Calcium channels in smooth muscle

GASTROENTEROLOGY

PROGRESS

1984:87:960-70

ARTICLE

Calcium Channels in Smooth Muscle HIDEAKI

KARAKI

and GEORGE

Department of Veterinary Pharmacology, Research Department, Pharmaceuticals

B. WEISS

The University of Tokyo, Bunkyo-ku. Tokyo. Japan and Division, CIBA-GEIGY Corporation, Summit, New Jersey

It appeurs thut, in smooth muscle, there ure two a voltage-dependent distinct types of Ca” channel, Cu2+ chunnel and a receptor-linked Ca2’ channel. The former is activated by decreases in membrane potential and Ihe latter is regulated by drug-receptor interactions. These Ca2+ channels exist as separute channels in the uorta of the adult rabbit and of some mt ycI~II.“, ctminc. r1ronnir ontorrrlnist< .%.. V’Oy’L’v rrr2+ -‘P--=---- and sodil_l-m nitroprusside selectively inhibit each of these two respective channels. By examining the effects oj’ these two specific untagonists, churacterizution of the Ca2’ channels in other types of smooth muscle was attempted. In u wide variety of vasculnr smooth muscle [except uorta of ubove-mentioned cmimals), showed some however, these two Cu’+ chunnels sensitivity to both types of inhibitor. It is proposed that in most types of vascular smooth muscle us well as in gastric fundus and corpus, Ihe two types of Ca2+ channel ure functionally not completely separated. These subtypes of Ca2~+ channels ure at least partly sensitive to both organic Ca”’ antugonists and sodium nitroprusside. Intestinul, genital, and trucheal smooth muscles also seem lo have two types of Ca2+ channel. These subtypes of Ca’+ channels are, however, ssnsilive only to organic Co”+ antagonists und are not afiected by sodium nitroprusside. Contraction of smooth muscle can be initiated by changes in membrane permeability after either binding of agonists to their receptors or exposure to high Kf concentrations (1). In some cases receptor agonists induce contraction without changing membrane potential in certain smooth muscles that do not generate action potentials or in depolarized __ Received October 17. 1983. Accepted May 18, 1984. Address requests for reprints to: Dr. George B. Weiss. Cardiopulmonary Research, CIBA-GEIGY Corporation, 556 Morris Avrnue. Summit, New Jersey 07901. This work was supported by U.S. Public Health Service grants HL-14775 and HL-27145. 0 1984 by the American Gastroenterological Association 00165085/84/$X00

smooth muscles (2). In either instance, electrical or chemical cell membrane signals activate contractile elements by releasing membrane-bound Ca” or increasing Ca”+ influx, or both. It has been suggested that there are two pathways of transmembrane influx of Ca’+: (a) a voltage-dependent Ca” channel activated by changes in membrane potential and (b] a recentor-linked Ca2+ channel -__-_--_-_ activated --__. -_-- hv -i hindine --------ST nf -agonists to their receptors (l-7). A group of compounds, termed organic Ca2+ antagonists or Ca” + channel blockers [including verapamil, methoxyverapamil (DSOO), nifedipine, diltiazem, and flunarizine] have been described as specific inhibitors of Ca”+ influx through voltage-dependent Ca” channels (3-6). These agents inhibit both the contraction and the increase in Ca”’ influx induced by high concentrations of K' ,whereas they have little effect on both the contraction and Ca’+ movements elicited with norepinephrine or histamine in rabbit aorta (see next section]. On the other hand, sodium nitroprusside (see next section) inhibits the changes induced by norepinephrine, histamine, and angiotensin II but not those obtained with high K’ concentrations (suggesting that sodium nitroprusside may be a selective inhibitor of the receptor-linked Ca2+ channel). In this review, we will use information about these two types of selective blockers [voltage-sensitive and receptor-dependent) to attempt to delineate relationships between these two Ca2+ channels in various types of smooth muscle.

Selective

Antagonists

of CaZf Channels

Kabbit aorta is one of the most extensively investigated vascular smooth muscle preparations. In this smooth muscle, high concentrations of K’ depolarize the cell membrane and, in this manner, induce contractile responses. Conversely, norepinephrine elicits contractions without changing or only slightly depolarizing the cell membrane (8,9). In a solution without added Ca” +, the K’ -induced contraction is rapidly abolished (10.11). On the other hand, a relatively sustained contraction induced by

