Opioid and Nonopioid Cardiovascular Effects of Dynorphins

Michel Dumont Simon Lemaire Department of Pharmacology University of Ottawa Ottawa, Ontario Canada K I H EM5

Opioid and Nonopioid Cardiovascular Effects of Dynorphins

1. Introduction The endogenous opioid peptides were first recognized for their ability to bind to specific opioid receptors in the brain and cause analgesia in mammals (Ramabadran and Bansinath, 1990),but they also exert profound effects on other systems, such as the respiratory, gastrointestinal, and cardiovascular systems. These peptides are derived from three separate protein precursors, which upon proteolytic cleavage generate distinct classes of opioid compounds. Thus, proopiomelanocortin (POMC) generates pendorphin (@-End)(Nakanishi et al., 1979), proenkephalin (proEnk) generates four copies of [Mets]-enkephalin (Met-Enk) and one copy each of [Leu5]-enkephalin(Leu-Enk), Met-Enk-Arg-Phe, and Met-Enk-Arg-Gly-Leu (Noda et al., 1982), and prodynorphin (proDyn) generates Dyn A, Dyn B, a- and @-neo-End,and leumorphin (Kakidani et al., 1982). All the proDynderived peptides contain Leu-Enk at their N-terminus. The actions of endogeAdvances m Pharmacology, Volume 37 Copyright 0 1997 by Academic Press, Inc. All rights of reproduction in any form reserved

I

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Michel Dumont and Simon Lemaire

nous opiod peptides are mediated by various types of opioid receptors, each peptide family displaying some degree of selectivity for a particular class of opioid receptor. Thus, /3-End, Enks, and proDyn-derived peptides display some binding selectivity for the d p , 8, and K opioid receptors, respectively. For more complete descriptions of the mechanisms regulating the processing of pro-opioid polypeptides, the interaction of the processed peptides with opioid receptors, and the resulting opioid activities, the reader is referred to reviews by Simon (1991),Pleuvry (1991), and Smith and Lee (1988). Dyn A-(1-13) (a Dyn A fragment possessing the same potency as Dyn A) was first described as the most potent opioid peptide when tested in the peripheral guinea pig ileum assay (Goldstein et al., 1979). Although this peptide shows a high binding affinity and some selectivity for the K opioid receptor (Chavkin et al., 1982), its in vivo antinoceptive activity is weak compared with that of prototypic K opioid analgesics, such as U-50488H, and it is directed toward specific types of pain stimuli (the chemical and mechanical types of pain rather than the thermal type) (Walker et al., 1982; Smith and Lee, 1988).Moreover, analgesia resulting from spinal or supraspinal administration of Dyn A-(1-13) is accompanied by nonopioid effects (motor disturbance, spinal cord injury, hindlimb paralysis, hyperalgesia) that impair the assessment of its antinociceptive activity (Smith and Lee, 1988; Shukla and Lemaire, 1994). The motor effects of Dyn A were attributed to a possible facilitation of excitatory amino acid activity (Long et al., 1994; Shukla and Lemaire, 1994). The involvement of the N-methyl-Daspartate (NMDA) receptor, rather than opioid receptors, in the motor effects of Dyn A-(1-13) was demonstrated by their resistance to naloxone and their blockade by competitive and noncompetitive NMDA receptor antagonists (Shukla and Lemaire, 1994).In addition, intrathecal (i.t.) administration of Dyn A-(1-13) was accompanied by local ischemia (Long et al., 1994), a phenomenon known to induce the secretion of excitatory amino acids (Benveniste et al., 1984). Thus, even though Dyn A was first described as a potent endogenous opioid peptide, its physiological or pathophysiological function (or both) was proposed to also depend on its interaction with nonopioid receptors (Faden, 1990; Shukla and Lemaire, 1994). A cardiovascular modulatory function for Dyn A and related peptides was first suggested by the finding of Dyn A and K opioid receptors in brain nuclei and peripheral organs that are involved in the regulation of cardiovascular functions (Holaday, 1983). However, measurement of the cardiovascular effects of Dyn A and related peptides yielded conflicting results depending on the dose and mode of administration of the peptides, as well as the state of consciousness and type of animals being used. The aim of the present review is to analyze these data in light of the recent evidence that indicates that the cardiovascular effects of Dyn A and related peptides may depend on their interaction with both opioid and nonopioid receptors (Dumont and Lemaire, 1993).

Dynorphin and the Cardiovascular System

3

II. The Central Dynorphinergic System A. Central Localization of Dynorphin and K Opioid Receptors Dyn A was first isolated from porcine pituitary (Goldstein et al., 1979, 1981).Subsequent studies indicated a wide CNS distribution with the following order of concentrations: posterior lobe of the pituitary > > > > hypothalamus > > striatum > midbrain = hippocampus = medulla-pons = spinal cord > cortex > cerebellum (Goldstein and Ghazarossian, 1982; Gramsch et al., 1982; Zamir et al., 1983). The cardiovascular centers that contain immunoreactive Dyn A (ir-Dyn A) comprise discrete nuclei of the hypothalamus, such as the anterior (AHA), lateral (LHA), dorsomedial (DMHA), and ventrolateral (VLHA) hypothalamic areas, the lateral (LPN) and medial preoptic (MPN)nuclei, the paraventricular ( P A W )and periventricular ( P E W ) nuclei, and the supraoptic (SON) and suprachiasmatic (SCN)nuclei (Molineaux et al., 1982; Conway et al., 1987).In the P A W a n d the SON, Dyn A is colocalized with the pressor peptide arginine-vasopressin (AVP) (Watson et al., 1982). In the brainstem, Dyn A is found in the nucleus ambiguus (NA) and the nucleus tractus solitarius (NTS) (Molineaux et al., 1982; Conway et al., 1987).Immunohistochemical studies have also shown that Dyn A, Dyn B, and a-neo-End are colocated in the same CNS nuclei, including those regulating cardiovascular functions, such as the LHA, the P A W , the SON, and the NTS (Watson etal., 1983; Maysinger etal., 1982). Autoradiographic measurement of K opioid receptors in the different compartments of the CNS reveals a distribution similar to that of Dyn A. High densities of K opioid receptors are present in the LHA, the P A W , the P E W , the SCN, the MI", the SON, and the NTS (Castanas et al., 1986; Mansour et al., 1986; Morris and Herz, 1986; Nock et al., 1988). In the spinal cord, the K~ opioid receptor mRNA is mainly observed in small and medium size neurons of the dorsal horn along with ir-Dyn A (Botticeli et al., 1981; Mansour et al., 1995). However, the fact that Dyn A and K opioid receptors are located in CNS nuclei that are involved in the regulation of cardiovascular functions must be interpreted with caution, since correlations have also been made between the localization of Dyn A, K opioid receptors, and brain nuclei involved in nociception, analgesia, and learning and memory functions (Khachaturian et al., 1985; Itoh et al., 1993; Wagner et al., 1993; Weisskopf etal., 1993.) Of course, the cardiovascular, antinociceptive, and mnemonic effects of Dyn A and related peptides may be interdependent and involve the stimulation of common CNS nuclei (Holaday, 1983). It may also be important to mention that most studies concerning the central distribution of Dyn A and related peptides do not provide information about the projections of Dyn-containing neurons, and no data are yet available on the CNS distribution of Dyn-specific nonopioid binding sites (Dumont

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Michel Durnont and Simon Lernaire

and Lemaire, 1993; Shukla and Lemaire, 1994). The multiplicity of Dyncontaining brain nuclei combined with the large number of Dyn binding sites (opioid and nonopioid) may explain the diversity of biological responses, including those that relate to the modulation of cardiovascular functions.

