset et al., 1997b). Du€ et al. (1997) found an increase in action potential duration in neonatal mouse ventricle, following dexamethasone treatment. This is associated with a retaining of dofetilide binding sites, which normally decrease. They suggest that the normal post-natal decrease in IKr is blunted by this treatment (although, paradoxically, action potentials are concomitantly prolonged, rather than abbreviated, as would be expected with more IKs available). Furthermore, the same group found that the post-natal development of the transient outward current It in mouse ventricle is also blunted by dexamethasone (Wang et al., 1997a,b). Current density was found to be attenuated, with no change in current kinetics, following 5 days of

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

95

treatment. These results suggest a regulatory role for glucocorticoids in the post-natal development of di€erent potassium channels. In adult rat hearts, adrenalectomy was found to decrease, and dexamethasone to increase the message levels for the a1C subunit of of the L-type calcium channel (Takimoto et al., 1997), in both atria and ventricles. The number of dihydropyridine binding sites, a rough estimate of the number of total (possibly including non-functional) calcium channels, was also augmented, as has also been found in skeletal muscle (Braun et al., 1995). Thus, these hormones may have a wider role in regulating the expression of di€erent cardiac ion channels. This may be of importance in heart failure, where corticosteroids have been found to be bene®cial, partly by restoring responsiveness to catecholamines (Nishimura et al., 1997).

12. Glucagon This hormone is mainly involved in elevating blood glucose levels, by regulating glycogenolysis. However, it is also known to have inotropic and chronotropic e€ects on cardiac muscle, which, like its e€ects in the liver, are mediated by elevation of cAMP levels (Farah, 1983; Chernow et al., 1987). Its bene®cial e€ects are often utilized in emergency situations in which adrenergic mechanisms are compromised (Sauvadet et al., 1996). However, surprisingly few studies have been devoted to addressing the direct actions of glucagon on cardiac ion currents. These studies report a cAMP-dependent enhancement of the L-type calcium current, in frog and rat ventricular myocytes (Mery et al., 1990). However, the mechanisms appear to be di€erent: in rat myocytes augmented cAMP levels (and hence channel phosphorylation) are achieved by activation of adenylyl cyclase, whereas in frog myocytes glucagon is suggested to act by inhibition of cAMP phosphodiesterase activity (Mery et al., 1990), with no e€ect on adenylyl cyclase. However, an additional study has shown a PTX-sensitive, G-proteindependent inhibition of phosphodiesterase by glucagon in mouse and guinea pig ventricle as well (Brechler et al., 1992). Interestingly, the cholinergic modulation of the L-type calcium current in primary pacemaker cells is also mediated by modulating a phosphodiesterase (Han et al., 1995, 1998), similarly to the mechanism in frog myocytes (Mery et al., 1993) but di€erent from the mechanism in mammalian ventricular cells (Mery et al., 1991), indicating that pacemaker cells may be more similar to amphibian cells than to ventricular cells. Thus, it is tempting to speculate that the positive chronotropic e€ect of glucagon may be mediated by an e€ect on L-type calcium currents, mediated by the inhibition of a cAMP-dependent phosphodiesterase, although this has not been studied. More recently, supporting evidence for an enhancement of the calcium current and of sarcoplasmic reticulum calcium content by glucagon has been obtained (Sauvadet et al., 1996), with the additional information that glucagon may be processed and converted to miniglucagon prior to exerting its e€ects. As with other hormones, the e€ects of glucagon are diminished in severe heart failure (Farah, 1983).

96

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

13. Ovarian hormones It has long been known that the heart has a variety of steroid receptors, unevenly distributed (Stumpf, 1990). For example, most of the receptors for estradiol are located in the atria (Stumpf, 1990). It is also recognized that both acute and chronic administration of estrogen can a€ect cardiac function (Collins et al., 1993). Gender di€erences in the electrophysiological properties of the heart have long been recognized, with a longer Q-T interval (re¯ecting longer ventricular action potentials) found in females (Rautaharju et al., 1992). Ovariectomy leads to a shorter Q-T interval in isolated rabbit hearts (Drici et al., 1996a). Treating ovariectomized rabbits with estradiol or dihydroxytestostreone (DHT) was found to prolong the Q-T interval (Drici et al., 1996a), suggesting that these hormones play a major role in determining action potential duration. Although a prolonged Q-T (and action potential) in females may become a risk factor for some types of arrhythmias such as torsades de pointes (Makkar et al., 1993), it is generally accepted that estrogen has an important cardioprotective e€ect (Collins et al., 1993). Thus, the investigation of the cardiovascular e€ects of estrogen is of great clinical relevance. While the increase in risk of cardiovascular disease in postmenopausal women is largely attributed to coronary artery disease (O'Keefe et al., 1997), the widespread use of estrogen replacement therapy requires a more complete understanding of the mechanisms of the acute and chronic direct actions of gonadal steroids on cardiac muscle.

13.1. Calcium currents Earlier work showed that an acutely-added estradiol analogue, DES, reduced contractile force with no change in rabbit papillary muscle action potentials (Khan and Wohlfart, 1981). Later work in guinea pig ventricular cells con®rmed the acute reduction of contraction by 17bestradiol and also indicated a reduction in the L-type calcium current, as well as in systolic calcium levels (Jiang et al., 1992). More recently, acutely-added non-physiological concentrations of 17b-estradiol were found to decrease the L-type calcium current in rat and rabbit ventricular myocytes (Berger et al., 1997; Patterson et al., 1998). This compound also decreased L-type calcium currents which had been augmented by endothelin-1, in guinea pig ventricular cells (Liu et al., 1997). Congruently, in estrogen receptor-de®cient mice, the L-type calcium channel expression and action potential duration are signi®cantly enhanced (Johnson et al., 1997), although Patterson et al. (1998) found no changes in current density in ovariectomized rabbits. Furthermore, they showed that estrogen replacement (7 days) does not a€ect the calcium current, although the number of nitrendipine binding sites are reduced (Patterson et al., 1998). A longer treatment (35 days) in ovariectomized rats increased the density of dihydropyridine binding sites (Bowling et al., 1997). The reasons for these discrepancies are unclear, but species di€erences and/or length of treatment may be responsible. In human atrial and ventricular muscle, acutely-added 17b-estradiol was also found to reduce contractile force, although it was suggested that this may not involve interaction with calcium channels (Sitzler et al., 1996). The attenuation of the L-type calcium current by acute addition of supraphysiologic concentrations of estradiol suggests that non-speci®c receptors

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

97

(possibly the channels themselves) are present, since the e€ects are rapid and not mediated by nuclear responses and transcriptional changes (Patterson et al., 1998). 13.2. Potassium currents Investigation of the e€ects of gonadal steroids on potassium currents has mainly been indirect. Thus, Hara et al. (1998) found that ECG's from ovariectomized rabbits were similar in untreated and in estradiol-treated animals. The rate-dependent ventricular repolarization was sensitive to estradiol and dihydrotestosterone (DHT) in papillary muscles of these ovariectomized rabbits. Action potentials in papillary muscles from estradiol-treated rabbits were also more sensitive to E-4031, a speci®c blocker of IKr, with a larger prolongation of the action potential than in papillary muscles from ovariectomized rabbits not receiving estradiol. This suggests that IKr is altered by estradiol and that these steroids participate in determining ventricular repolarization. Additional results showing that the message levels of two delayed recti®er potassium currents, HK2 and IsK, are reduced in hearts from ovariectomized rabbits, chronically treated with either estradiol or DHT (Drici et al., 1996a) also suggest a role for ovarian steroids in controlling repolarization. Concordantly, the Q-T interval in these animals was prolonged, due to the attenuation in K+ currents. Berger et al. (1997) also found an attenuation in the transient outward current and a partial reduction in IK1, in rat ventricular myocytes exposed acutely to very high concentrations of 17b-estradiol. Expressed minK currents in Xenopus oocytes are also attenuated by estrogens (Waldegger et al., 1996). An attenuation of potassium currents by estrogen and its analogues may underlie the smaller densities of IK1 and Ito (It) in ventricular cells from female rabbits, in comparison to males (Drici et al., 1996b). In combination, the attenuation of di€erent K+ currents by ovarian steroids may underlie the prolongation of the ventricular action potential and the associated Q-T interval in the female ECG. This will have mixed e€ects in the context of arrhythmogenesis, since prolonged action potentials can be either arrhythmogenic (Makkar et al., 1993), or protective, depending on speci®c conditions and the type of arrhythmia. In some cases, acute administration of 17bestradiol was found to improve a supraventricular arrhythmia which was resistant to standard antiarrhythmic agents (Cagnacci et al., 1992). Acutely-added estradiol was also found to ameliorate ischemia and reperfusion-induced arrhythmias (Node et al., 1997). Although most actions of steroid hormones are presumed to be mediated by nuclear receptors, acting by mediation of transcription (Pelzer et al., 1997b), there are also indications that nitric oxide may be involved in some actions of estrogens (Ma et al., 1997; Node et al., 1997). Since estrogens attenuate L-type calcium currents, an NO-dependent mechanism would be congruent with the attenuating actions of NO on L-type calcium currents found in SA node cells (Han et al., 1998).