October 1984

CALCIUM

CHANNELS

IN SMOOTH

MUSCLE

961

norepinephrine is not readily abolished in a solution separated cellular Ca*+ in vascular smooth muscle without added Ca2+, but is strongly inhibited in the into two fractions that were designated high-affinity presence of ethyleneglycol-bis(/3_aminoethylether)and low-affinity bound cellular Ca2+ (20,21,27,28). N,N’-tetraacetic acid (EGTA) or ethylenediamineteThese two cellular Ca2+ components differed not only kinetically but also pharmacologically. High K+ traacetic acid (EDTA) (10,12,13). Because EGTA and EDTA do not penetrate the cell membrane (l4,15) concentrations increased the amount of low-affinity and remove the superficially bound 45Ca that is not Ca2+ and had almost no effect on high-affinity Ca’+. released a portion of the high-affiniremoved by a solution without added Ca*+ (151, Norepinephrine had no effect on ty Ca 2+ . Although norepinephrine some of the activator Ca2+ for the norepinephrineinduced sustained contraction may be derived from the total amount of low-affinity Ca2+ (20,29,30), the superficially located sources. In the presence of rate of exchange of Ca *+ at this site was increased by EGTA, however, the initial exposure to norepinephnorepinephrine (31-33). Histamine had effects simiiar to norepinephrine at these sites (unpubiished rine induces transient contraction and the second observations). When high concentrations (~10~’ M) exposure to norepinephrine has little effect on musof norepinephrine were added, the cellular lowcle tension. Thus, norepinephrine may release cellular bound Ca2+ from a limited compartment affinity bound Ca2+ increased in a dose-dependent of norepimanner (20).Such a high concentration (13,16,17). La3+, which displaces superficially bound membrane Ca2+ and also inhibits transmemnephrine has been reported to depolarize the rabbit aortic cell membrane (8,9). Also, it was found that, in brane Ca2+ influx (18,19), has effects similar to the Kf-depolarized aorta, application of norepiEGTA on norepinephrine-induced transient and susnephrine (C10-6 M) induced additional increases in tained contractions (13,16). The contractions inmuscle tension and in low-affinity bound Ca”+ duced by histamine and angiotensin II are inhibited (20,27). The amount of Ca”+ accumulated at lowby EDTA or La”+ in a manner similar to those affinity sites was at least 1 nmol/g wet tissue. Various induced by norepinephrine (10,16). On the basis of these nhservatinns. of inhibitors of mitochondriai Ca2+ uptake (e.g, anti___1_. - _--__-, three different mechanisms Ca2+ mobilization have been suggested for rabbit mycin A, oligomycin, KCN, hypoxia) inhibited the aortic smooth muscle (4,20,21). The first one is an high K+-induced Ca2+ accumulation without altering muscle contraction (34-36). Thus, the increase influx of extracellular Ca2+ through voltage-dependent Caz+ channels in the cell membrane. Extracelin the cellular low-affinity Ca2+ retention may result from mitochondrial accumulation of Ca’+. From lular Ca2+ loosely bound to the surface of the cell these results, it was concluded that Ca2+ is taken up membrane is transported into the cell (mobilized) by the cell and accumulates in mitochondria during through this Ca ‘+ channel (4,22). The second mechamuscle contraction induced by high concentrations nism, activated by norepinephrine, histamine, or angiotensin II, is an influx of that Ca2+ fraction of K+, whereas norepinephrine releases cellular Ca*+ and also increases the rate of Ca2+ influx. The bound to the surface of the cell membrane in such a manner that the bound Ca2+ is not easily removed in Ca2+ taken up is accumulated in the depolarized cell a solution without added Ca2+ but is removed by but not in the polarized cell. -^- . Eli'l‘A or La”‘. The Ca”’ entering the ceii may Contractions of rabbit aorta induced by these difactivate the contractile machinery directly or indiferent mechanisms of Ca2+ mobilization are modirectly through a Ca*+-induced CaZ+-release mechafied in differing ways by various smooth muscle relaxants, as is shown in Table 1 (type 1) and Figure nism. The receptor-linked Ca2+ channel may be 1. Concentrations of organic Ca2+ antagonists [e.g., involved in this Ca2+ mobilization. The third mechaverapamil, D~oo, nifedipine, p-diethylaminoethyldinism, responsible for the norepinephrine-induced phenylprophylacetate (SKF525A, Smith Klein & transient contraction, is a receptor-linked release of French, Philadelphia, Pa.), diltiazem] that were intracellularly bound Ca’+. ~10~” M inhibited the contraction induced by high These different modes for Ca2+ movements can be K+ concentrations as well as the K+-induced inconfirmed by experiments with radioactive Ca2+ crease in cellular Caz+ content (20,26,27,33-35,37(‘%a). New techniques and approaches used to 40). Similar concentrations of the same compounds, delineate different Ca2+ sites and pathways have however, have little effect on contractions induced been described elsewhere (4,20,23,24). Briefly, 45Ca by norepinephrine (35,37-39,41), histamine (unpubtaken up by the smooth muscle tissue was separated lished observations), or angiotensin II (42). Only into extracellular bound 45Ca and cellular 45Ca frac(>lO-” M) of the organic tions by techniques using lanthanum (20,25,26). very high concentrations inhibit the norepinephrine-inCa2+ antagonists Additionally, Scatchard-coordinate plots were used duced contraction, and this action could be due to to identify and characterize discrete components of nonspecific, local anesthetic effects of the organic Ca’+ binding (23,24). With these approaches, we

962

KARAKI AND WEISS

GASTROENTEROLOGY

Table 1. Effects of Organic Ca2+ Antagonists and Sodium Nitroprusside on Contractions in Various