B. Central Cardiovascular Effects of Dynorphin Dyn A and related peptides can induce profound changes in cardiovascular parameters when injected into the CNS (Table I). Opposing cardiovascular effects are observed depending on the animal species, the state of consciousness of the animal, and the site of administration of the peptide. In anesthetized animals, administrations of Dyn A (Feuerstein and Faden, 1984), Dyn A-(1-13) (Feuerstein and Faden, 1982; Laurent and Schmitt, 1983; Hassen et al., 1984; Punnen and Sapru, 1986; van Giersbergen et al., 1991; Rabkin, 1993),and/or K opioid benzomorphans (Laurent and Schmitt, 1983; Wu and Martin, 1983; Hassen et al., 1984) in the ventricles (i.c.v.), the MPN and PEVN nuclei of the hypothalamus, the AHA, the NTS, the NA nucleus of the brainstem, the cisterna magna (CM), and the pressor (VLPA)area of the ventrolateral medulla cause naloxone-reversible hypotension and bradycardia. However, microinjections of Dyn A-(1-13) in the depressor (VLDA) area of the ventrolateral medulla produce naloxonereversible hypertension and tachycardia (Punnen and Sapru, 1986).In addition, Dyn A-( 1-13)and the K opioid agonist, U-50488H, microinjected in the NTS, induce pressor and bradycardic responses antagonized by the K opioid antagonist, MR-2266 (Carter and Lightman, 1985). Interestingly, these latter effects are also antagonized by the selective AVP-VI antagonist, d(CHJSTyr(Me)AVP,and they are not observed in the AVP-deficient Brattleboro rats. These data suggest that the pressor effects of Dyn A-(1-13) and K opioid compounds, when injected in the NTS, are mediated by APV, a peptide that is released on stimulation of the K opioid receptor (Carter and Lightman, 1985). In conscious animals, i.c.v. administrations of Dyn A, Dyn A-(1-13) (Holaday et al., 1984; Saunders and Thornhill, 1987; Glatt et al., 1987; Overton and Fisher, 1989) and the K benzomorphan derivative, MRZ-2549 (Pfeiffer et al., 1983b),evoke pressor and tachycardic responses that are antagonized by naloxone and MR-2266. However, these hemodynamic responses are accompanied by profound changes in behavior, including wet dog shakes, barrel rolling, and increased feeding and grooming (Saunders and Thornhill, 1987; Glatt et al., 1987). Thus, the pressor and tachycardic effects observed in conscious rats may be due to behavioral activation. On the other hand, leumorphin, a naturally occurring proDynderived peptide, produces a naloxone-reversible fall in blood pressure after i.c.v. administration in conscious rats (Itoh et al., 1988). Taken together, these data indicate that central administrations of Dyn A and related peptides produce both hypotension and hypertension, depending on the site of injec-

Dynorphin and the Cardiovascular System

5

tion and the state of consciousness of the animal. A contribution of the APV-V, receptor in the pressor effects of the peptide can also be considered. Intrathecal (i,t.) administration of Dyn A and Dyn A-(1-13) into lower thoracic spinal segments in either anesthetized or conscious animals produces hypertension accompanied by either tachycardia (anesthetized animals: Thornhill et al., 1989a; Rochford et al., 1991) or bradycardia (conscious animals: Thornhill and Pittman, 1990) (Table I). Interestingly, the pressor and tachycardic responses obtained in anesthetized animals are not antagonized by the selective K opioid antagonist, norbinaltorphimine (norBNI) (Rochford et al., 1991). Moreover, these hemodynamic changes are mimicked by Dyn A-(3-13), a nonopioid form of Dyn A, suggesting that the pressor and tachycardic responses elicited by i.t. administration of Dyn A in anesthetized animals are mediated by a nonopioid mechanism. On the other hand, the pressor and bradycardic responses observed in conscious animals are blocked by the K opioid antagonist, MR-2266 (Thornhill and Pittman, 1990). The difference in opioid antagonism may be explained by the different state of consciousness of the animals or by the different techniques used to block the action of the opioid peptide, i.e., i.t. infusion versus bolus injection of opioid antagonists. In conscious rats, the blockade of the effects of Dyn A-(1-13) by i.t. infusion of MR-2266 was not observed with bolus administration of the compound. It is possible that the hemodynamic effects of i.t. Dyn A and related peptides are mediated by both opioid and nonopioid mechanisms. Studies have indicated that i.t. administration of Dyn A-(1-13) causes local ischemia by a nonopioid mechanism (Thornhill et al., 1989a; Long et al., 1994). Ischemia, in turn, may induce a cascade of events leading to the release of exitatory amino acids, such as glutamate and aspartate (Benveniste et al., 1984), and a concomitant rise in blood pressure.

111. The Peripheral Dynophinergic System

A. Peripheral Localization of Dynorphin and K

Opioid Receptors

Dyn A and K opioid receptors are present in tissues that constitute the peripheral cardiovascular system. These include the adrenal glands, the kidneys, and the heart. In the rat adrenal gland, the levels of ir-Dyn A are relatively low and are confined to the cortex (Day et al., 1991). Higher levels of ir-Dyn A are found in bovine adrenal glands, being more concentrated in norepinephrine-containing chromaffin cells (Dumont et al., 1983). In the rat adrenal gland, the K opioid receptor is seen in the cortex (Quirion et al., 1983), whereas in bovine adrenal gland, it is observed on nerve tracks and epinephrine-containing cells of the medulla (Bunn et al., 1988). Rat kidneys contain both ir-Dyn A and the K opioid receptor. The levels of ir-Dyn A in

b

TABLE I Effects of Dynorphin A, Related Peptides, and

K

Opioid Analgesics on Blood Pressure and Heart Rate"

Compound

Species

Route

Anesthetic

Central conscious Dyn A

SD rats

Dyn A-(1-13)

SD rats

i.c.v. i.t. i.c.v. i.c.v. i.c.v. i.c.v. i.t.

Conscious Conscious Conscious Conscious Conscious Conscious Conscious Conscious Conscious Conscious Conscious Conscious Conscious Conscious Conscious

Dyn A-(1-10) Dyn A-(1-8) Dyn B a-Neo-End /3-Neo-End Leumorphin MR-2034 MRZ-2549 Central anesthetized Dyn A

SD rats SD rats SD rats SD rats SD rats W rats SD rats SD rats SD rats

1.t.

i.c.v. 1.t.

1.t. 1.t.

i.c.v. AHA i.c.v. MPN 1.t.

Dyn A-(l-l3)

SD rats

MPN MPN PEW NTS NTS NA i.t. i.t.

Pentobarbital Urethane Pentobarbital Pentobarbital Pentobarbital Pentobarbital Urethane Pentobarbital Urethane Inactin

Blood pressure

T T T

t t

Heart rate

t

1

NC

t

NC

NC

t

NC NC NC NC NC NC

NC NC NC NC NC ND NC

.1 t .1 .1

-1 t 1 J.

1

NC

1

NC

f

ND

t

.1

t

1

t

t

1

t

1 J.

T

Opioid antagonism

Reference

ND ND ND Yes ND ND Yes Yes Yes

Overton and Fisher (1989) Thornhill and Pittman (1990) Holaday e i al. (1984) Saunders and Thornhill (1987) Glatt et al. (1987) Overton and Fisher (1989) Thornhill and Pittman (1990) Thornhill and Pittman (1990) Overton and Fisher (1989) Thornhill and Pittman (1990) Thornhill and Pittman (1990) Thornhill and Pittman (1990) Itoh et al. (1988) Pfeiffer et al. (1983a) Pfeiffer et al. (1983b)

ND No ND Yes Yes ND ND ND No No

Feuerstein and Faden (1984) Rochford et al. (1991) Feuerstein and Faden (1984) Feuerstein and Faden (1982) Feuerstein and Faden (1982) Hassen et al. (1984) Carter and Lightman (1985) Hassen et al. (1984) Rochford et al. (1991) Thornhill et al. (1989a)

SD rats LE rats HOB

CM i.c.v. i.c.v. VLPA VLDA AHA PHA NTS i.t. MPN NTS NA NA NTS CM NA NA NTS NTS NTS NTS

Urethane Urethane Pentobarbital Urethane Urethane Pentobarbital Pentobarbital Pentobarbital Urethane Pentobarbital Pentobarbital Pentobarbital Pentobarbital Pentobarbital Urethane Decerebrate Pentobarbital Pentobarbital Urethane Urethane Urethane

SD rats

1.v.