14. Growth hormone An excess of growth hormone leads to cardiac hypertrophy, congestive heart failure and volume overload, conditions which have been found to be associated with various

98

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

electrophysiological changes. In a small number of studies on rats with growth hormone secreting tumors, a pronounced prolongation of the ventricular action potential has been documented, associated with a reduction in the transient outward current (Xu and Best, 1991). The L-type calcium currents in atrial and ventricular cells were unchanged, although the T-type calcium current was signi®cantly enhanced in atrial cells (Xu and Best, 1990). 15. Parathyroid hormone Parathyroid hormone has long been known to produce positive inotropic and chronotropic e€ects on the heart (Bogin et al., 1981; Katoh et al., 1981; Kondo et al., 1988). Although initial work suggested an indirect e€ect mediated partly by release of catecholamines, it is now wellestablished that the e€ects are direct (Wa ng et al., 1993), and are mediated by adenylyl cyclase activation (Wang et al., 1991a,b). E€ects on current kinetics were also shown, as well as a shift in the voltage-dependence of activation (Wang et al., 1994). It was shown that the active fragment of parathyroid hormone selectively augments the L-type calcium current, but not the T-type current, in neonatal rat ventricular cells (Wang et al., 1991a,b). A recent study has shown that parathyroid hormone accelerates the heart, in a mechanism attributed to an increase in the pacemaker current If (Hara et al., 1997). The e€ect was due to a change in maximal conductance, and not to a shift in the voltage dependence of activation, as occurs with b-adrenergic stimulation of this current. Outward currents seem to be una€ected (Kondo et al., 1988). Table 1 A summary of published results on the e€ects of various hormones on cardiac ion channels. Where di€erent or contrasting e€ects have been reported, all of these are indicated. An increase, decrease or no e€ect are marked as +, ÿ, and =, respectively. Symbols in parenthesis indicate inferred e€ects, not directly measured. Key: ICa-L: L-type calcium current; ICa-T: T-type calcium current; INa: fast sodium current; IK1: background inwardly rectifying potassium current; Ito: calcium-independent transient outward current; IDR: delayed recti®er potassium current(s); IKr: rapidly activating potassium current; IKs: slowly activating potassium current; If : hyperpolarization-activated pacemaker current; ICl: cAMP-dependent chloride current; Ip: sodium±potassium pump current; Na/Ca: sodium±calcium exchanger current and Na/H: sodium±hydrogen exchanger current

Adrenaline a Adrenaline b Angiotensin ADH ANP Aldosterone T3 Insulin Growth hormone Estrogen Glucocorticoids Glucagon

ICa-L

ICa-T

INa

IKl

Ito

IDR

=, + + =, +, ÿ + ÿ

+ =, + +

ÿ +, ÿ +

ÿ ÿ +

ÿ

ÿ +

=, ÿ

=, ÿ

=, + = = ÿ + +

+ +

+ = ÿ

ÿ ÿ

+

+ + ÿ ÿ ÿ

+ + (+)

IKr

IKs

If

ICl

Ip

= +

+ ÿ

+

ÿ, +, = + ÿ, +

+ +

+ + + (+)

Na/Ca

Na/H +

+, = ÿ

+

ÿ ÿ, + +

+ (+)

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

99

In summary, Table 1 shows the e€ects of the hormones discussed above on the di€erent ionic currents and pumps/exchangers. Increases, decreases and no e€ect are denoted as +, ÿ or =. Wherever con¯icting results have been documented, more than one symbol is given. 16. Conclusion It is obviously impossible to draw a common thread through the multitude of disparate e€ects of the di€erent hormones on cardiac ion channels. Many of the con¯icting results are either known or suspected to be due to binding to di€erent receptor subtypes, and/or activation of di€erent signal transduction cascades. This will at least partly explain the multiple examples, given above, which show a given e€ect to be species-, age- or tissue-dependent. In addition, a striking feature is obvious when surveying the regulation of the various channels by di€erent hormones; this regulation is not a constant, ®xed aspect of ion channel activity. The regulatory processes can vary and can themselves be modulated by changes occurring in the target tissue or in other stages of the modulatory mechanism. In addition, an emerging aspect of the hormonal regulation of channels is the interaction between di€erent systems, such as the stimulation of ANP release by a-adrenergic activation (e.g. Schiebinger et al., 1992) or the activation of the cardiac renin±angiotensin system by thyroid hormones (Kobori et al., 1997). Heart disease changes the levels and actions of many of the hormones surveyed here, which emphasizes the need to more fully understand the way in which ionic channels are regulated. The study of ion channel function is greatly aided by new developments, allowing expression of cloned channels and receptors in a variety of systems, which in turn allows a more detailed study of the di€erent components of channel activity and its modulation (as in Tseng et al., 1997). The emerging use of transgenic animals allows the study of overexpressed or missing elements of regulatory signaling systems (e.g. Akhter et al., 1997; Withers et al., 1998). This will greatly facilitate and enhance the acquiring of a more detailed understanding of the mode of action of di€erent hormones and will enable a more de®nitive review to be written in the coming years. References Abdellatif, M.M., Neubauer, C.F., Lederer, W.J., Rogers, T.B., 1991. Circ. Res. 69, 800±809. Accili, E.A., Redaelli, G., DiFrancesco, D., 1997a. J. Physiol. 500, 643±651. Accili, E.A., Robinson, R.B., DiFrancesco, D., 1997b. Am. J. Physiol. 272, H1549±H1552. Aggarwal, R., Boyden, P.A., 1996. J. Cardiovasc. Electrophysiol. 7, 20±35. Ai, T., Horie, M., Obayashi, K., Sasayama, S., 1998. P¯uegers Arch. 436, 168±174. Airaksinen, K.E.J., 1985. Ann. Clin. Res. 17, 135±138. Akhter, S.A., Milano, C.A., Shotwell, K.F., Cho, M.C., Rockman, H.A., Lefkowitz, R.J., Koch, W.J., 1997. J. Biol. Chem. 272, 21253±21259. Allen, I.S., Cohen, N.M., Dhallan, R.S., Gaa, S.T., Lederer, W.J., Rogers, T.B., 1988. Circ. Res. 62, 524±534. An, R., Heath, B.M., Higgins, J.P., Koch, W.J., Lefkowitz, R.J., Kass, R.S., 1999. J. Physiol. 516, 19±30. Andersen, G.O., Enger, M., Thoresen, G.H., Skomedal, T., Osnes, J.B., 1998. Am. J. Physiol. 275, H641±H652. Anyukhovsky, E.P., Steinberg, S.F., Cohen, I.S., Rosen, M.R., 1994. Circ. Res. 74, 937±944.