Smooth

K+ Type 1 CaZ+ antagonists” Nitroprusside Type 2 Ca2+ antagonists Nitroprusside

Type 3 CaZ+ antagonists Nitroprusside

f

Muscles Receptor agonists” _

+ + +-2

+

+ +-f +-t

Preparation

Aorta (rabbit, adult; rat, some strains) Stomach corpus and fundus (guinea pig: canine: cat), aorta (rat, some .l”^:-“. g”llle’ _..:_..-d p’ -:_. blldlllb, g, rabbit, new born). cerebral artery (canine: rabbit], carotid artery (rabbit), coronary artery (canine: swine), renal artery (canine). mesenteric arteq (canine: rabbit], ear artery (rabbit), saphenous vein (canine), portal vein (canine), umbilical artery (human), trachea (monkey]

f-2 _

sustained contraction induced by norepinephrine may also result from inward translocation of Ca2+ from the surface membrane. In guinea pig portal vein and cat stomach fundus, similar contractions were reported to be dependent on transmembrane Ca”+ sources but resistant to organic Ca”+ antagonists (44,45). Inorganic Ca’+ antagonists such as La”+, on the other hand, do not have the specificity of organic Ca2+ antagonists. La”+ not only displaces superficially bound Ca ‘+, but also inhibits Ca”+ influx through both types of membrane channels and inhibits even resting Ca”+ influx (3,13,19,25). This ion inhibits the contractions induced by high K’ concentrations as well as the sustained contractions induced by norepinephrine. The other group of compounds of interest are the nitro-containing compounds (sodium nitroprusside, nitroglycerine, sodium nitrite). These compounds inhibit rabbit aortic contractions induced by norepinephrine (33,37,41,46), histamine (unpublished ob-

Rabbit

Taenia coli (guinea pig], ileum (guinea pig), duodenum (rat]. colon [canine), stomach antrum (cat: canine), uterus (rat: guinea pig), vas deferens (rat; guinea pig), trachea (canine; rabbit), portal vein (rat; guinea pig).

L’L.:+:?...Lu~e~-ou~w -Inn/ onw luuiuitiDii, :-L’L’*’ , 2. Ziid -1 ~8O’j’oiihiuluuu.

2fid

Vol. 87, No. 4

aorta

Rat aorta

IrK

LY!Scll

CZO”X:,

inhibition, respectively, by the inhibitors at concentrations 110 i M. ’ Norepinephrine, histamine, angiotensin II, acetylcholine. carbachol, 5-hydroxytryptamine. oxytocin. h Verapamil. D600. nifedipine, SKF525A, diltiazem. flunarizine.

Ca2+ antagonists (1,5,13,43,44). In studies on excitation-contraction coupling in smooth muscle, the organic Ca2+ antagonists are frequently used to inhibit Ca2+ influx. Based on the assumption that transmembrane Ca2+ transport inhibited by the organic Ca2+ antagonists is the only transmembrane transport of activator Ca”‘, it is sometimes concluded that contractions that are not inhibited by organic Ca2+ antagonists can be attributable to release of cellular Ca2+. However, as described previously, the

lo

9

8

7

Verapamil Figure

6

6

C-log

10 M)

9

8

7

6

6

Nitroprusside

1. Effects of verapamil and sodium nitroprusside on contractions in rabbit aorta, rat aorta, and guinea pig taenia coli. K’-Isosmotic 65.4 mM K+ for rabbit and rat aorta .__,I ~~~ auu nyperosmotic 45.4 mivi K’ for guinea pig iaenia coli. Norepinephrine-10 ” M for rabbit aorta and 10m7 M for rat aorta. Histamine-10 ” M. Inhibitors were added during sustained contractions by each agonist.

October

1984

servation), and angiotensin II (46), but have no effect on the contractions induced by high Kf concentrations (33,37). In the presence of sodium nitroprusside, addition of norepinephrine has little effect on smooth muscle tension (33,37,41). Therefore, sodium nitroprusside may inhibit both the receptorlinked Ca2+ channel and receptor-linked release of cellular Ca’+, but not the voltage-dependent Ca”+ channel. Nitroglycerine has effects similar to those of sodium nitroprusside, (46,47).The additional increase in ceiiuiar Ca”’ content induced by norepinephrine in depolarized aorta is inhibited by sodium nitroprusside but not by D600 (17). The increase in the rate of 45Ca uptake induced by norepinephrine, which is not inhibited by D600 (31) or verapamil (33), is inhibited by sodium nitroprusside (33). Nitro-containing compounds seem to have multiple mechanisms of action. The first mechanism is membrane hyperpolarization due to either activation of electrogenic Na+ pumping (47,48) or increase in K+ permeability (49,50). This mechanism may be only partly responsible for the relaxant action (47), and it does not explain why these compounds relax the contraction in depolarized smooth muscle (27,47,51,52). The second mechanism is an increase in Ca2+ sequestration or extrusion (53,54), which explains why these compounds inhibit the contraction induced by a release of cellular Ca2+ in the absence of external Ca’+. This mechanism, however, does not explain the differential effects of these compounds on K+- and norepinephrine-induced contractions, both of which are due to Ca2+ influx. The third mechanism, which has been cited in the present review, is an inhibition of Ca2+ influx (51,551 through specific Ca2+ channels (27,33). The 1 .I *. mnioirory effects of nitro-containing compounds may result from an increase in cellular 3’,5’-cyclic guanosine monophosphate (cGMP) (56-58). However, little is known about the mechanism by which cGMP modulates Ca2+ movements. Moreover, why these compounds have little or no inhibitory effects even though they increase cellular cGMP in such smooth muscles as vas deferens and taenia coli (59,60) is not clear except that the cGMP-dependent protein phosphorylation (61)might not be coupled to the relaxant effects. These results clearly indicate that, in rabbit aorta, the voltage-dependent Ca2+ channel and the receptor-linked Ca*+ channel are independent; the former is activated by membrane depolarization whereas the latter is activated by binding of agonists to their receptors. Very high concentrations of receptor agonists would depolarize the cell membrane and thus activate voltage-sensitive Ca2+ channels. Furthermore, the results suggest that organic Ca2+ antagonists are relatively selective inhibitors of the voltage-