Conscious Conscious Conscious Conscious Conscious Conscious Conscious Conscious Conscious

W rats

Dyn A-(l-8)

SD rats

Bremazocine

SD rats

EKC

W rats Dog SD rats

MRZ-2549 U-50488H Peripheral conscious Dyn A - ( l - l 3 )

1.v.

HEB rats HOB rats FE lamb

i.v. I.V. i.v. S.C. i.v. i.v. i.v.

1

1 1 1

1 1

I t

I T

.1

1

NC

NC

I 1

1

1

1

NC NC

NC NC NC

NC

NC

I

1

.1

1

1 NC

t

1

1

NC

t 1

1

T 1

ND

t

1

1

NC NC NC

T T

1

NC

t

T T

1 I

1 .1

1

Yes Yes Yes Yes Yes Yes Yes ND ND No Yes Yes No Yes Yes Yes ND

Laurent and Schmitt (1983) vanGiersbergen et al. (1991) Rabkin (1993) Punnen and Sapru (1986) Punnen and Sapru (1986) Rabkin (1993) Rabkin (1993) Rabkin (1993) Xie et al. (1986) Feuerstein and Faden (1984) Hassen et al. (1984) Hassen ei al. (1984) Hassen et al. (1984) Hassen et al. (1984) Laurent and Schmitt (1983) Wu and Martin (1983) Hassen et a[. (1984) Hassen et al. (1984) Carter and Lightman (1985) Carter and Lightman (1985) Carter and Lightman (1985)

Yes No No ND ND

Thornhill et al. (1989b) Thornhill et al. (1990) Dixon and Chang (1990) Holaday et al. (1984) Glatt et al. (1987) Holaday ei al. (1984) Thornhill et al. (1990) Thornhill et al. (1990) Dunlap and Valego (1989)

-

No No ND

(continues )

TABLE I (continued)

Compound

Species

Peripheral anesthetized Dyn A Dyn A-(1-13)

PSD rats W rats PW rats HEB rats HOB rats P rabbit

Dyn A-(l-10)NH2 Bremazocine

EKC

W rats SD rats Rabbit P rabbit

W rats

Route

I.V.

i.v. i.v. i.v. i.v. i.v. inf. inf. J.V. i.v. I.V. inf. inf. I.V. 1.v.

S pirado1ine

Tifluadom U-50488H

PW rats Dog Rabbit Cat Dog SD rats Rabbit SD rats Dog Rabbit

i.v. i.v. i.v. i.v. i.v. I.V.

i.v. i.v. i.v. i.v.

Anesthetic

Halothane Pentobarbital Urethane Pento barbital Pentobarbital Pentobarbital Pentobarbital Pentobarbital Urethane Urethane Halothane Pentobarbital Pentobarbital Pentobarbital Urethane Pentobarbital Decerebrate Halothane Chloralose Pentobarbital Urethane Halothane Urethane Pentobarbital Halothane

Blood pressure

1 1

Heart rate

NC

-1

NC

NC

t

t

NC NC

-1 1

ND ND

-1

NC ND ND

1

1

1

1 -1

1

NC NC

-1

1

1

1 .1

1

NC

1 1 1

NC

NC

1

1 1 1

1

1

-1 -1 1

1

1

I

Opioid

antagonism

No Yes Yes No No Yes Yes Yes ND Yes Yes Yes Yes Yes Yes Yes Yes ND Yes Yes Yes Yes

Reference

Eirmel and Feuerstein (1986) Gautret and Schmitt (1985) Laurent and Schmitt (1983) Gautret and Schmitt (1985) Thornhill et al. (1990) Thornhill et al. (1990) Szabo et al. (1988) Szabo et al. (1986) Xie et al. (1988) Gulati and Bhargava (1988) Clarke and Ford (1987) Szabo et al. (1986) Ensinger e t a [ . (1986) Gautret and Schmitt (1984) Laurent and Schmitt (1983) Gautret and Schmitt (1984) Wu and Martin (1989) Clarke and Ford (1987) Hall et al. (1988) Hall et al. (1988) Gulati and Bhargava (1988) Clarke and Ford (1987) Gulati and Bhargava (1988) Hall et al. (1988) Clarke and Ford (1987)

Dyn, dynorphin; SD, Sprague-Dawley; W, Wistar; HEB, heterozygous Brattelboro; HOB, homozygous Brattelboro; FE, fetal; P, pithed; LE, Long-Evans: i.c.v., intracebroventricular; i.t., intrathecal; i.v., intravenous; s.c., subcutaneous; MPN, medial preoptic nucleus; P E W , periventricular nucleus; NTS, nucleus tractus solitarius; NA, nucleus ambiguus; CM, cisterna magna; VLPA, ventrolateral pressor area; VLDA, ventrolateral depressor area; AHA, anterior hypothalamic area; PHA, posterior hypothalamic area: T, increase; 1, decrease, NC, no change; ND, not determined.

Dynorphin and the Cardiovascular System

9

the kidneys are relatively low as compared with those of the adrenal glands, but they are detectable (Maysinger et al., 1982). The K opioid receptor at this level is more concentrated in the cortex than in the outer and inner parts of the medulla (Quirion et al., 1983). Ir-Dyn A is also present in the heart (Spampinato and Goldstein, 1983; Weihe et al., 1985; Bhargava et al., 1988; Dumont et al., 1990; Spampinato et al., 1991). The cardiac peptide is mainly present in sympathetic nerve terminals. It disappears after chemical sympathectomy (Weihe et al., 1985; Wegener and Kummer, 1994). Moreover, cardiac proDyn mRNA is also observed in ventricular cardiomyocytes (Pittius et al., 1987; Canossa et al., 1993). Ventricular proDyn mRNA can be induced in vitro by K' (Ventura et al., 1994). However, its in vivo expression and translation into proDyn have not yet been assessed and may occur mainly under pathophysiological conditions, such as hypertension, cardiac myopathies, or myocardial infarction (Dumont et al., 1990). On the other hand, cardiac K opioid receptors are observed on both sympathetic nerve terminals (Ledda et al., 1985; Starke et al., 1985; Fuder et al., 1986) and cardiomyocytes (Mantelli et al., 1986; Ventura et al., 1991a,b; 1992; Tai et al., 1992),indicating that cardiac Dyn A and related peptides may subserve local functions. 6. Cardiovascular Effects of Circulating Dynorphin

Intravenous (i.v.) administrations of Dyn A-(1-13)(Gautret and Schmitt, 1985), Dyn A-(1-10)amide (Xie et al., 1988),and K opioid ligands (Gautret and Schmitt, 1984; Clarke and Ford, 1987; Wu and Martin, 1988; Gulati and Bhargava, 1988; Hall et al., 1988) in anesthetized animals produce hypotension associated with bradycardia, both responses being blocked by naloxone and MR-2266 (Table I). Interestingly, these effects are also observed in pithed rats (Gautret and Schmitt, 1985; Eirmel and Feuerstein, 1986) and rabbits (Ensinger et al., 1986; Szabo et al., 1986, 1988) and are blocked by adrenal demedullation and naltrexone methyl bromide (Gulati and Bhargava, 1988), a quaternary opioid antagonist that does not pass the blood-brain barrier. Thus, the depressor effects of i.v. administration of these compounds in the rat involve the stimulation of peripheral opioid receptors and the participation of the adrenal medulla. However, in conscious animals, i.v. administration of Dyn A-( 1-13)evokes hypertension and bradycardia (Thornhill etal., 1989b, 1990; Dunlap and Valego, 1989; Dixon and Chang, 1990). These latter effects are not antagonized by MR-2266 but by the AVP-V1 antagonist, d(CHJS Tyr(Me)AVP(Dunlap and Valego, 1989; Thornhill etal., 1990),suggesting a possible interaction of Dyn A with the AVP-Vl receptor. To demonstrate if such interaction exists, Thornhill et al., (1989b)have used the AVP-deficient Brattelboro rats. They have shown that the pressor effect of Dyn A-(1-13) is antagonized by d(CH2),Tyr (Me)AVPin both control and AVP-deficient Brattelboro rats. They conclude