100

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

Aoki, H., Izumo, S., Sadoshima, J., 1998. Circ. Res. 82, 666±676. Apkon, M., Nerbonne, J.M., 1988. Proc. Natl. Acad. Sci. USA 85, 8756±8760. Bahouth, S.W., 1995. Biochem. J. 307, 831±841. Baker, K.M., Booz, G.W., Dostal, D.E., 1992. Ann. Rev. Physiol. 54, 227±241. Ballard, C., Moza€ari, M., Scha€er, S., 1994. Mol. Cell. Biochem. 135, 113±119. Banyasz, T., Kovacs, T., 1998. Exp. Physiol. 83, 65±76. Beaulieu, P., Cardinal, R., Page, P., Francoeur, F., Tremblay, J., Lambert, C., 1997. Am. J. Physiol. 273, H1933± H1940. Bean, B.P., 1985. J. Gen. Physiol. 86, 1±30. Beavo, J., 1995. Physiol. Rev. 75, 725±748. Benz, I., Herzig, J.W., Kohlhardt, M., 1992. J. Mem. Biol. 130, 183±190. Berger, F., Borchard, U., Hafner, D., Putz, I., Weis, T.M., 1997. Naunyn Schmiedebergs Arch. Pharmacol. 356, 788±796. Bescond, J., Bois, P., Petit-Jacques, J., Lenfant, J., 1994. Mem. Biol. 140, 153±161. Bilzekian, J.P., Loeb, J.N., 1983. Endocr. Rev. 4, 378±388. Binah, O., Rubinstein, I., Gilat, E., 1987. P¯uegers Arch. 409, 214±216. Bkaily, G., Perron, N., Wang, S., Sculptoreanu, A., Jacques, D., Menard, D., 1993. J. Mol. Cell. Cardiol. 25, 1305± 1316. Boerth, S.R., Artman, M., 1996. Cardiovasc. Res. 31, E145±E152. Bogin, E., Massry, S.G., Harary, I., 1981. J. Clin. Invest. 67, 1215±1227. Borghi, C., Ambrosioni, E., 1998. J. Cardiovasc. Pharmacol. 32, S24±S35. Bosch, R.F., Wible, B.A., Wang, Z., Li, G.R., Nattel, S., 1997. Circulation 96, I499. Boutjdir, M., Restivo, M., Wei, Y., Stergiopoulos, K., El-Sherif, N., 1994. J. Cardiovasc. Electrophysiol. 5, 609±620. Bowling, N., Bloomquist, W.E., Cohen, M.L., Bryant, H.U., Cole, H.W., Magee, D.E., Rowley, E.R., Vlahos, C.J., 1997. J. Pharmacol. Exp. Ther. 281, 218±225. Braun, A.P., Fedida, D., Clark, R.B., Giles, W.R., 1990. J. Physiol. 431, 689±712. Braun, A.P., Fedida, D., Giles, W.R., 1992. P¯uegers Arch. 421, 431±439. Braun, S., Sarkozi, E., McFerrin, J., Askanas, V., 1995. J. Neurosci. Res. 41, 727±733. Brechler, V., Pavoine, C., Hanf, R., Garbarz, E., Fischmeister, R., Pecker, F., 1992. J. Biol. Chem. 267, 15496± 15501. Brent, G.A., Moore, D.D., Larsen, P.R., 1991. Ann. Rev. Physiol. 53, 17±35. Bristow, M.R., Hershberger, R.E., Port, J.D., Gilbert, E.M., Sandoval, A., Rasmussen, R., Cates, A.E., Feldman, A.M., 1990. Circulation 82 (2 suppl.), 112±125. Brodde, O.E., 1993. Pharmacol. Ther. 60, 404±430. Brodde, O.E., Vogelslang, M., Broede, A., Michel-Reher, M.J., et al., 1998. Cardiovasc. Pharmacol. 31, 585±594. Brown, A.M., Birnbaumer, L., 1988. Am. J. Physiol. 254, H401±H410. Brown, H.F., DiFrancesco, D., Noble, D., 1979. Nature 280, 235±236. Buccino, R.A., Spann, J.F., Pool, P.E., Sonnenblick, E.H., Braunwald, E., 1967. J. Clin. Invest. 46, 1669±1682. Burgess, M., 1979. Am. J. Physiol. 236, H391±H402. Burgstahler, A.D., Nathanson, M.H., 1995. Am. J. Physiol. 269, G789±G799. Butta, N., Martin-Requero, A., Urcelay, E., Parrilla, R., Ayuso, M.S., 1996. Br. J. Pharmacol. 118, 1797±1805. Cagnacci, M.D., Soldani, R., Puccini, E., Fioretti, P., Melis, G.B., 1992. Acta Obstr. Gynecol. Scand. 71, 639±641. Camilion de Hurtado, M.C., Alvarez, B.V., Perez, N.G., Ennis, I.L., Cingolani, H.E., 1998. Circ. Res. 82, 473±481. Canga, D., Sterin-Borda, L., 1986. Br. J. Pharmacol. 87, 157±165. Cerbai, E., Barbieri, M., Mugelli, A., 1996. Circulation 94, 1674±1681. Charnet, P., Lory, P., Bourinet, E., Collin, T., Nargeot, J., 1995. Biochimie 77, 957±962. Chen, Y.L., Messina, E.J., 1996. Am. J. Physiol. 270, H2120±H2124. Chen, S.A., Chang, M.S., Chiang, B.N., Lin, C.I., 1991. J. Mol. Cell. Cardiol. 23, 483±493. Chen, L., El-Sherif, N., Boutjdir, M., 1996. Circ. Res. 79, 184±193. Chernow, S., Zaloga, G.P., Malcolm, D., Willey, S.C., Clipper, M., Holaday, J.W., 1987. J. Pharmacol. Exp. Ther. 241, 833±837. Cheta, D., 1998. J. Pediatr. Endocrinol. Metab. 11, 11±19.

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

101

Cody, R.J., 1997. Am. J. Cardiol. 79, 9±11. Collins, P., Rosano, G.M., Jiang, C., Lindsay, D., Sarrel, P.M., Poole-Wilson, P.A., 1993. Lancet 341, 1264±1265. Corr, P.B., Cra€ord, W., 1981. Am. Heart J. 102, 605±612. Cote, M., Payet, M.D., Gallo-Payet, N., 1997a. Endocrinology 138, 69±78. Cote, M., Payet, M.D., Dufour, M.N., Guillon, G., Gallo-Payet, N., 1997b. Endocrinology 138, 3299±3307. Coulombe, A., Momtaz, A., Richer, P., Swynghedauw, B., Coraboeuf, E., 1994. P¯uegers Arch. 427, 47±55. Craelius, W., Green, W.L., Harris, D.R., 1990. Biosci. Rep. 10, 309±315. Crozatier, B., Su, J.B., Corsin, A., Bouanani, N.H., 1991. Circ. Res. 69, 1234±1243. Cua, M., Shvilkin, A., Danilo, P., Rosen, M.R., 1997. J. Cardiovasc. Electrophysiol. 8, 865±871. Cui, G., Sen, L., 1992. Circulation 86, I564. Daleau, P., Turgeon, J., 1994. P¯uegers Arch. 427, 553±555. Davido€, A.J., Ren, J., 1997. Am. J. Physiol. 272, H159±H167. De Bruyne, M.C., Hoes, A.W., Kors, J.A., Hofman, A., van Bemmel, J.H., Grobbee, D.E., 1998. Circulation 97, 467±472. De Mello, W.C., 1997. J. Cardiovasc. Pharmacol. 29, 273±277. De Mello, W.C., Crespo, M.J., 1995. J. Cardiovasc. Pharmacol. 25, 51±56. De Mello, W.C., Crespo, M.J., Altieri, P., 1993. J. Cardiovasc. Pharmacol. 22, 259±263. De Mello, W.C., Cherry, R.C., Manivannan, S., 1997. J. Card. Fail. 3, 53±61. Deng, X.F., Mulay, S., Varma, D.R., 1997. Am. J. Physiol. 273, H1113±H1118. DiFrancesco, D., Tortora, P., 1991. Nature 351, 145±147. Dillmann, W.H., 1989. Ann. Rev. Med. 40, 373±394. Dillmann, W.H., 1990. Am. J. Med. 88, 626±630. Dodge, S.M., Beardslee, M.A., Darrow, B.J., Green, K.G., Beyer, E.C., Satz, J.E., 1998. J. Am. Coll. Cardiol. 32, 800±807. Doohan, M.M., Gray, D.F., Hool, L.C., Robinson, B., Rasmussen, H.H., 1997. Am. J. Physiol. 272, H1589±H1597. Dosemeci, A., Dhallan, R.S., Cohen, N.M., Lederer, W.J., Rogers, T.B., 1988. Circ. Res. 62, 347±357. Dostal, D.E., Baker, K.M., 1998. Circ. Res. 83, 870±873. Dostal, D.E., Hunt, R.A., Kule, C.E., Bhat, G.J., Karoor, V., McWhinney, C.D., Baker, K.M., 1997. J. Mol. Cell. Cardiol. 29, 2893±2902. Drici, M.D., Burklow, T.R., Haridasse, V., Glazer, R.I., Woosley, R.L., 1996a. Circulation 94, 1471±1474. Drici, M.D., Ducic, I., Morad, M., Woosley, R.L., 1996b. Circulation 94, I473. Duan, D., Fermini, B., Nattel, S., 1995. Circ. Res. 77, 379±393. Dudley, S.C., Baumgarten, C.M., 1993. Circ. Res. 73, 301±313. Du€, H.J., Feng, Z.P., Wang, L., Sheldon, R.S., 1997. J. Mol. Cell. Cardiol. 29, 1959±1965. Earm, Y., Shimoni, Y., Spindler, A.J., 1983. J. Physiol. 342, 569±590. Eckel, J., Reinauer, H., 1990. Am. J. Physiol. 259, H554±H559. Egan, T.M., Noble, D., Noble, S.J., Powell, T., Twist, V.W., 1987. Nature 328, 634±637. Egan, T.M., Noble, D., Noble, S.J., Powell, T., Twist, V.W., Yamaoka, K., 1988. J. Physiol. 400, 299±320. Enous, R., Coetzee, W.A., Opie, L.H., 1992. J. Cardiovasc. Pharmacol. 19, 17±23. Ertel, S.I., Ertel, E.A., Clozel, J.P., 1997. Cardiovasc. Drugs Ther. 11, 723±739. Ewart, H.S., Klip, A., 1995. Am. J. Physiol. 269, C295±C311. Ewart, H.S., Severson, D.L., Shimoni, Y., 1998. J. Physiol. 511, 148P. Ewing, D.J., Boland, O., Neilson, J.M.M., Cho, C.G., Clarke, B.F., 1991. Diabetologia 34, 182±185. Farah, A.E., 1983. Pharmacol. Rev. 35, 181±217. Fedida, D., Shimoni, Y., Giles, W.R., 1989. Am. J. Physiol. 256, H1500±H1504. Fedida, D., Braun, A.P., Giles, W.R., 1991. J. Physiol. 441, 673±684. Fedida, B., Braun, A.P., Giles, W.R., 1993. Physiol. Rev. 73, 469±487. Fein, F.S., Kornstein, L.B., Strobeck, J.E., Capasso, J.M., Sonnenblick, E.H., 1980. Circ. Res. 47, 922±933. Fein, F.S., Sonnenblick, E.H., 1985. Prog. Cardiovas. Dis. 27, 255±270. Fein, F.S., Miller-Green, B., Zola, B., Sonnenblick, E.H., 1986. Am. J. Physiol. 250, H108±H113. Felzen, B., Sweed, Y., Binah, O., 1989. J. Mol. Cell. Cardiol. 21, 1151±1161. Feng, J., Wible, B., Li, G.R., Wang, Z., Nattel, S., 1997. Circ. Res. 80, 572±579.