CALCIUM

CHANNELS

IN SMOOTH

MUSCLE

963

dependent Ca2+ channel and sodium nitroprusside is a relatively selective inhibitor of the receptorlinked Ca2+ channel. With these two specific inhibitors of different Ca2+ channels, it might be possible to identify which types of Ca2+ channel are present in various smooth muscle preparations. This is attempted in the following section.

Inhibition by Organic Ca2+ Antagonists and Sodium Nitroprusside Smooth Muscles Sensitive

to Both Inhibitors

There are a large number of smooth muscles in which contractions induced by high K+ concentrations are strongly inhibited by organic Ca’+ antagonists and are also inhibited to a greater or lesser degree by sodium nitroprusside. Similarly, the contractions of these smooth muscles induced by muscarinic agonists, norepinephrine, angiotensin II, or serotonin are inhibited by sodium nitroprusside and are also inhibited (at least partly) by organic CaZi antaennistn (3-‘--1" CTnhlp \--l-v

1_, tvrw .,r-

71 !t has _,'

sg~_pti~_es

beep_

observed that the portion of the contraction not inhibited by the organic Ca2+ antagonists is inhibited by sodium nitroprusside (52,62-64).However, the effects of the Ca2+ antagonists and sodium nitroprusside are not always additive. Each antagonist can inhibit the contraction independent of the other. As is shown in Figure 1, for example, muscle contractions induced in rat aorta by either high Kf concentrations or norepinephrine were almost completely inhibited by either D600 or sodium nitroprusside; the inhibitory effects of verapamil on contractions induced by K+ or norepinephrine were antagonized by raising the externai Ca”’ concentrations, whereas the inhibitory effects of sodium nitroprusside on these contractions were not (33). This group includes a wide variety of smooth muscles. In some smooth muscles such as guinea pig aorta (65,66), the contractions induced by high Kf concentrations were less sensitive to sodium nitroprusside and those induced by norepinephrine were less sensitive to D600 than were corresponding responses in rat aorta (44,55,67-69). Furthermore, there may be strain-related differences in the sensitivity of rat aorta to the inhibitors, because rat aorta in one laboratory (70,711 behave like rabbit aorta, whereas in others they do not (33,72). Other smooth muscles included in this group are guinea pig (73-76), canine (44,77), and cat (44,78) stomach corpus and fundus; monkey trachea (79); vascular smooth muscle of the rabbit basilar (801, ear (unpublished observation), mesenteric (81),and carotid (82)arteries as well as canine basilar (801,coronary (83,84), renal (52,63), and mesenteric (85)arteries and saphenous (86,871

964 KARAKI AND WEISS

GASTROENTEROLOGY Vol.87,No. 4

and portal (86) veins; swine coronary artery (62); and human umbilical artery (64). Aorta of rabbits within 1 mo of delivery behaves like rat aorta, and the sensitivity of this smooth muscle to the inhibitors gradually changes with age (unpublished observation). In Table 1, this group of smooth muscles is designated as type 2 to illustrate differences from type 1 smooth muscles. In guinea pig (65) and rat (88) aorta and human umbilical vessels (64), high Kt concentrations induced contractions as well as increases in cellular Ca2+ content; both of these effects were abolished by verapamil. In rat aorta, both of these effects were also inhibited by sodium nitroprusside (33). In canine renal artery (89), both high Kt concentrations and norepinephrine increased the cellular Ca2+ content. In guinea pig stomach (73), cellular Ca”+ content increased during muscle contractions induced either by high K+ concentrations or by acetylcholine; nifedipine completely inhibited both the contractions and increases in Ca’+ content induced by high Kf concentrations, whereas both of the effects induced by acetylcholine were partly inhibited by nifedipine. Also; in the cat sto_mach fundus (44), a portion of the contraction induced by acetylcholine was insensitive to D600. However, this DGOO-insensitive contraction was attributed to Ca2+ influx and was inhibited by sodium nitroprusside. In rat aorta, the incremental increases in both muscle tension and Ca2+ influx elicited with norepinephrine were inhibited either by verapamil or by sodium nitroprusside (33). In canine renal artery, the increase in cellular Ca2+ induced by K+ or by norepinephrine was inhibited by either verapamil or sodium nitroprusside (52). These results suggest that, in these types of smooth muscle preparations, high K’ concentrations activate not only Ca2+ channels inhibited by organic Ca2+ antagonists, but also Ca”+ channels sensitive to sodium nitroprusside. Similarly, various receptor agonists appear to open Ca’+ channels susceptible to sodium nitroprusside as well as Ca”+ channels inhibited by the organic Ca2+ antagonists.