10

Michel Dumont and Simon Lemaire

that such effect does not involve the release of AVP but rather a direct interaction of the opioid peptide with the AVP-V, receptor. Taken together, these data indicate that i.v. administration of Dyn A-(1-13)in rats evokes both depressor and pressor effects, depending on the state of consciousness of the animal, and these effects are most likely mediated by opioid and nonopioid receptors, respectively. The nonopioid pressor effect of the peptide may involve the participation of the AVP-V, receptor. C. Effects of Dynorphin on Blood Vessels 1. Presence of Dyn in Blood Vessels

A role for Dyn on the autonomic functions of the vasculature is suggested by the presence of ir-Dyn A and ir-Dyn B in nerve fibers within the walls of cerebral arteries and within the walls of systemic blood vessels (arteries and veins) from human and other species (Moskowitz et al., 1986, 1987; Tong et al., 1994). More detailed studies in the guinea pig uterine artery (Morris et al., 1985) and small cutaneous blood vessels (Gibbins and Morris, 1990) showed the presence of ir-Dyn A in nonadrenergic-vasoactive intestinal polypeptide (VIP)-neuropeptideY (NPY), noradrenergic-NPY, and noradrenergic axons. Hardebo et al. (1994)demonstrated that ir-Dyn B coexists with substance P and calcitonin-gene-related peptides as well as with VIP in sensory and parasympathetic nerves innervating pial arteries from guinea pig. 2. Opioid Inhibition of Sympathetic Nerve Activity

The effects of Dyn A and related peptides on blood vessels mainly pertain to the stimulation of K opioid receptors and a concomitant inhibition of the release of norepinephrine from sympathetic nerve terminals. Dyn A, related peptides, and K opioid analgesics inhibit the contractile responses induced by electrical field stimulation in the rat mesenteric (Nguyen et al., 1991) and tail (Illes et al., 1987) arteries, dog mesenteric artery (Sun and Zhang, 1985), and rabbit mesenteric (Nguyen et al., 1991), pulmonary (Seelhorst and Starke, 1986), ear (Berzetei et al., 1988; Illes et al., 1984), jejunal (Ramme etal., 1986),and ileocolic (vonKiigelgen etal., 1985) arteries and portal vein (Szabo et al., 1987). In addition, K opioid ligands also inhibit the release of [3H]norepinephrinefrom electrically stimulated rabbit pulmonary (Seelhorst and Starke, 1986), ear (Berzetei et al., 1988; Illes et al., 1984), jejunal (Ramme et al., 1986), and ileocolic (von Kiigelgen et al., 1985) arteries and portal vein (Szabo et al., 1987). The inhibitory effects of Dyn A-(1-13) and K opioid ligands are antagonized by naloxone. In contrast, the contractile responses to exogenously applied norepinephrine are not inhibited by these opioid compounds (Illes et al., 1987; Seelhorst

Dynorphin and the Cardiovascular System

II

and Starke, 1986; vonKiigelgen et al., 1985). In pithed rabbits, Dyn A-(113) inhibits the rise in blood pressure induced by electrical stimulation of the sympathetic outflow but not that induced by exogenous norepinephrine (Ensinger et a/., 1986; Szabo et al., 1986, 1988). These data indicate that the postganglionic sympathetic axons present in peripheral arteries and veins possess presynaptic K opioid receptors that, when stimulated by Dyn A or K opioid analgesics, modulate the release of norepinephrine from the nerve terminals. 3. Nonopioid Modulation of Vascular Muscle Activity

Binding studies confirmed the presence of the K opioid receptor in blood vessels (Sun et al., 1983; Sun and Zhang, 1985). However, some of the effects of K opioid agonists on vascular smooth muscles may also involve an interaction with nonopioid binding sites. Interestingly, Dyn A (Chen et al., 1991) and K opioid agonists (Altura et al., 1984) contracted cerebral blood vessels. The Dyn A-induced contractions were mimicked by Dyn A(2-17),an inactive opioid peptide, and antagonized by (+)-3-hydroxyphenyl propyl piperidine [( +)-3-PPP], a cr receptor ligand, but not by nalmefene, a K opioid antagonist (Chen et al., 1991). A direct interaction of Dyn A with c opioid receptors has already been observed (Lemaire and Dumont, 1992). Moreover, the contractile response produced by K opioid analgesics in cerebral blood vessels was prevented by preincubation with PCP, a noncompetitive NMDA receptor antagonist (Altura et al., 1984). In addition, Dyn A-(1-13)caused naloxone-insensitive and norBNI-insensitive increases in tension of isolated rat descending thoracic aortae (Thornhill and PowellJones, 1987) and rat tail artery (Wong and Ingenito, 1995). Dyn A-(1-13) increased basal tone and the magnitude of electrically induced contraction response in rat tail artery (Wong and Ingenito, 1995). However, the slow development of the potentiation of the contraction in response to Dyn A(1-13) led the authors to suggest the possible involvement of a subcellular mechanism, such as the mobilization of Caz+from the sarcoplasmic reticulum (Wong and Ingenito, 1995). Thus, vascular smooth muscles possess both opioid and nonopioid receptors for Dyn A and related peptides. Stimulation of presynaptic K opioid receptors inhibits the release of norepinephrine and causes vasodilatation, whereas the stimulation of presynaptic or postsynaptic nonopioid receptors may induce vasoconstriction. Vasoconstriction may also result from an inhibition of norepinephrine reuptake by sympathetic nerve terminals. A nonopioid interaction of Dyn A with the (T receptor would explain such effect, since (T compounds are potent inhibitors of the uptake of norepinephrine by brain synaptosomes (Rogers and Lemaire, 1991; Massamiri and Piper Duckles, 19911, tail artery (Massamiri and Piper Duckles, 1991), and adrenal chromaffin cells (Rogers and Lemaire, 1991).