102

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

Ferraro, S., Perrone-Filardi, P., Maddalena, G., Desiderio, A., Gravina, E., Turco, S., Chiariello, M., 1993. Am. J. Cardiol. 71, 409±414. Fiset, C., Clark, R.B., Shimoni, Y., Giles, W.R., 1997a. J. Physiol. 500, 51±64. Fiset, C., Clark, R.B., Larsen, T.S., Giles, W.R., 1997b. J. Physiol. 504, 557±563. Foy, J.M., Lucas, P.D., 1978. J. Pharm. Pharmac. 30, 558±562. Fozzard, H.A., Hanck, D.A., 1996. Physiol. Rev. 76, 887±926. Francis, G.S., 1998. J. Cardiovasc. Pharmacol. 32, S16±S21. Franklyn, J.A., Gammage, M.D., 1996. Tr. Endocr. Metab. 7, 50±54. Fredlund, B.O., Olsson, S.B., 1983. Acta Med. Scand. 213, 231±235. Freedberg, A.S., Papp, J.G., Vaughan Williams, E.M., 1970. J. Physiol. 207, 357±369. Freer, R.J., Pappano, A.J., peach, M.J., Bing, K.T., McLean, M.J., Vogel, S., Sperelakis, N., 1976. Circ. Res. 39, 178±183. Fukai, D., Wada, A., Tsutamoto, T., Kiaoshita, M., 1998. Jpn. Circ. J. 62, 604±610. Galli, A., DeFelice, L.J., 1994. Biophys. J. 67, 2296±2304. Ganote, C., Armstrong, S., 1993. Cardiovasc. Res. 27, 1387±1403. Gao, J., Cohen, I.S., Mathias, R.T., Baldo, G.J., 1994. J. Physiol. 477, 373±380. Garcia, L.J., Rosado, J.A., Gonzalez, A., Jensen, R.T., 1997. Biochem. J. 327, 461±472. Giles, W., Shimoni, Y., 1989. J. Physiol. 417, 465±481. Gilman, A.G., 1987. Ann. Rev. Biochem. 56, 615±649. Gintant, G.A., Liu, D.W., 1992. Circ. Res. 70, 844±850. Gisbert, M.P., Fischmeister, R., 1988. Circ. Res. 62, 660±667. Gomberg-Maitland, M., Frishman, W.H., 1998. Am. Heart J. 135, 187±196. Gonzalez-Juanatey, J.R., Garcia-Acuna, J.M., Pose, A., Varela, A., Calvo, C., Cabezas-Cerrato, J., de la Pena, M.G., 1998. Am. J. Cardiol. 81, 170±174. Gotzsche, L.B., Rosenqvist, N., Gronbaek, H., Flyvbjerg, A., Gotzsche, O., 1996. Eur. J. Endocr. 134, 107±113. Guo, W., Kamiya, K., Toyama, 1997. J. Mol. Cell. Cardiol. 29, 617±627. Habuchi, Y., Lu, L.L., Morikawa, J., Yoshimura, M., 1995a. Am. J. Physiol. 268, H1053±H1060. Habuchi, Y., Lu, L.L., Okamoto, S., Komori, T., Takahashi, H., Morikawa, J., Yoshimura, M., 1995b. Clin. Exp. Pharmacol. Physiol. 22, S105±S106. Hagiwara, N., Irisawa, H., Kameyama, M., 1988. J. Physiol. 395, 233±253. Hall, P.F., Can, 1984. J. Biochem. Cell. Biol. 62, 653±665. Hamilton, M.A., Stevenson, L.W., Fonarow, G.C., Steimle, A., Goldhaber, J.I., Child, J.S., Chopra, I.J., Moriguchi, J.D., Hage, A., 1998. Am. J. Cardiol. 81, 443±447. Han, H.M., Robinson, R.B., Bilzekian, J.P., Steinberg, S.F., 1989. Circ. Res. 65, 1763±1773. Han, J., Leem, C., So, I., Kim, E., Hong, S., Ho, W., Sing, H., Earm, Y.E., 1994. J. Mol. Cell. Cardiol. 26, 925± 935. Han, X., Shimoni, Y., Giles, W.R., 1995. J. Gen. Physiol. 106, 45±65. Han, X., Kobzik, L., Severson, D., Shimoni, Y., 1998. J. Physiol. 509, 741±754. Hansen, P.S., Gray, D.F., Rasmussen, H., 1995. Circulation 92, I638. Hara, M., Liu, Y.M., Zhen, L., Cohen, I.S., Yu, H., Danilo, P., Ogino, K., Bilzekian, J.P., Rosen, M.R., 1997. Circulation 96, 3704±3709. Hara, M., Danilo, P., Rosen, M.R., 1998. J. Pharmacol. Exp. Ther. 285, 1068±1072. Harris, D.R., Green, W.L., Craelius, W., 1991. Biochim. Biophys. Acta 1095, 175±181. Hartzell, H.C., 1988. Prog. Biophys. Mol. Biol. 52, 165±247. Hartzell, H.C., Mery, P.F., Fischmeister, R., Szabo, G., 1991. Nature 351, 573±576. Harvey, R.D., Hume, J.R., 1989a. Am. J. Physiol. 257, H818±H823. Harvey, R.D., Hume, J.R., 1989b. Science 244, 983±985. Harvey, R.D., Clark, C.D., Hume, J.R., 1990. J. Gen. Physiol. 95, 1077±1102. Hattori, Y., Kanno, M., 1997. Eur. J. Pharmacol. 329, 165±168. Henegar, J.R., Janicki, J.S., 1996. Circulation 94, 1±672. Hermsmeyer, K., 1980. Circ. Res. 47, 524±529.