Smooth Muscles Sensitive Ca”+ Antagonists

Only to Organic

As is shown in Table 1 (type 3) and Figure 1, the third type of smooth muscle is sensitive only to the organic Ca2+ antagonists. Sodium nitroprusside has almost no effect on the contractions induced by high K+ concentrations, muscarinic agonists, norepinephrine, histamine, angiotensin II, or oxytocin in intestinal smooth muscle like guinea pig taenia coli (22,66,76,78,90-93) and ileum (66,94-97), rat duodenum (55) and canine colon (84), rat vas defer-

ens (55,95,98) and uterus (42,551, guinea pig vas deferens (99) and uterus (44,66), canine (100,101) and rabbit (79) [but not monkey (i’9)] trachea, and rat (102) and guinea pig (66,103) [but not canine (SS)] portal vein. The stomach antrum of cat (78) and canine (77) also appears to be of this type. In these smooth muscles, contractions are usually associated with an increase in spike discharges (104). Because the contractions in these smooth muscles are rapidly inhibited in the absence of external Ca”+ (33,105-107) or by La3+ (93), activator Ca2+ appears to be derived from the extracellular space. It is also suggested that the initial transient contraction in taenia coli is due to release of cellular bound Ca”+ fraction that is rapidly lost in the absence of external Ca” (22,108,109). Verapamil or D600 completely inhibited the sustained phase of the contraction in guinea pig taenia cob (22,90,91, 94) and ileum (94), whereas a transient contraction was induced by stimulants in the presence of organic Ca2+ antagonists (22,33,55,60,77,78,91,94,110,112). Sodium nitroprusside, on the other hand, had little fif nnvl pffm-t nn the rnntrartinnc inrl~~rcwi hlr hinh 1-- ---_T I “YVUL “II Lll” UYIILIUULIVIIU AllUUUUU “J “‘&+A

K+ concentrations, muscarinic agonists, or histamine in taenia coli (33,60), ileum (unpublished observation), or rat duodenum (55). During the contraction induced in the ileum by a muscarinic agonist (94) and in taenia coli by high Ki concentrations (3594,110) or by histamine (331, cellular Ca2+ content increased. Verapamil and D600 inhibited both of these changes, whereas sodium nitroprusside did not inhibit the increase in Ca’+ content (33). Therefore, it is likely that both high K’ concentrations and various receptor agonists activate only the Ca’+ channel sensitive to the organic Ca” antagonists (the Ca” channel sensitive to sodium nitroprusside does not play an important role in these smooth muscles). There are smooth muscles in which a portion of the contraction is sensitive only to organic Ca’+ antagonists and other portions of the contraction are sensitive to both organic Ca2+ antagonists and sodium nitroprusside. In the lower esophageal sphincter of the opossum, sodium nitroprusside did not inhibit the contraction induced by carbachol (111). Resting tone of this sphincter, however, was strongly inhibited by sodium nitroprusside as well as by the organic Ca2+ antagonists (111.112]. Also, in the canine lower esophageal sphincter (771, contractions induced by norepinephrine were partly inhibited by the organic Ca2+ antagonists but were sensitive to sodium nitroprusside. The contractions induced by acetylcholine, however, were sensitive to both of the antagonists. Therefore, this type of smooth muscle may be classified between the second and the third types of smooth muscles.

October

CALCIUM

1984

Dual-Channel

Model

In adult rabbit aorta, there are two separate Ca’+ channels. It appears that organic Ca2+ antagonists are specific inhibitors of voltage-dependent Ca2+ channels and sodium nitroprusside is a specific inhibitor of receptor-linked Ca”+ channels. Based on this dual-channel model, the characteristics of various types of smooth muscles can be explained. In the second type of smooth muscle, contractions induced by receptor agonists were inhibited not only by sodium nitroprusside but also by organic Ca”+ antagonists (suggesting that the receptor agonists activate both types of Ca 2+ channel). Bolton (1) has postulated that binding of agonists to their receptors opens receptor-linked Ca2+ channels, increases membrane permeability to Ca2+ or Nat, or both, depolarizes the cell membrane, and activates voltage-dependent Ca”+ channels. Because it was also observed that the contraction induced by high K+ concentrations was inhihitd nnt nnlv hv nronnir fL”+ antaonnidc hilt ““‘Ub”““‘” .,-. --..IIuIL”U LlV. V”‘J “J V’b”“‘U u.. also by sodium nitroprusside, we also have to assume that high K+ concentrations activate at least a part of the receptor-linked Ca”+ channel in addition to effects on voltage-sensitive Ca’+ channels. This may be the case with guinea pig portal vein (45) and rat tail artery (113) in which a part of K+-induced contraction is due to the endogenous catecholamines released by high K’ concentrations. In general, however, the larger part of K’-induced contractions is attributable to the direct effect on smooth muscle through membrane depolarization. The assumption that high K+ concentrations directly activate receptor-iinked CaZ+ channeis contradicts the definition of receptor-linked Ca 2+ channels (channels activated only by receptor agonists). Furthermore, it is difficult to visualize how membrane depolarization could control receptor-linked Ca2+ channels that are relatively independent of changes in membrane potential and can be activated even in depolarized smooth muscle. Finally, if a stimulant activates both types of channel, inhibition of only one type of channel should not result in a total inhibition of muscle contraction. However, either organic Ca2+ antagonists or sodium nitroprusside, added alone, almost completely inhibit contractions in some smooth muscles of the second type (type 2 in Table 1,Figure 1). It was Golenhofen and coworkers (41,44,45,74,78) who first used the specific effects of the organic Ca”+ antagonists and sodium nitroprusside to characterize smooth muscle contractions. They classified Ca2+ mobilization patterns in various smooth muscles into P (phasic) and T (tonic) systems. The P system is associated with spike discharge and is selectively inhibited by the organic Ca2+ antago-