12

Michel Dumonc and Simon Lemaire

D. Cardiac Effects of Dynorphin 1. Presence of Dyn in the Heart

The presence of Dyn A in the heart was first reported by Spampinato and Goldstein (1983). Since then, several laboratories have confirmed the presence of Dyn A and related peptides in rat heart (Bhargava et al., 1988; Dumont et al., 1990) and in the heart of other species, such as the guinea pig (Weihe et al., 1985; Archelos et al., 1987; Spampinato et al., 1991),the rabbit (Spampinato et al., 1991), the porcine (Pittius et al., 1987), and humans (Spampinato et al., 1991). In rat and human hearts, Dyn A and related peptides are mainly present under precursor forms (proDyn),whereas in guinea pig and rabbit hearts, they are processed peptides (Dyn A, Dyn B, a-neo-End) (Spampinato et al., 1991). The levels of proDyn peptides in the atria are higher than in the ventricles. Such localization was first assessed by radioimmunoassay (Weihe et al., 1985; Spampinato et al., 1991) and later confirmed by immunohistochemistry (Archelos et al., 1987; Wegener and Kummer, 1994). In these latter studies, ir-a-neo-End-containing nerve fibers were shown to mainly supply the arteries and myocytes of the atria. No ir-a-neo-End nerve fiber was seen in the sinoatrial and atrioventricular nodes. Dyn A and a-neo-End ir-nerve fibers disappeared in response to chemical sympathectomy (6-OH-dopamine treatment), as did the cardiac contents of Dyn A-(1-8) and a-neo-End, suggesting that these peptides are contained in postganglionic sympathetic nerve fibers innervating coronary blood vessels and cardiac muscles. On the other hand, proDyn mRNA was also observed in porcine atria and ventricles (Pittius et al., 1987) and isolated rat cardiomyocytes (Canossa et al., 1993; Ventura et al., 1994). 2. Cardiac Opioid and Nonopioid Receptors for Dynorphin

The presence of opioid receptors in the heart was first reported in the late 1970s and early 1980s (Simantov et al., 1978; Burnie, 1981). However, the first study mentioning the presence of the K opioid receptor in the heart appeared in 1985. This article indicated that etylketocyclazocine displaces the specific binding of the nonselective opioid antagonist, t3H]diprenorphine, from rat heart membranes (Krumins et al., 1985). Using the more selective K opioid ligand, [3H]U-69593, our laboratory (Dumont et al., 1990) and others (Ventura et al., 1989; Tai et al., 1991; Xia et al., 1994) confirmed the presence of the K opioid receptor on cardiac membrane preparations. The K opioid receptor is not evenly distributed in the heart, being mostly concentrated in the right atrium (Tai et al., 1991). Subcellular localization studies showed the presence of a postsynaptic K opioid receptor on the cardiac sarcolemmal membranes (Ventura et al., 1989), whereas studies with isolated atria and ventricles have demonstrated the presence of a presynaptic K opioid receptor on noradrenergic nerve terminals (Starke et al., 1985; Fuder et al., 1986; Mantelli et al., 1986).

Dynorphin and the Cardiovascular System

13

More recently, the presence of low-affinity, high-capacity nonopioid binding sites for [3H]Dyn A-(1-13) was also demonstrated in rat heart (Dumont and Lemaire, 1993). These sites were sensitive to nonopioid Nterminally truncated Dyn A-(1-13) fragments, such as Dyn A-(2-13) and Dyn A-(3-13) but were insensitive to selective ligands for p, 8, and K opioid receptors and PCP and u receptors. The rank order of potency of various analogs and fragments of Dyn A in displacing the binding of [3H]Dyn A-( 1-13) to heart membrane preparations (Dumont and Lemaire, 1993) paralleled their potency in inhibiting the uptake of [3H]norepinephrine by cardiac synaptosomes (Dumont and Lemaire, 1995) and the binding of [3H]~uabain to cardiac sarcolemma membranes (unpublished observations). Dyn A-(1-13) interacted selectively and noncompetitively with the lowaffinity binding site, a site that corresponds to the a1 subunit of Nat-K+ATPase. Thus, whereas the stimulation of K opioid receptors by Dyn A and related peptides is usually ascribed to the modulation of sympathetic nerve activity, the stimulation of nonopioid Dyn A binding sites may lead to inhibition of Nat-K+-ATPase activity and blockade of norepinephrine uptake, resulting in pressor and tachycardic responses. The contraction of cerebral blood vessels (Chen et al., 1991), thoracic aortae (Thornhill and Powell-Jones, 1987), and tail artery (Wong and Ingenito, 1995) and the inhibition of Na+-K+-ATPase(Maeda et al., 1988) and norepinephrine uptake (Dumont and Lemaire, 1995) in response to Dyn A may then be mediated by the stimulation of Dyn-specific nonopioid receptors. 3. Cardiac Effects of Dynorphin and

K

Opioid Compounds

Dyn A and related peptides were reported to cause multiple effects on the heart (Table 11).These were mediated by the stimulation of presynaptic and postsynaptic receptors of both opioid and nonopioid natures. With guinea pig isolated atria and ventricles, rat isolated hearts and rabbit hearts, Dyn A-(1-13),related peptides, and K opioid benzomorphans were shown to inhibit electrically induced contractions. [3H]-norepinephrine efflux, and heart rate (Starke et al., 1985; Fuder et al., 1986; Mantelli et al., 1986; Archelos et al., 1987; Xia et al., 1994).These inhibitory effects were antagonized by naloxone and MR-2266. However, the contractile and inotropic effects of exogenous norepinephrine were not inhibited by Dyn A and other K opioid agonists (Ledda et al., 1985; Starke et al., 1985; Mantelli et al., 1986). A local action of Dyn-related peptides at the myocardial level is supported by the fact that intracoronary injection of Dyn A-(1-9) in the dog results in a decrease in the left ventricular contractile force (Caffrey et al., 1985). Furthermore, Dyn A and other K opioid ligands inhibit fieldstimulated induced contractions in isolated left ventricular myocytes (Ventura et al., 1992). At the cellular level, K opioid receptor-mediated effects include stimulation of atrial natriuretic peptide (ANP) secretion (Tang et al., 1987; Stasch et al., 1989; Yamada et al., 1991), activation of NAD(P)H-

TABLE II Effects of Dynorphin A, Related Peptides, and Compound

Species

Cardiac preparation

Dyn A

N rats

Atrial cardiocytes

SD rats W rats

Sarcolemmal membranes Ventricular myocytes Cardiac synaptosomes Sarcolemmal membranes Isolated atria

Dyn A-(1-13)

Bovine G Pig

Isolated ventricles SD rats

Dyn B

W rats W rats

Isolated atria Isolated heart Ventricular myocytes Sarcolemmal membranes Cardiac synaptosomes Cardiac synaptosomes

K

Opioid Analgesics on Cardiac Functions"

Effects

t

ANP secretion; .1 CAMP production .1 Na+-K+-ATPase .1 Inotropic response .1 ['HI-NE uptake .1 NAD(P)H dehydrogenase 4 ['HI-NE efflux .1 Inotropic response .1 Inotropic response .1 Inotropic response .1 Inotropic response t Inotropic response Cardiac arrythmias; T CAMP production t Intracellular CaZ+ 1 Na+-K+-ATPase .1 ['HI-NE uptake 1 ['HI-NE uptake

Opioid antagonism

References

Yes

Yamada et al. (1991)

No ND No Yes ND Yes ND ND Yes No Yes

Maeda et al. (1988) Ventura et al. (1992) Dumont and Lemaire (1995) Ventura et al. (1988) Fuder et al. (1986) Ledda et al. (1985) Ledda et al. (1989) Ledda et al. (1989) Mantelli et al. (1986) Maeda et al. (1987) Lee and Wong (1987a); Wong and Lee (1987) Tai et al. (1992) Maeda et al. (1988) Dumont and Lemaire (1995) Dumont and Lemaire (1995)

Yes No No No

Rabbit G Pig SD rats

Cardiac synaptosomes Cardiac synaptosomes Isolated atria Atria Heart Isolated atria Isolated atria Isolated atria Sarcolemmal membranes Isolated heart Isolated atria Isolated heart

W rats

Ventricular myocytes Ventricular myocytes

a-Neo-End Dyn A-(2-13) Dyn A-(l-10)HH2

W rats W rats W rats

Dyn A-(1-9) Ala2-Dyn A-( 1-9) EKC

M dogs G Pig G Pig SD rats

MR-2033 U-50488H

U-62066E a

N rats

Atrial cardiocytes

.1 [ W - N E uptake .1 [3H]-NEuptake t ANP secretion .1 ANP levels .1 LVCF

J. Inotropic response

.1 [3H]-NEefflux f Inotropic response 1 NaC-Kt-ATPase 4 Heart rate 4 [3H]-NEefflux Cardiac arrythmias 3 Heart rate .1 Force of contraction T Intracellular Ca” T Cytosolic pH; T intracellular CaZt -1 Inotropic response T IPj formation f ANP secretion

No No Yes Yes Yes Yes Yes No No Yes Yes Yes Yes Yes Yes Yes

Dumont and Lemaire (1995) Dumont and Lemaire (1995j Stasch et al. (1989) Tang et al. (1987) Caffrey et al. (1985) Archelos et al. (1987) Fuder et al. (1986) Maeda et al. (1987) Maeda et al. (1988) Starke et al. (1985) Fudar et al. (1986) Wong et a[. (1990) Xia et al. (1994) Xia et al. (1994) Tai et al. (1992) Ventura et al. (1991b)

Yes Yes Yes

Ventura et al. (1992) Ventura et al. (1991a, 1992) Yamada et al. (1991)

Dyn, dynorphin; N, neonatal; SD, Sprague Dawley; W, Wistar; WKY, Wistar Kyoto; SHR, spontaneously hypertensive; G, guinea; M, mongrel; ANP, atrial natriuretic peptide; NE, norepinephrine; LVCF, left ventricular contractile force; f , stimulation; .1 , inhibition.