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

103

Hohl, C.M., Wetzel, S., Fertel, R.H., Wimsatt, D.K., Brierly, G.P., Altschuld, R.A., 1989. Am. J. Physiol. 257, C948±C956. Hojo, Y., Ikeda, U., Tsuruya, Y., Ebata, H., Murata, M., Okada, K., Saito, T., Shimada, K., 1997. J. Cardiovasc. Pharmacol. 29, 75±80. Homcy, C.J., Vatner, S.G., Vatner, D.E., 1991. Ann. Rev. Physiol. 53, 137±159. Hool, L.C., Harvey, R.D., 1997. Am. J. Physiol. 273, H1669±H1676. Hool, L.C., Middleton, L.M., Harvey, R.D., 1998. Circ. Res. 83, 33±42. Hoppe, U.C., Jansen, E., Sudkamp, M., Beuckelmann, D.J., 1998. Circulation 97, 55±65. Hori, M., Sato, H., Kitakaze, M., Iwai, K., Takeda, H., Inoe, M., Kamada, T., 1994. Circ. Res. 75, 324±334. Hume, J.R., Harvey, R.D., 1991. Am. J. Physiol. 261, C399±C412. Hupf, H., Grimm, D., Riegger, G.A.J., Schunkert, H., 1999. Circ. Res. 84, 365±370. Hwang, I.S., Ho, H., Ho€mann, B.B., Reaven, G.M., 1987. Hypertens. 10, 512±516. Inoguchi, T., Battan, R., Handler, E., Sportsman, J.R., Heath, W., King, G.L., 1992. Proc. Natl. Acad. Sci. USA 89, 11059±11063. Jiang, C., Poole-Wilson, P.A., Sarrel, P.M., Mochizuki, S., Collins, P., MacLeod, K.T., 1992. Br. J. Pharmacol. 106, 739±745. Johansson, C., Thoren, P., 1997. Acta Physiol. Scand. 160, 133±138. Johnson, P.N., Freedberg, A.S., Marshall, J.M., 1973. Cardiology 58, 273±289. Johnson, B.D., Zheng, W., Korach, K.S., Scheuer, T., Catterall, W.A., Rubanyi, G.M., 1997. J. Gen. Physiol. 110, 135±140. Jourdon, P., Feuvray, D., 1993. J. Physiol. 470, 411±429. Ju, H., Scammel-La Fleur, T., Dixon, I.M., 1996. J. Mol. Cell. Cardiol. 28, 1119±1128. Jurevicius, J., Fischmeister, R., 1996. Proc. Natl. Acad. Sci. USA 93, 295±299. Kaibara, M., Mitarai, S., Yano, K., Kameyama, M., 1994. Circ. Res. 75, 1121±1125. Kamitani, T., Ikeda, U., Muto, S., Kawakami, K., et al., 1992. Circ. Res. 71, 1457±1464. Kass, R.S., Blair, M.L., 1981. J. Mol. Cell. Cardiol. 13, 797±809. Katoh, Y., Klein, K.L., Kaplan, R.A., Sanborn, W.G., Kurokawa, K., 1981. Endocrinology 109, 2252±2254. Katsube, Y., Yokoshiki, H., Nguyen, L., Sperelakis, N., 1996. Eur. J. Pharmacol. 317, 391±400. Kecskemeti, V., Pacher, P., Pankucsi, C., Nanasi, P., 1996. Mol. Cell. Biochem. 160-161, 53±59. Khan, A.R., Wohlfart, B., 1981. Acta Physiol. Scand. 111, 201±204. Khandoudi, N., Bernard, M., Cozzone, P., Feuvray, D., 1990. Cardiovasc. Res. 24, 873±878. Kim, D., Smith, T.W., Marsh, J.D., 1987. J. Clin. Invest. 80, 88±94. Kirstein, M., Hu, K., Katzer, A., 1995. Circulation 92, I638±I639. Kirstein, M., Eickhorn, R., Kochsiek, K., Langenfeld, H., 1996. P¯uegers Arch. 431, 395±401. Kjeldsen, K., Braendgaard, H., Sidenius, P., Larsen, J.S., Norgaard, A., 1982. Diab. 36, 842±848. Klein, I., 1990. Am. J. Med. 88, 631±637. Kobayashi, M., Furukawa, Y., Chiba, S., 1978. Eur. J. Pharmacol. 50, 17±25. Kobori, H., Ichihara, A., Suzuki, H., Takenaka, T., Miyashita, Y., Hayashi, M., Saruta, T., 1997. Am. J. Physiol. 273, H593±H599. Kondo, N., Shibata, S., Tenner, T.E., Pang, P.K., 1988. J. Cardiovasc. Pharmacol. 11, 619±625. Korichneva, I., Puceat, M., Van Brussel, E., Geraud, G., Vassort, G., 1995. J. Mol. Cell. Cardiol. 27, 2521±2528. Koukouritaki, S.B., Margioris, A.N., Gravanis, A., Hartig, R., Stournaras, C., 1997. J. Cell. Biochem. 65, 492±500. Koumi, S., Backer, C.L., Arentzen, C.E., Sato, R., 1995. J. Clin. Invest. 96, 2870±2881. Krizanova, Orlicky, J., Masanova, C., Juhaszova, M., Hudecova, S., 1997. J. Mol. Cell. Cardiol. 29, 1739±1746. Kurachi, Y., Ito, H., Sugimoto, T., Shimizu, T., et al., 1989. P¯uegers Arch. 414, 102±104. Ladenson, P.W., Bloch, K.D., Seidman, J.G., 1988. Endocrinology 123, 652±657. Lader, A.S., Xiao, Y.F., Ishikawa, Y., Cui, Y., Vatner, D.E., Vatner, S.F., Homcy, C.J., Cantiello, H.F., 1998. Proc. Natl. Acad. Sci. USA 95, 9669±9674. Lagadic-Gossmann, D., Chesnais, J.M., Fuevray, D., 1988. P¯uegers Arch. 412, 613±617. Lagadic-Gossmann, D., Buckler, K.J., Le Prigent, K., Feuvray, D., 1996. Am. J. Physiol. 270, H1529±H1537. LaManna, V.R., Ferrier, G.F., 1981. Am. J. Physiol. 240, H636±H644. Lambert, C., Godin, D., Fortier, P., Nadeau, R., 1991. Can. J. Physiol. Pharmacol. 69, 389±392.

104

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

Lantz, R.C., Elsas, L.J., DeHaan, R.L., 1980. Proc. Natl. Acad. Sci. USA 77, 3062±3066. Leclerq, R.S., Lemaire, S., Piot, C., Nargeot, J., 1998. Cardiovasc. Res. 37, 300±311. Lederer, W.J., Tsien, R.W., 1976. J. Physiol. 263, 73±100. Lee, S.L., Ostadalova, I., Kolar, F., Dhalla, N.S., 1992. Mol. Cell. Biochem. 109, 173±179. Legaye, F., Beigelman, P., Deroubaix, E., Coraboeuf, E., 1988. Life Sci. 42, 2269±2274. Legrand, A.M., Boudot, J.P., Coraboeuf, E., Ro, J., Cavero, I., 1981. J. Mol. Cell. Cardiol. 13, 833±842. Le Grand, B., Deroubaix, E., Couetil, J.P., Coraboeuf, E., 1992. P¯uegers Arch. 421, 486±491. Levine, M.A., Feldman, A.M., Robishaw, J.D., Ladenson, P.W., Ahn, T.G., Moroney, J.F., Smallwood, P.M., 1990. J. Biol. Chem. 265, 3553±3560. Li, G.R., Feng, J., Wang, Z., Fermini, B., Nattel, S., 1996. Circ. Res. 78, 903±915. Liang, F., Gardner, D.G., 1998. J. Biol. Chem. 273, 14612±14619. Light, P., Shimoni, Y., Harbison, S., Giles, W., French, R.J., 1998. J. Membr. Biol. 162, 217±223. Litowski, S.H., Antzelevitch, C., 1988. Circ. Res. 62, 116±126. Liu, S.J., Kennedy, R.H., 1998. Am. J. Physiol. 274, H2203±H2207. Liu, Q.Y., Karpinski, E., Pang, P.K.T., 1994a. J. Pharmacol. Exp. Ther. 271, 935±943. Liu, Q.Y., Karpinski, E., Pang, P.K., 1994b. FEBS Lett. 338, 234±238. Liu, Q.Y., Karpinski, E., Pang, P.K., 1994c. J. Pharmacol. Exp. Ther. 271, 944±951. Liu, P., Fei, L., Wu, W., Li, J., Wang, J., Zhang, X., 1996. Cardiovasc. Drugs Ther. 10, 369±378. Liu, B., Hu, D., Wang, J., Liu, X.L., 1997. Methods Find. Exp. Clin. Pharmacol. 19, 19±25. Lo, S.S., Sutton, M.S., Leslie, R.D., 1993. Am. J. Cardiol. 72, 305±309. Lu, H.K., Fern, R.J., Luthin, D., Linden, J., Liu, L.P., Cohen, C.J., Barrett, P.Q., 1996. Am. J. Physiol. 271, C1340±C1349. Ma, L., Robinson, C.P., Thadani, U., Patterson, E., 1997. J. Cardiovasc. Pharmacol. 30, 130±135. Macias-Silva, M., Garcia-Sainz, J.A., 1994. Toxicon 32, 105±112. MacLeod, K.M., McNeill, J.H., 1981. Can. J. Physiol. Pharm. 59, 1039±1049. Mager, S., Palti, Y., Binah, O., 1992. P¯uegers Arch. 421, 425±430. Magyar, J., Rusznak, Z., Szentesi, P., Szucs, G., Kovacs, L., 1992. J. Mol. Cell. Cardiol. 24, 841±853. Magyar, J., Cseresnyes, Z., Risznak, Z., Sipos, I., Szucs, G., Kovacz, L., 1995. Gen. Physiol. Biophys. 14, 191±201. Main, M.J., Grantham, C.J., Cannell, M.B., 1997. P¯uegers Arch. 435, 112±118. Maki, T., Gruver, E.J., Davido€, A.J., Izzo, N., Toupin, D., Colucci, W., Marks, A.R., Marsh, J.D., 1996. J. Clin. Invest. 97, 656±663. Makino, N., Dhruvarajan, R., Elimban, V., Beamish, R.E., Dhalla, N.S., 1985. Can. J. Cardiol. 1, 225±232. Makkar, R.R., Fromm, B.S., Steinman, R.T., Meissner, M.D., Lehmann, M.H., 1993. JAMA 270, 2590±2597. Malhotra, A., Reich, D., Reich, A., Nakouzi, A., Sanghi, V., Geenen, D.L., Buttrick, P.M., 1997. Circ. Res. 81, 1027±1033. Maltsev, V.A., Undrovinas, A.I., 1997. Am. J. Physiol. 273, H1832±H1840. Maltsev, V.A., Ji, G.J., Wobus, A.M., Fleischmann, B.K., Hescheler, J., 1999. Circ. Res. 84, 136±145. Mazzanti, M., Assandri, R., Ferroni, A., DiFrancesco, D., 1996. FASEB J. 10, 357±361. Mazzolai, L., Nussberger, J., Aubert, J.F., Brunner, D.B., Gabbiani, G., Brunner, H.R., Pedrazzini, T., 1998. Hypertens. 31, 1324±1330. McDonald, T.F., Pelzer, S., Trautwein, W., Pelzer, D.J., 1994. Physiol. Rev. 74, 366. Meo, S.D., de Martino Rosaroli, P., Piro, M.C., De Leo, T., 1994. Arch. Int. Physiol. Biochim. Biophys. 102, 153± 159. Mery, P.F., Brechler, V., Pavoine, C., Pecker, F., Fischmeister, R., 1990. Nature 345, 158±161. Mery, P.F., Lohman, S.M., Walter, U., Fischmeister, R., 1991. Proc. Natl. Acad. Sci. USA 88, 1197±1201. Mery, P.F., Pavoine, C., Belhassen, L., Pecker, F., Fischmeister, R., 1993. J. Biol. Chem. 268, 26286±26295. Meszaros, J., Levai, G., 1992. Eur. J. Pharmacol. 210, 333±338. Michel-Reher, M., Gross, G., Jasper, J.R., Bernstein, D., Olbricht, T., Brodde, O.E., Michel, M.C., 1993. Biochem. Pharmacol. 7, 1417±1423. Middlekau€, H.R., Mark, A.L., 1998. Int. Med. 37, 112±122. Middleton, L.M., Harvey, R.D., 1998. Am. J. Physiol. 275, C293±C302. Mihailidou, A.S., Buhaglar, K.A., Rasmussen, H.H., 1998. Am. J. Physiol. 274, C175±C181.