CHANNELS

IN SMOOTH

MUSCLE

965

nists, whereas the T system is due to spike-free depolarization and is not inhibited by the organic Ca’+ antagonists but is inhibited by sodium nitroprusside. P and T systems exist in parallel in the chain of events leading from the binding of agonists at receptors to muscle contraction, and each one of the two systems is able to produce a maximal contraction. One type of receptor may trigger only one of the systems, whereas another receptor may trigger both systems. Although these systems were not correlated with Ca’+ channels (44). this model has a problem similar to the dual-channel model; although an inhibition of one of the systems should not inhibit all of the response, this is actually what happens in some smooth muscles, as described previously. Thus, Goyal and Rattan (112) suggested that these Ca2+ activation systems may exist in series rather than in parallel. In the third type of smooth muscle, sodium nitroprusside was almost ineffective. All of the contracinitisrl trQncinnt nno UU" AIIP tn 3 PDIP~QP tinnc ovront the LL"LL.J,"AubyL L&l" LlllllUl LlUllUlUlll "ll" I" u l"l"UUV of cellular Ca’+, were inhibited by the organic Ca2+ antagonists. In this type of smooth muscle, therefore, there is no reason to assume the existence of the receptor-linked Ca2+ channel sensitive to sodium nitroprusside. Brading and Sneddon (22) also sUggested that the maintained tension induced by high K+ concentrations and by carbachol may be due to activation of the same voltage-dependent Ca”+ channel. Even in the type 2 and 3 smooth muscles, however, there seem to be two separate Ca”+ channels for the following reasons: (a) Although the organic Ca2+ antagonists inhibit both K’- and norepinephrineinduced contractions, the former contraction is more sensitive to these inhibitors than is the latter in most vascular smooth muscles (5,114 and Figure 1).Also in taenia coli, K’-induced contraction is more sensitive to verapamil than is the histamine-induced contraction (33 and Figure 1).(b) Bassianolide, a cyclodepsipeptide and a possible channel inhibitor, inhibits the contraction induced in taenia coli by receptor activation by acetylcholine, histamine, and 5-hydroxytryptamine but not the K+-induced contraction (115,116). (c) Various receptor agonists induce additive contractions in K+-depolarized smooth muscle in which voltage-dependent Ca2+ channels may have been fully activated (117-119). (d) When drug-induced depolarization in taenia coli is matched by depolarization induced by passive current, the increase in membrane conductance is implying that drug-induced conductance less, changes are not simply due to the opening of voltage(e)In the absence of dependent Ca2+ channels (120). external Ca2 + , 8YSr enters the cell and supports K+-induced contraction, whereas there is little or no

966

KARAKI

GASTROENTEROLOGY

AND WEISS

“Sr entry nor muscle contraction induced by norepinephrine or histamine in rabbit or rat aorta and guinea pig taenia coli (121),suggesting that K+induced contraction is mediated by a Ca*+ channel with a different sensitivity from that responsible for norepinephrineor histamine-induced contraction.