I4

Michel Oumont and Simon Lemaire

vanadate dehydrogenase (Ventura et al., 1988), and increases in myocardial cytosolic pH (Ventura et al., 1991b) in inositol phosphate (IP3) (Ventura et al., 1991a, 1992). Dyn A, related peptides, and K opioid ligands can also produce nonopioid effects on the heart. These include the positive inotropic response in isolated rat atria (Maeda et al., 1987), inhibition of rat sarcolemma1 Na+-K+-ATPase(Maeda et al., 1988), and inhibition of synaptosomal norepinephrine uptake (Dumont and Lemaire, 1995).

IV. Dynorphin and Cardiovascular Pathologies

A. Circulatory Shock A role for endogenous opioid peptides in circulatory shock was initially proposed from experiments showing that naloxone improves cardiovascular functions and survival in animal models of endotoxic (Holaday and Faden, 1978; Faden and Holaday, 1980; Holaday et al., 1984), and hemorrhagic shocks (Faden and Holaday, 1979; Vargish et al., 1980; Curtis and Lefer, 1980). The hypotension associated with i.v. administration of Escherichia coli lipopolysaccharide endotoxin was reversed by the specific S opioid antagonist, ICI 154129, suggested that the 6 opioid receptor is involved in the pathophysiology of endotoxic shock (Holaday et al., 1982; D’Amato and Holaday, 1984). In addition, several studies indicate that Dyn A and K opioid receptors are involved in hemorrhagic shock. Thus, the K opioid antagonist, WIN 44,441-3, improved cardiovascular functions in hypovolemic cats (Curtis and Lefer, 1982). Twenty-four hours after hemorrhagic shock, a time when blood pressure has returned to a normal value, a decrease in Dyn A levels and a concomitant increase in Leu-Enk were observed in the neurointermediate lobe (NIL) of rat pituitary (Feuerstein et al., 1984b, 1985a). The decrease in Dyn A corresponded to an increase in the density of K opioid receptors in the brainstem (Feuerstein et al., 1984a). In the NIL of the pituitary, Dyn A is colocalized with AVP (Watson et a]., 1982), and under physiological conditions, autoinhibition of AVP release most likely occurs via the stimulation of K opioid receptors (Leander, 1983). Feuerstein et al. (1984b, 1985a) have postulated that hemorrhagic shock induces the conversion of Dyn A to Leu-Enk. During hemorrhagic shock, decreased levels of Dyn A are associated with a reduced activity of this particular opioid peptide system in the NIL, thereby increasing plasma AVP. On the other hand, increased levels of Leu-Enk may ensure the recovery of blood pressure via the stimulation of 6 opioid pressor sites in the CNS (Pfeiffer et al., 1983a). The spontaneous recovery of blood pressure after bleeding may be due to a reduced K opioid receptor-mediated depressor effect combined with increased 6 opioid and AVP-VI receptor-mediated pressor effects. This hypothesis is supported by the observation that central administra-

Dynorphin and the Cardiovascular System

17

tion of U-50488H suppresses the spontaneous recovery of blood pressure after hemorrhage (Feuerstein et al., 1985b), whereas i.v. injection of [DAla2-D-Leu5]-Enk,a 6 opioid agonist, accelerates the rate of normalization of blood pressure (Slepushkin and Grassler, 1986). The beneficial effects of K opioid antagonists in the treatment of endotoxic shock may be due to their blockade of the K opioid receptor-mediated depressor system located in the NIL and the peripheral sympathetic nervous system. 9. Hypertension

The first observations evoking a possible link between hypertension and endogenous opioid systems came from studies on pain sensitivity. It was shown that hypertensive humans (Zamir and Shuber, 1980; Ghione et al., 1988) and animals (Zamir and Segal, 1979; Saavedra, 1981; Maixner et al., 1982; Naranjo and Fuentes, 1985) have a higher tolerance to noxious stimuli, suggesting that elevated levels of endogenous opioid peptides accompany hypertension. Furthermore, opioid antagonists administered i.v. in anesthetized rats (Quock et al., 1985) and i.c.v. in conscious rats (Delbarre et al., 1982; Levin et al., 1986) decrease blood pressure in spontaneously hypertensive rats (SHR) but not in their normotensive counterpart, Wistar Kyoto rats (WKY).The hypothesis that endogenous opioid peptides contribute to the development of hypertension was further supported by the fact that opioid antagonists retard the development of high blood pressure in different models of hypertension, including the SHR rat (Quock et aL, 1984; Kraft etal., 1991a,b), the two-kidneys one-clip Goldblatt rat (Szilagyi, 1988; Chen et al., 1990), the one-kidney one-clip dog (Szilagyi et al., 1986), the Dahl salt-sensitive rat (Johnson and Richmond, 1992), the Doca salthypertensive rat (Zhai and Malvin, 1991), and the stress-induced hypertensive rat (Florentino et al., 1987; Szilagyi, 1991). One interesting study demonstrates that the K opioid antagonists, MR-2266 and MR-1452, are able to retard the development of hypertension in SHR rats (Kraft et al., 1991a). In addition, increased levels of K opioid receptors are found in the cortex and hypothalamus of SHR as compared with WKY rats (Bhargava and Das, 1986; Bhargava and Gulati, 1988). Further evidence for a role of Dyn A in hypertension is provided by several studies that indicate that the levels of ir-Dyn A in various parts of the brain (Feuerstein et al., 1983; Kouchich et al., 1984; Li et al., 1989) and peripheral tissues (Bhargava et al., 1988; Dumont et al., 1990) are changed in SHR as compared with WKY rats. For instance, the levels of Dyn A in the hypothalamus and NIL of the pituitary of SHR are particularly low (Feuerstein et al., 1983; Kouchich et al., 1984; Li et al., 1989). As mentioned for hemorrhagic shock, a decrease in the levels of Dyn A in these regions may correspond to a reduced K opioid receptor-mediated depressor mechanism, leaving the AVP pressor system unopposed by the opioid peptide. This is likely to increase blood pressure.