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

105

Miyazawa, K., Hashimoto, H., Uematsu, T., Nakashima, M., 1989. Br. J. Pharmacol. 97, 1093±1100. Momtaz, A., Couombe, A., Richer, P., Mercadier, J.J., Coraboeuf, E., 1996. J. Mol. Cell. Cardiol. 28, 2511±2522. Moorman, J.R., Kirsch, G.E., Lacerda, A.E., Brown, A.M., 1989. Circ. Res. 65, 1804±1809. Morita, H., Kimura, J., Endoh, M., 1995. J. Physiol. 483, 119±130. Morkin, E., Flink, I.L., Goldman, S., 1983. Prog. Cardiovasc. Dis. 25, 435±465. Mukherjee, R., Hewett, K.W., Walker, J.D., Basler, C.G., Spinale, F.G., 1998. Cardiovasc. Res. 37, 432±444. Munger, T.M., Johnson, S.B., Packer, D.L., 1994. Circ. Res. 75, 511±519. Murray, K.T., Hu, N.N., Daw, J.R., Shun, H.G., Watson, M.T., Mashburn, A.B., George, A.L., 1997. Circ. Res. 80, 370±376. Muscelli, E., Emdin, M., Natali, A., Pratali, L., Camastra, S., Gastaldelli, A., Baldi, S., Carpeggiani, C., Ferrannini, E., 1998. J. Clin. Endocrinol. Metab. 83, 2084±2090. Neumann, J., Gupta, R.C., Schmitz, W., Scholz, H., Nairn, A.C., Watanabe, A.M., 1991. Circ. Res. 69, 1450±1457. Ng, Y.C., Tolerico, P.H., Cook, C.B., 1993. Am. J. Physiol. 265, E243±E251. Nicholl, T.A., Lopaschuk, G.D., McNeill, J.H., 1991. Am. J. Physiol. 261, H1053±H1059. Nicholls, M.G., Richards, A.M., Agarwal, M., 1998. J. Hum. Hypertens. 12, 295±299. Nilius, B., Tytgat, J., Albitz, R., 1989. Biochim. Biophys. Acta 1014, 259±262. Nishimura, H., Yoshikawa, T., Kobayashi, N., Anzai, T., Nagami, K., Handa, S., Ogawa, S., 1997. Heart Vess. 12, 84±91. Nishio, Y., Kashiwagi, A., Ogawa, T., Asahina, T., Ikebuchi, M., Kodama, M., Shigeta, Y., 1990. Diab. 39, 1064± 1069. Nobe, S., Aomine, M., Arita, M., Ito, S., Takaki, R., 1990. Cardiovasc. Res. 24, 381±389. Noble, D., 1992. Ann. N. Y. Acad. Sci. 644, 1±22. Node, K., Kitakaze, M., Kosaka, H., Minamino, T., Funaya, H., Hori, M., 1997. Circulation 96, 1953±1963. Obayashi, K., Horie, M., Xie, L.H., Tsuchiya, K., Kubota, A., Ishida, H., Sasayama, S., 1997. Circulation 95, 197± 204. O'Brien, R.M., Granner, D.K., 1996. Physiol. Rev. 76, 1109±1161. Ohnishi, J., Ishido, M., Shibata, T., Inagami, T., Murakami, K., Miyazaki, H., 1992. Biochem. Biophys. Res. Commun. 186, 1094±1100. Ohyanagi, M., Iwasaki, T., 1996. Mol. Cell. Biochem. 160-161, 153±158. O'Keefe, J.H., Kim, S.C., Hall, R.R., Cochran, V.C., Lawhorn, S.L., McAllister, B.D., 1997. J. Am. Coll. Cardiol. 29, 1±5. Olshausen, K.V., Bisco€, S., Kahaly, G., Mohr-Kahaly, S., Erbel, R., Beyer, J., Meyer, J., 1989. Am. J. Cardiol. 63, 930±933. Ono, K., Moscucci, A., January, C.T., Fozzard, H.A., 1992. Circulation 86, I564. Opasich, C., Pacini, F., Ambrosino, N., Riccardi, P.G., Febo, O., Ferrati, R., Cobelli, F., Tavazzi, L., 1996. Eur. Heart J. 17, 1860±1866. Orlowski, J., Lingrel, J.B., 1990. J. Biol. Chem. 265, 3462±3470. Osaka, T., Joyneer, R.W., 1992. Circ. Res. 70, 104±115. Ouadid, H., Albat, B., Nargeot, J., 1995. J. Cardiovasc. Pharm. 25, 282±291. Patterson, E., Ma, L., Szabo, B., Robinson, C.P., Thadani, U., 1998. J. Pharmacol. Exp. Ther. 284, 586±591. Pelzer, S., You, Y., Shuba, Y.M., Pelzer, D.J., 1997a. Am. J. Physiol. 273, H2539±H2548. Pelzer, T., Shamim, A., Wolfges, S., Schumann, M., Neyses, L., 1997b. Adv. Exp. Med. Biol. 432, 83±89. Penefsky, Z.J., Kahn, M., 1971. Eur. J. Pharmacol. 15, 259±266. Philipson, K.D., Edelman, I.S., 1977. Am. J. Physiol. 232, C196±C201. Pierce, G.N., Russell, J.C., 1997. Cardiovasc. Res. 34, 41±47. Pierce, G.N., Ramjiawan, B., Dhalla, N.S., Ferrari, R., 1990. Am. J. Physiol. 258, H255±H261. Pierce, G.N., Maddaford, T.G., Russell, J.C., 1997. Can. J. Physiol. Pharmacol. 75, 343±350. Pool, P.E., 1998. Cardiol. 90, 1±7. Porciatti, F., Pelzmann, B., Cerbai, E., Scha€er, P., Pino, R., Bernhart, E., Koidl, B., Mugelli, A., 1997. Br. J. Pharmacol. 122, 963±969. Ramirez-Gil, J.F., Trouve, P., Mougenot, N., Carayon, A., Lechat, P., Charlemagne, D., 1998. Cardiovasc. Res. 38, 451±462.