Model With Varied

Ca2+ Channels

Because the dual-channel model does not explain the effects of specific inhibitors in smooth muscles other than the aorta of adult rabbits and of some rat strains, an alternative model is proposed. As is shown in Figure 2, typical separate voltagedependent Ca’+ channels and receptor-linked Ca’+ channels may exist only in the aorta of the aforementioned animals. In the second type of smooth muscle, these two Ca”+ channels are functionally not clearly separated; the voltage-dependent Ca”+ chan0077‘.;t:.,n ,7,7tqnfi77;ct0 ;0 -Ien nel JG1lJlll” I7 to nV.m”,?;P “l@UU~ r-2+ ULl aUUg”llr.JIJ lil (1IJ” partly sensitive to sodium nitroprusside, whereas the receptor-linked Ca”+ channel sensitive to sodium nitroprusside is also partly inhibited by organic Ca2+ antagonists. Thus, these two Ca’+ channels share a common mechanism sensitive to both types of inhibitor. Such Ca’+ channels are illustrated in Figure 2 as type 2 channels. The portion of the channels sensitive to both of the inhibitors may differ from one type of muscle to another. This hypothesis explains why the organic Ca2+ antagonists and sodium nitroprusside independently inhibit a contraction induced by either type of stimulant. The third type of smooth muscle also has two Ca2+ channels (type 3 in Figure 2). The difference between the type 2 and the type 3 channels is that the type 3 Ca2+ channels are sensitive only to Ca” antagonists and not to sodium nitroprusside. Lower esophageal sphincter muscle might have type 2 and type 3 Ca ‘+ channels together. One receptor may be linked to the former while the other receptor is linked to the latter Ca”+ channel. Thus, the contraction induced by one receptor agonist is inhibited by sodium nitroprusside while the other contraction is insensitive to sodium nitroprusside in this type of smooth muscle: Release of cellular Ca2+ is not shown in Figure 2. In type 1 smooth muscle, only receptor agonists appear to release cellular Ca’+ and the contraction induced by this type of Ca2+ mobilization is inhibited by sodium nitroprusside but not by organic Ca2+ antagonists. In the second and the third types of smooth muscle, both high K’ concentrations and receptor agonists appear to release cellular Ca’+. Organic Ca” + antagonists are again ineffective, whereas sodium nitroprusside inhibits the contrac-

Type 1

I

Receptor-linked

Vol. 87, No. 4

Membrane

,

channel

Voltage-dependent

Ca

channel

Ca

‘be 2 Receptor-linked

channel

Voltage-dependent

Type

Ca

Ca

channel

3

Receptor-linked

Ca

channel

Voltage-dependent

Ca

channel

1 1

Nitroprusside-sensitive Verapamil-sensitive

Figure 2 Proposed Ca”+ channels in various smooth muscles. Type 1 represents Ca”+ channels in aorta of adult rabbit and of some rat strains. There are two Ca’+ channels: one is regulated by membrane potential and inhibited by organic Ca ‘+ antagonists like verapamil and the other is receptor-regulated and is inhibited by sodium nitroprusside. Type 2 represents Ca” channels in most vascular as well as in gastric smooth muscles. In these smooth muscles, the two Ca”+ channels are at least partly sensitive to both organic Ca’+ antagonists and sodium nitroprusside. Type 3 represents Ca’:’ channels in intestinal, genital, and tracheal smooth muscles. These Ca”+ channels are sensitive only to organic Ca2+ antagonists and not to sodium nitroprusside. For further details see text.

tion induced muscle. Ca”

by CaZ+ release only in type 2 smooth

Channeis ?’

in Other Tissues

In cardiac muscle, organic Ca” + antagonists inhibit contraction by selectively inhibiting a slow Ca2+ channel that contributes to the late plateau phase of the action potential and has little effect on a fast Na+ channel that initiates the action potential (122). There are also Ca2+ channels in squid giant axon, a fast Na+ channel that is also used by Ca2+, and a slow Ca’+ channel that is inhibited by organic Ca2+ antagonists (123). High Kt concentrations re-

October

1984

CALCIUM

CHANNELS

IN SMOOTH

MUSCLE

967

lease neurotransmitter from brain synaptosomes, and this effect is inhibited by organic Ca”+ antagonists (124). In adrenal chromaffin cells, both acetylcholine and high K+ concentrations induce a Ca”dependent secretion of catecholamines that is inhibited by D600 (125). Furthermore, it has been reported that glucose-induced release of insulin in pancreatic p-cells (126) and release of vasopressin and oxytocin after increased Ca’+ uptake in pituitary cells are inhibited by organic Ca’+ antagonists (127). These results suggest that receptor-linked or voltagesensitive Ca2+ channels, or both, are operative in these cells and are inhibited by organic Ca’+ antagonists (5,128). The Ca 2+-dependent release of norepinephrine from vascular tissue induced by high Kt concentrations (129), however, was not inhibited by verapamil (82,130,131). Actually, high concentrations of organic Ca2+ antagonists increased release of norepinephrine in rabbit aorta and this action was not affected by removing external Ca2+ (131). In the r-t A;nnh,,,,rn no,..,,, ,,.or.ln nvnnnrnt;nn II CZ'JI h;nh IrlL ulapuLa)yll 11G1“CT?-,IIUJL,G p’~pa”l”“” I’ d&,, Illpl