18

Michel Dumont and Simon Lernaire

Therefore, the hypertensive state in SHR rats may, in part, be due to a reduction of the depressor effect of central K opioid receptor stimulation. Our laboratory has investigated the role of cardiac Dyn A in the development of hypertension in SHR rats. A marked transitory increase in the cardiac levels of Dyn A was observed in the initial phases (4- and 8-weekold SHR rats) of hypertension (Dumont et al., 1990). In older animals (16week-old rats), in which hypertension is fully established, a decrease in cardiac Dyn A levels was observed, concomitant with an increase in LeuEnk levels (Dumont et al., 1990; Dumont and Lemaire, 1988).The increase in Leu-Enk levels was thought to be due to the processing of Dyn A, since it corresponded to the decrease in Dyn A levels, and little or no processing of cardiac proEnk is expected to occur based on the high Leu-EnWMet-Enk ratio, a ratio that does not correspond to the content of these peptides in proEnk (Weihe et al., 1985). The decrease in the cardiac levels of Dyn A in 16-week-old SHR rats was not accompanied by any change in the density of the cardiac K opioid receptor but rather by a downregulation of the low-affinity 6 opioid binding site (Dumont and Lemaire, 1988; Dumont et al., 1990). Based on these data, cardiac Dyn A and related peptides are suggested to induce two opposite effects: hypertension and hypotension. The hypotensive effect may result from presynaptic or postsynaptic K opioid receptor stimulation, leading to inhibition of norepinephrine release from sympathetic nerve terminals (Ledda et al., 1985) or stimulation of ANP secretion from atrial granule-containing cells (Tang et al., 1987; Stasch et al., 1989; Yamada et al., 1991), respectively. On the other hand, as mentioned previously, Dyn A may also cause hypertension by a blockade of the uptake of norepinephrine via the stimulation of Dyn-specific nonopioid receptors (Dumont and Lemaire, 1995). The nature of the response of the heart to the presence of Dyn A and related peptides may depend on the physiological or pathophysiological (or both) state of the animal. The stimulation of K opioid receptors present on cardiomyocytes by Dyn A, related peptides, and K opioid analgesics was suggested to induce the following cascade of intracellular and extracellular events (Ventura et al., 1991a, 1992).These compounds may first activate phospholipase C (PLC) and induce an increased phosphoinositide turnover, leading to the production of inositol triphosphate ( IP3)and 1,2-diacylglycerol (DAG). Increased ID3 may cause mobilization of ca'+, from the sarcoplasmic reticulum, and increased DAG may stimulate protein kinase C (PKC) and activate Na+H+ exchange, thereby increasing the efflux of H+ ([H+],)and the influx of Na' ([Naili), which, in turn, elevates [Caz+],via an increase in the Na+Ca2+ exchange mechanism (Ventura et al., 1991b). Such mechanism of action for Dyn A in SHR is supported by the observation that vascular smooth muscle cells of SHR possess high levels of PLC activity (Vehara et al., 1988) and increased Na+-H' exchange (Berk et al., 1989). Moreover,

Dynorphin and the Cardiovascular System

19

cardiac PKC activity (Makita and Yasuda, 1990) and DAG levels (Kondo et al., 1990) and myocardial cell [Cazt], (Andrawis et al., 1988) are elevated in SHR as compared with WKY rats. Dyn A has also been shown to inhibit cardiac Na+-K+-ATPase(Maeda et a!., 1988). The receptor involved is nonopioid. This may result from the stimulation of Dyn-specific nonopioid binding sites present in the heart (Dumontand Lemaire, 1993),leading to inhibition of norepinephrine uptake (Dumont and Lemaire, 1995). In this regard, the atria of SHR rats have a reduced neuronal uptake mechanism, as compared with WKY rats (Rho et al., 1981). Inhibition of Na+-K+-ATPasemay increase [Na’I1 and, via the Na+-Ca2+exchanger, elevate [Ca”],. Both of these effects can generate an increase in [Ca2+],,and this may explain the high [Ca’+],observed in cardiac myocytes of hypertensive rats (Andrawis et al., 1988). A high [CaZt], in myocardial cells of SHR combined with a high sympathetic activity may explain the enhanced myocardiac cell reactivity to various types of stimuli, including those involved in cell growth and hypertrophy (Judy et al., 1976; Berk et al., 1989; Lograno et al., 1989). In 16-week-old SHR rats, an age that corresponds to the fully established state of hypertension, the decrease in cardiac Dyn A and the concomitant increase in Leu-Enk may favor cardiac tonic sympathetic hyperactivity (Dumont et al., 1990). A reduction in the stimulation of K opioid receptors present on sympathetic nerve terminals consecutive to the decrease in Dyn A may lead to an increase in the release of norepinephrine from these nerve terminals, whereas increased 6 opioid receptor stimulation consecutive to the increase in Leu-Enk (Wong-Dusting and Rand, 1985; Weitzell et al., 1984) may induce a blockade of acetylcholine secretion from vagus nerve terminals, leaving the high sympathetic innervation of the heart unopposed by vagal nerve discharge. Thus, in SHR rats, the establishment and maintenance of high blood pressure may be due partly to Dyn-induced blockades of catecholamine reuptake and Na+-K+-ATPase(Maeda et al., 1988) as well as to a late Leu-Enk-mediated inhibition of vagal nerve discharge (Dumont and Lemaire, 1988) (Fig. 1).

C. Ischemia Reperfusion Injury The suggestion of a role for endogenous opioid peptides in myocardial ischemia and reperfusion injury came from the observation that naloxone (Fagbermi et al., 1982; Zhan et al., 1985; Lee and Wong, 1986, 1987b) and naltrexone (Liu et al., 1988; McIntosh et al., 1992) are able to attenuate arrhythmias during ischemia and reperfusion. The importance of peripheral opioid receptors is supported by the antiarrythmic effects of MrZ 2593, a quaternary complex of naloxone that does not cross the blood-brain barrier (Boachie-Ansah et al., 1989). Studies have shown that the opioid antagonists, WIN 44,441-3, MR 1452 (Parratt and Sitsapesan, 1986), MR 2266 (Sit-

20

Michel Dumont and Simon Lemaire

DEPRESSOR

PRESSOR

I

I

Delta receptor

Kappa

Nonopioid

I

I

Kappa

Nerve terminal

Myocyte

Nerve terminal

Nerve terminal

Acetylcholine release block

Stimulation of PLC

Norepinephrine uptake block

Norepinephrine release block

Parasympatholytic

Ca2+overload

Ca2+overload

I

I

I

I

I

I

I

I

I

I

I Sympatholytic

I

Activation Sympathomimetic of myocyte & activation of functions myocyte functions FIGURE I Possible role of cardiac dynorphins. In healthy animals, the relatively low levels of Dyn secreted by cardiac sympathetic nerve terminals may modulate the release of norepinephrine from these nerve terminals through the stimulation of K opioid receptors and thus ensure a proper sympathetic innervation. Under pathophysiological conditions (circulatory shock, hypertension, ischemidreperfusion injury), increased sympathetic nerve activity is accompanied by an important release of Dyn from the nerve terminals and a possible induction of preproDynmRNA in cardiomyocytes. High concentrations of extracellular Dyn may cause a nonopioid block of Na'-K+-ATPase located on the membranes of sympathetic neurons and cardiomyocytes, inhibit norepinephrine uptake and favor Ca" overload in both nerve terminals and cardiomyocytes. Finally, at the late stage of hypertension, Dyn may be converted into LeuEnk and block vagal nerve discharge through the stimulation of S opioid receptors.

sapesan and Parratt, 1989; Wong et al., 1990), and norBNI (McIntosh et al., 1992), which display some selectivity for the K opioid receptor, reduce the arrhythmias resulting from ischemia and reperfusion. The particular importance of K opioid receptors is supported by the arrhythmogenic effects of Dyn A-(1-13) and U-50488H(Lee and Wong, 1987a; Wong and Lee, 1987; Wong et al., 1990). Numerous cellular changes accompany ischemia reperfusion injury. During ischemia, the myocardial concentrations of extracellular K' ([K'],) (Hirche etal., 1980),[H'], (Hirche etal., 1980),extracellular norepinephrine (Hirche et al., 1980; Schomig et al., 1984), [Na+Ii(Renlund et al., 1984), and [Caz+li(Steenberger et al., 1987; Nayler, 1987; Watts et al., 1990) are increased. These ionic changes in myocardial cells largely contribute to the eIectrica1 instability of the heart. Furthermore, the Ca2+ overload of the