106

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

Rautaharju, P.M., Zhou, S.H., Wong, S., Calhoun, H.P., Berenson, G.S., Prineas, R., Davignon, A., 1992. Can. J. Cardiol. 8, 690±695. Ren, J., Davido€, A.J., 1997. Am. J. Physiol. 272, H148±H158. Richard, S., Leclercq, F., Lemaire, S., Piot, C., Nargeot, J., 1998. Cardiovasc. Res. 37, 300±311. Rodrigues, B., McNeill, J.H., 1992. Cardiovasc. Res. 26, 913±922. Rozanski, G.J., Witt, R.C., 1994. Am. J. Physiol. 267, H1361±H1367. Rubinstein, I., Binah, O., 1989. Naunyn Schmiedebergs Arch. Pharmacol. 340, 705±711. Rusznak, Z., Cseresnyes, Z., Sipos, I., Magyar, J., Kovacs, L., Szucs, G., 1996. Gen. Physiol. Biophys. 15, 225±238. Sadoshima, J., Izumo, S., 1997. Ann. Rev. Physiol. 59, 551±571. Sakaguchi, Y., Cui, G., Sen, L., 1996. Endocrinology 137, 4744±4751. Sako, H., Green, S.A., Kranias, E.G., Yatani, A., 1997. Am. J. Physiol. 273, C1666±C1672. Saltiel, A.R., 1996. Am. J. Physiol. 270, E375±E385. Sanguinetti, M.C., Jurkiewicz, N.K., 1990. J. Gen. Physiol. 96, 194±214. Sanguinetti, M.C., Jurkiewicz, N.K., Scott, A., Siegl, P.K.S., 1991. Circ. Res. 68, 77±84. Santana, L.F., Gomez, A.M., Lederer, W.J., 1998. Science 279, 1027±1033. Sarma, J.S., Venkataraman, K., Nicod, P., Polikar, R., Smith, J., Schoenbaum, M.P., Singh, B.N., 1990. Am. J. Cardiol. 66, 959±963. Sato, R., Koumi, S., 1995. J. Memb. Biol. 148, 185±191. Sato, A., Liu, J.P., Funder, J.W., 1997. Endocrinology 138, 3410±3416. Sauvadet, A., Rohn, T., Pecker, F., Pavoine, C., 1996. Circ. Res. 78, 102±109. Sauviat, M.P., Feuvray, D., 1986. Bas. Res. Cardiol. 81, 489±496. Sawicki, P.T., Dahne, R., Bender, R., Berger, M., 19996. Diabetologia 39, 77±81. Scha€er, S.W., Allo, S., Punna, S., White, T., 1991. Am. J. Physiol. 261, E369±E376. Scha€er, S.W., Ballard-Croft, C., Boerth, S., Allo, S.N., 1997. Cardiovasc. Res. 34, 129±136. Schiebinger, R.J., Parr, H.G., Cragoe, E.J., 1992. Endocrinology 130, 1017±1023. Schmidt, H.H., Lohmann, S.M., Walter, U., 1993. Biochim. Biophys. Acta 1178, 153±175. Schubert, B., VanDongen, A.M., Kirsch, G.E., Brown, A.M., 1989. Beta-adrenergic inhibition of cardiac sodium channels by dual G-protein pathways. Science 245, 516±519. Schwartz, D.D., Na€, B.P., 1996. Circulation 94, I188. Sechi, L.A., Grin, C.A., Schambelan, M., 1994. Diab. 43, 1180±1184. Segal, J., 1989. J. Mol. Cell. Cardiol. 21, 323±334. Senges, J., Brachmann, J., Pelzer, D., Hasslacher, C., Weihe, E., Kubler, W., 1980. J. Mol. Cell. Cardiol. 12, 1341± 1351. Shah, A., Cohen, I.S., Rosen, M.R., 1988. Biophys. J. 54, 219±225. Shannaho€-Khalsa, D.S., Kennedy, B., Yates, F.E., Ziegler, M.G., 1998. Am. J. Physiol. 272, R962±R968. Shannon, K.M., Klitzner, T.S., Chen, F., Van Dop, C., 1995. Pediatr. Res. 37, 277±282. Sharp, N.A., Neel, D.S., Parsons, R.L., 1985. J. Mol. Cell. Cardiol. 17, 119±132. Shehadeh, A., Regan, T.J., 1994. Clin. Cardiol. 18, 301±305. Shimoni, Y., Banno, H., 1993a. Am. J. Physiol. 264, H74±H77. Shimoni, Y., Banno, H., 1993b. Am. J. Physiol. 265, H1875±H1883. Shimoni, Y., Severson, D.L., 1995. Am. J. Physiol. 268, H576±H583. Shimoni, Y., Firek, L., Severson, D., Giles, W., 1994. Circ. Res. 74, 620±628. Shimoni, Y., Qi, A., Severson, D., Giles, W.R., 1995a. J. Physiol. 485, 43±44P. Shimoni, Y., Severson, D., Giles, W., 1995b. J. Physiol. 488, 673±688. Shimoni, Y., Fiset, C., Clark, R.B., Dixon, J.E., McKinnon, D., Giles, W.R., 1997. J. Physiol. 500, 73±75. Shimoni, Y., Ewart, H.S., Severson, D., 1998a. J. Physiol. 507, 485±496. Shimoni, Y., Light, P.E., French, R.J., 1998b. Am. J. Physiol. 275, E568±E576. Shimoni, Y., Ewart, H.S., Severson, D., 1999. J. Physiol. 514, 735±745. Shuba, Y.M., Iwata, T., Naidenov, V.G., Oz, M., Sandberg, K., Kraev, A., Carafoli, E., Morad, M., 1998. J. Biol. Chem. 273, 9±18825. Sicouri, S., Antzelevitch, D., Heilmann, C., Antzelevitch, C., 1997. J. Cardiovasc. Electrophysiol. 8, 1280±1290.