Dynorphin and the Cardiovascular System

21

myocardium triggers Caz+-dependent degenerative processes (Katz et al., 1979). Recently, oxygen-derived free radicals were also demonstrated to be important mediators of the deleterious effects of ischemia in the myocardium, being generated during cardiac reperfusion (Zweier, 1988; Yang et al., 1995).Thus, it was found that treatment with superoxide dismutase and catalase (oxygen free radical scavengers) protects against oxygen-induced reperfusion injury (Otani et al., 1986). The increased oxygen free radicals may be produced by cardiomyocytes and leukocytes attached to vascular endothelial cells (Braunwald and Kloner, 1985). Finally myocardial ischemiaheperfusion injury can also be caused by an impaired coronary circulation, most likely resulting from intracoronary platelet aggregation (Swies et al., 1990), blockade of microcirculation in the coronary vessels, and concomitant formations of thromboxane A2 (Swies et al., 1990) and serotonin (Vanhoutte, 1990). In turn, thromboxane A2 and serotonin may cause vasoconstriction and further damage the myocardium. Interestingly, Dyn A is able to produce similar effects, either alone or in conjunction with ischemia (Table 11). The receptors involved are more likely opioid ( K ) and nonopioid. A Dyn hypothesis may be proposed to explain the deleterious changes observed during ischemiah-eperfusion injury (Fig. 2). As already mentioned, cardiac Dyn A and related peptides are located mainly in sympathetic nerve terminals along with norepinephrine. Since cardiac ischemia is accompanied by the release of norepinephrine (Hirche et al., 1980; Schomig et al., 1984), it is presumed that colocalized Dyn A is also released during this process. Preliminary data in our laboratory indicate that myocardial infarction in rats is causing a reduction in the cardiac level of ir-Dyn A. Stimulation of cardiac K opioid receptors by Dyn A during ischemia may activate PLC and increase phosphoinositide turnover, leading to increases in IP3 and DAG. Increased IP3 levels may cause the mobilization of Ca2+from the sarcoplasmic reticulum, and increased DAG levels may activate PKC, leading to the stimulation of Na'-H' exchange, increased [Na+Ii,and, through the Na+-Ca2+exchanger, a major entry of Ca2+(Ventura et al., 1992).In this regard, it was shown that PKC activation aggravates hypoxic myocardial injury by the stimulation of Na+-H+ exchange (Ikeda et al., 1988). In addition, K opioid receptor stimulation is coupled to an increase in NAD(P)H-vanadatedehydrogenase and NAP(P)H oxidase activity, producing oxygen free radicals in cardiac myocytes and leukocytes, respectively (Sharp et al., 1985; Ventura et al., 1988). O n the other hand, the stimulation of a Dyn-specific nonopioid receptor (Dumont and Lemaire, 1993) may inhibit Na+-K'-ATPase (Maeda et al., 1988) and induce ( 1 ) an increase in [K+Ie(Hirche et al., 1980) and a carriermediated efflux of norepinephrine from nerve terminals (Schomig et al., 1984; Longuemare and Swanson, 1995), both effects leading to an increase in extracellular norepinephrine concentration, and (2) an increase in "a+];

22

Michel Dumont and Simon Lemaire

ISCHEMlAmEPERFUSlON INJURY

DYNORPHlN

NOREPINEPHRINE

Beta

exch.

exch.

K+

PKC

CARDIOMYOCYTE

DAG

t Ca2+

PLC

IP,

J

PKA

Overstimulation & Cellular damage

FIGURE 2 Possible mechanisms of action of dynorphin in ischemialreperfusion injury: role of calcium. kchemidreperfusion injury may first induce and excessive release of Dyn and norepinephrine from cardiac sympathetic nerve terminals. Cardiac Dyn may stimulate K opioid receptors present on cardiomyocytes and, through activation of the formation of inositol triphosphate (IP3), stimulate mobilization of Ca” from sarcoplasmic reticulum (SR). The formation of diacylglycerol (DAG) will stimulate the Na+-H+exchange mechanism through the activation of protein kinase C (PKC). Dyn may also inhibit Na*-K+-ATF’ase,causing the accumulation of intracellular Nat and a further activation of Na+-Caz+exchanges. The initial large release of norepinephrine in ischemia may favor the entry of Ca2+through the phosphorylation of membrane channels.

(Renlund et al., 1984), which via the Na+-Ca2+exchanger may cause a further CaZ+overload. This hypothetical mechanism is in agreement with the observed inhibition of Na+-K+-ATPaseactivity during myocardial ischemia (Bersohn et al., 1982).Furthermore, stimulation of the Dyn-sensitive nonopioid receptor can also impair the coronary microcirculation consecutive to the vasoconstrictive properties of Dyn A (Thornhill and Powell-Jones, 1987; Chen et al., 1991; Wong and Ingenito, 1995). Thus, some of the deleterious effects of ischemia/reperfusion injury may be mediated by Dyn A and related peptides that are present in the heart and other organs that constitute the cardiovascular system (Fig. 2). However, this hypothesis remains to be established.

Dynorphin and the Cardiovascular System

23

V. Concluding Remarks The contribution of Dyn A to the regulation of cardiovascular functions is important. It can be seen at both the CNS and the peripheral levels and is mediated by both opioid ( K ) and nonopioid receptors. The beneficial effects of K opioid antagonists against circulatory shock, hypertension, and ischemiaheperfusion injury suggest that these cardiovascular pathologies may, in part, result from K opioid receptor stimulation. A blockade of K opioid receptors may lead to an increase in AVP and cause some beneficial effects in cases of hemorrhage. On the other hand, the blockade of K opioid receptors on some central and peripheral blood vessels and cardiomyocytes may reduce calcium overload and antagonize sympathetic hyperactivity, arrhythmias, myocardial cell hyperactivity, and cellular damages observed in cases of hypertension, circulatory shock, and ischemiaheperfusion injury (Fig. 2). However, since K opioid receptor antagonists can only attenuate the arrhythmogenic effects of U-50488H and do not generally antagonize the hypertensive effect of Dyn A, it is presumed that other receptors are involved in the cardiovascular effects of Dyn A and K opioid analgesics. One possibility is that Dyn A and related peptides may interact with a nonopioid receptor present in cerebral arteries and the heart and produce sympathomimetic effects via the inhibition of Na+-K+-ATPaseand modulation of norepinephrine uptake (Fig. 1). On the other hand, blockade on Na+-K+-ATPasemay also increase "a'], in cardiomyocytes and potentiate calcium overload in cases of hypertension and ischemiaheperfusion injury (Fig. 2). In healthy subjects, the levels of central and peripheral Dyn A and related peptides may allow the organism to maintain homeostasis by ensuring a balance between pressor and depressor functions (Fig. 1).The marked CNS and peripheral changes in Dyn A levels observed during hypertension and other cardiovascular diseases indicate that Dyn A and related peptides may participate in the etiology and maintenance of cardiovascular dysfunctions. A better understanding of the mechanism of action of Dyn A and related peptides in regard to their interaction with both opioid and nonopioid receptors may help to design therapeutic approaches for the management of cardiovascular diseases.

References Altura, B. T., A h a , B. M., and Quirion, R. (1984). Identification of benzomorphan-K opiate receptors in cerebral arteries which subserve relaxation. Br. J. Pharmacol. 82,459-466. Andrawis, N. S., Kuo, T. H., Giacomelli, F., and Wiener, J. (1988). Altered calcium regulation in the cardiac plasma membrane in experimental renal hypertension. J. Mol. Cell. Cardzol. 20,625-634. Archelos, J., Xiang, J. Z., Reinecke, M., and Lang, R. E. (1987). Regulation of release and function of neuropeptides in the heart. 1. Curdiovasc. Pharmacol. lO(Supp1 12), S45-SSO.

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