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

107

Silvestre, J.S., Robert, V., Heymes, C., Aupetit-Faisant, B., Mouas, C., Moalic, J.M., Swynghedauw, B., Delcayre, C., 1998. J. Biol. Chem. 273, 4883±4891. Singer-Lahat, D., Lotan, I., Biel, M., Flockerzi, V., Hofmann, F., Dascal, N., 1994. Receptors Channels 2, 215±226. Sitzler, G., Lenz, O., Kilter, H., La Rosee, K., Bohm, M., 1996. Br. J. Pharmacol. 119, 43±48. Skeberdis, V.A., Jurevicius, J., Fischmeister, R., 1997. J. Pharmacol. Exp. Ther. 283, 452±461. Smith, P.R., Stoner, L.C., Viggiano, S.C., Angelides, K.J., Benos, D.J., 1995. J. Membr. Biol. 147, 195±205. Smith, J.M., Wahler, G.M., 1996. Mol. Cell. Biochem. 158, 43±51. Sorbera, L.A., Morad, M., 1990. Science 247, 969±973. Sorota, S., Rybina, I., Yamamoto, A., Du, X.Y., 1999. J. Physiol. 514, 413±423. Soustre, H., 1979. J. Physiol. (Paris) 75, 805±810. Spinale, F.G., Mukherjee, R., Iannini, J.P., Whitebread, S., Hebbar, L., Clair, M.J., Melton, D.M., Cox, M.H., Thomas, P.B., Gasparo, M., 1997. Circulation 96, 2397±2406. Stein, B.C., Levin, R.I., 1998. Am. Heart J. 135, 914±923. Steinberg, S.F., Kaplan, L.M., Inouye, T., Zhang, J.F., Robinson, R.B., 1989. J. Pharmacol. Exp. Ther. 250, 1141± 1146. Stengl, M., Mubagwa, K., Carmeliet, E., Flameng, W., 1998. Cardiovasc. Res. 38, 703±710. Stimers, J.R., Dobretsov, M., 1998. J. Membr. Biol. 163, 205±216. Strodter, D., Overbeck, A., Syed Ali, S., Seitz, S., Bretzel, R.G., Federlin, K., 1995. Exp. Clin. Endocrinol. Diabetes 103, 354±360. Stumpf, W.E., 1990. Experientia 46, 13±25. Surawicz, B., 1997. J. Cardiovasc. Electrophysiol. 8, 1009±1012. Swan, J.W., Walton, C., Godsland, I.F., Clark, A.L., Coats, A.J., Oliver, M.F., 1994. Eur. Heart J. 15, 1528±1532. Takimoto, K., Leviran, E.S., 1994. Circ. Res. 75, 1006±1013. Takimoto, K., Li, D., Nerbonne, J.M., Levitan, E.S., 1997. J. Mol. Cell. Cardiol. 29, 3035±3042. Talukder, M.A., Endoh, M., 1997. Naunyn Schmiedebergs Arch. Pharmacol. 355, 87±96. Tanaka, Y., Kashiwagi, A., Saeki, Y., Shigeta, S., 1992. Am. J. Physiol. 263, E425±E429. Tei, M., Horie, M., Makita, T., Suzuki, H., Hazama, A., Okada, Y., Kawai, C., 1990. Biochem. Biophys. Res. Commun. 167, 413±418. Ter Maaten, J.C., Voorburg, A., De Vries, P.M., Ter Wee, P.M., Donker, A.J., Gans, R.O., 1998. Eur. J. Clin. Invest. 28, 279±284. Terzic, A., Puceat, M., Clement, O., Scamps, F., Vassort, G., 1992. J. Physiol. 447, 275±292. Terzic, A., Puceat, M., Vassort, G., Vogel, S.M., 1993. Pharm. Rev. 45, 147±175. Tohse, N., Nakaya, H., Takeda, Y., Kanno, M., 1995. Br. J. Pharmacol. 114, 1076±1082. Tomlinson, K.C., Gardiner, S.M., Hebden, R.A., Bennett, T., 1992. Pharm. Rev. 44, 103±150. Trautwein, W., Cavalie, A., 1985. J. Am. Coll.Cardiol. 6, 1409±1416. Trautwein, W., Hescheler, J., 1990. Ann. Rev. Physiol. 52, 257±274. Trautwein, W., Osterrieder, W., 1986. In: Nathan, R.D. (Ed.), Cardiac Muscle: the Regulation of Excitation and Contraction. Orlando Academic, pp. 87±127. Tseng, G.N., Boyden, P.A., 1989. Circ. Res. 65, 1735±1750. Tseng, G.N., Boyden, P.A., 1991. Am. J. Physiol. 261, H364±H379. Tseng, G.N., Yao, J.A., Tseng-Crank, J., 1997. Am. J. Physiol. 272, H1275±H1286. Tsien, R.W., 1974. J. Gen. Physiol. 64, 293±319. Tsuchida, K., Watajima, H., Otomo, S., 1994. Am. J. Physiol. 267, H2280±H2289. Tsuchiya, K., Horie, M., Watanuki, M., Albrecht, C.A., Obayashi, K., Fujiwara, H., Sasayama, S., 1997. Circulation 96, 3129±3135. Valcavi, R., Menozzi, C., Roti, E., Zini, M., Lolli, G., Roti, S., Guiducci, U., Portioli, I., 1992. J. Clin. Endocr. Metab. 75, 239±242. Van Bilsen, M., 1997. Cardiovasc. Res. 36, 310±322. Vassort, G., Alvarez, J., 1994. J. Cardiovasc. Electrophys. 5, 376±393. Venkatesh, N., Lynch, J.J., Uprichard, A.C.G., Kitzen, J.M., Singh, B.N., Lucchesi, B.R., 1991. J. Cardiovasc. Pharmacol. 18, 703±710. Ver, A., Szanto, I., Banyasz, T., Csermely, P., Vegh, E., Somogyi, J., 1997. Diabetologia 40, 1255±1262.

108

Y. Shimoni / Progress in Biophysics & Molecular Biology 72 (1999) 67±108

Viamonte, V.M., Steinberg, S.F., Chow, Y.K., Legato, M.J., Robinson, R.B., Rosen, M.R., 1990. J. Pharmacol. Exp. Ther. 252, 886±891. Volders, P.G., Kulcsar, A., Vos, M.A., Spido, K.R., Wellens, H.J., Lazzara, R., Szabo, B., 1997. Cardiovasc. Res. 34, 348±359. Waldegger, S., Lang, U., Herzer, T., Suessbrich, H., et al., 1996. Naunyn Schmiedebergs Arch. Pharmacol. 354, 698±702. Walsh, K.B., Kass, R.S., 1988. Science 242, 67±69. Walsh, K.B., Long, K.J., 1994. Circ. Res. 74, 121±129. Wang, R., Karpinski, E., Pang, P.K., 1991a. J. Cardiovasc. Pharmacol. 17, 990±998. Wang, R., Wu, L.Y., Karpinski, E., Pang, P.K., 1991b. FEBS Lett. 282, 331±334. Wang, Z., Fermini, B., Nattel, S., 1993a. Circ. Res. 73, 1061±1076. Wang, R., Wu, L., Karpinski, E., Pang, P.K., 1993b. Life Sci. 52, 793±801. Wang, R., Karpinski, E., Pang, P.K., 1994. Regul. Pept. 54, 445±456. Wang, D.W., Kiyosue, T., Shigematsu, S., Arita, M., 1995. Am. J. Physiol. 269, H1288±H1296. Wang, L., Feng, Z.P., Du€, H.J., 1997a. Circulation 96, I499. Wang, Z., Mitsuiye, T., Rees, S.A., Noma, A., 1997b. J. Gen. Physiol. 110, 73±82. Wang, Y., Gao, J., Mathias, R.T., Cohen, I.S., Sun, X., Baldo, G.J., 1998. J. Physiol. 509, 117±128. Watanabe, A., Endoh, M., 1998. Cardiovasc. Res. 37, 524±531. Weight, H.U., Kwok, W.M., Rehmert, G.C., Turner, L.A., Bosnjak, Z.J., 1997. Anesthesiology 87, 1507±1516. Wettwer, E., Amos, G.J., Posival, H., Ravens, U., 1994. Circ. Res. 75, 473±482. Wichelhaus, A., Russ, M., Peterson, S., Eckel, J., 1994. Am. J. Physiol. 267, H548±H555. Wickenden, A.D., Kaprielian, R., Parker, T.G., Jones, O.T., Backx, P.H., 1997. J. Physiol. 504, 271±286. Williamson, A.P., Seifen, E., Lindemann, J.P., Kennedy, R.H., 1994. Can. J. Physiol. Pharmacol. 72, 1574±1579. Withers, D.J., Sanchez-Gutierrez, J., Towery, H., Burks, D.J., Ren, J.M., Previs, S., Zhang, Y., et al., 1998. Nature 391, 900±904. Woo, S.H., Lee, C.O., 1999. P¯uegers Arch. 437, 335±344. Xiao, R.P., Avdonin, P., Zhou, Y.Y., Cheng, H., et al., 1999. Circ. Res. 84, 43±52. Xu, X.P., Best, P.M., 1990. Proc. Natl. Acad. Sci. USA 87, 4655±4659. Xu, X.P., Best, P.M., 1991. Am. J. Physiol. 260, H935±H942. Xu, Z., Patel, K., Rozanski, G.J., 1996. Am. J. Physiol. 271, H2190±H2196. Yatani, A., Wakamori, M., Nidome, T., Yamamoto, S., et al., 1995. Circ. Res. 76, 335±342. Yokoyama, H., Yasutake, M., Avkiran, M., 1998. Circ. Res. 82, 1078±1085. Yu, Z., Quamme, G., McNeill, J.H., 1994. Am. J. Physiol. 266, H2334±H2342. Yu, J.Z., Rodrigues, B., McNeill, J.H., 1997a. Cardiovasc. Res. 34, 91±98. Yu, H., Rosen, M.R., Danilo, P., Steinberg, S.F., Wymore, R.S., Wang, H.S., McKinnon, D., Cohen, I., 1997b. Circulation 96, I295. Zaza, A., Robinson, R.B., DiFrancesco, D., 1996. J. Physiol. 491, 347±355. Zhang, S., Hirano, Y., Hiraoka, M., 1995a. Circ. Res., 592Ð599. Zhang, X.Q., Moore, R.L., Tillotson, D.L., Cheung, J.Y., 1995b. Am. J. Physiol. 269, C1464±C1473. Zhang, Z.H., Johnson, J.A., Chen, L., El-Sherif, N., Mochly-Rosen, D., Boutjdir, M., 1997. Circ. Res. 80, 720±729. Zhang, S., Hiraoka, M., Hirano, Y., 1998. J. Mol. Cell. Cardiol. 30, 1955±1965. Zhou, Z., Lipsius, S.L., 1993. J. Physiol. 466, 263±285. Zongazo, M.A., Carayon, A., Masson, F., Maistre, G., Noe, E., Eurin, J., Barthelemy, C., Komajda, M., Legrand, J.C., 1991. Eur. J. Pharmacol. 209, 45±55. Zygmunt, A.C., 1994. Am. J. Physiol. 267, H1984±H1995. Zygmunt, A.C., Gibbons, W.R., 1991. Circ. Res. 68, 424±437. Zygmunt, A.C., Gibbons, W.R., 1992. J. Gen. Physiol. 99, 391±414.