norepinephrine, histamine and potassium. J Pharmacol Exp Ther 1968;159:91-7. 11. Bohr DF. Vascular smooth muscle: dual effect of calcium. Science 1963:139:597-9. 12. Turlapaty PDMV, Hester RK. Carrier 0. Kale of calcium in different layers of vascular smooth muscle in norepinephrine contraction. Blood Vessels 1976;13:193-209. 13. Karaki H. Kubota H, Urakawa N. Mobilization of stored calcium for phasic contraction induced by norepinephrine in rabbit aorta. Eur J Pharmacol 1979;56:237-45. 14. Brading A, Jones AW. Distribution and kinetics of CoEDTA in smooth muscle, and its use as an extracellular marker. J Physiol (Lond) 1969;200:387-401. 15. Wheeler ES, Weiss GB. Correlation between response to norepinephrine and removal of ““Ca from high-affinity binding sites by extracellular EDTA in rabbit aortic smooth muscle. J Pharmacol Exp Ther 1979;211:353-9. 16. Deth R, van Breemen C. Agonist induced release of intracellular Ca’+ in the rabbit aorta. J Memb Biol 1977:30:363-80. 17. Freeman DJ. Daniel EE. Calcium movement in vascular smooth muscle and its detection using lanthanum as a tool. Can J Physiol Pharmacol 1973:51:900-13. 18. Goodman FR. Weiss GB. Dissociation by lanthanum of smooth muscle responses to potassium and acetylcholine. Am J Physiol 3971;220:759-66.

K+ concentrations increased the miniature end-plate potential (indicative of release of acetylcholine at the neuromuscular junction). Verapamil did not inhibit this release of acetylcholine but, instead, potentiated it (133,134). Thus, the voltage-sensitive CaZ+ channels in these nerve terminals appear to differ from those in other tissues.

19. Weiss GB. Cellular pharmacology of lanthanum. Annu Rev Pharmacol 1974;14:343-54. 20. Karaki H. Weiss GB. Alterations in high and low affinity binding of “‘Ca in rabbit aortic smooth muscle by norepinephrine and potassium after exposure to lanthanum and low temperature. J Pharmacol Exp Ther 1979:211:86-92. 21. Karaki H. Weiss GB. Dissociation of varied actions of norepinephrine on ‘“Ca uptake and release at different sites in rabbit aortic smooth muscle. J Pharmacol Exp Ther 1980: 215:363-8. 22. Brading AF. Sneddon P. Evidence for multiple sources of calcium for activation of the contractile mechanism of guinea-pig taenia coli on stimulation with carbachol. Br J Pharmacol 1980;70:229-40. 23. Weiss GB. Approaches to delineation of differing calcium binding sites in smooth muscle. In: Casteels R. Godfraind T. Ruegg JC. eds. Excitation-contraction coupling in smooth muscle. Amsterdam: ElsevieriNorth Holland Biomedical Press, 1977:253-60. 24. Weiss GB. Quantitative measurement of binding sites and washout components for calcium ion in vascular smooth muscle. In: Weiss GB, ed. Calcium in drug action. New York: Plenum. 1978:57-74. C, McNaughton E. The separation of cell 25. Van Breemen membrane calcium transport from extracellular calcium exchange in vascular smooth muscle. Biochem Biophys Res Commun 1970;39:567-74. C. Farinas BR. Gerba P. McNaughton ED. 26. Van Breemen Excitation-contraction coupling in rabbit aorta studied by the lanthanum method for measuring cellular calcium influx. Circ Res 1972;30:44-54. agents on mobili27. Karaki H. Weiss GB. Effects of stimulatory zation of high and low affinity site ‘“Ca in rabbit aortic smooth muscle. J Pharmacol Exp Ther 1980:213:450-5. differences in ““Ca efflux 28. Karaki H. Weiss GB. Qualitative from membrane sites in vascular smooth muscle when washout conditions are varied. Gen Pharmacol 198O;ll: 483-9. C, Lesser P. The absence of increased mem29. Van Breemen brane calcium permeability during norepinephrine stimulation of arterial smooth muscle. Microvasc Res 1971:3:11314.

References of action of transmitters and other 1. Bolton TB. Mechanisms substances on smooth muscle. Physiol Rev 1979;59:606718. and pharmaco2. Somlyo AV, Somlyo AP. Electromechanical mechanical coupling in vascular smooth muscle. 1Phamacol Exp Ther 1968;159:129-45. and contractility in vascular smooth 3. Weiss GB. Calcium muscle. In: Narahashi T, Bianchi CP, eds. Advances in general and cellular pharamacology. Vol. II. New York: Plenum, 1977:71-154. in vascular 4. Weiss GB. Sites of action of calcium antagonists smooth muscle. In: Weiss GB, ed. New perspectives on calcium antagonists. Baltimore: Williams & Wilkins, 1981: 83-94. basic chemical and pharma5. Triggle DJ. Calcium antagonists: cological aspects. In: Weiss GB. ed. New perspectives on calcium antagonists. Baltimore: Williams & Wilkins. 1981: 1-18. L. Triggle DJ. Calcium, calcium translocation 6. Rosenberger and specific calcium antagonists. In: Weiss GB. ed. Calcium in drug action. New York: Plenum, 1978:3-31. C, Aaronson P, Loutzenhiser R. Sodium7. Van Breemen calcium interactions in mammalian smooth muscle. Pharmacol Rev 1979;30:167-208. 8. Mekata F. Current spread in the smooth muscle of the rabbit aorta. J Physiol (Land) 1974;242:143-55. in the smooth muscle cell membrane 9. Mekata F. Rectification (Lond) 1976:258:269-78. of rabbit aorta. J Physiol 10. Hudgins PM, Weiss GB. Differential effects of calcium removal upon vascular smooth muscle contraction induced by

968

KARAKI

AND

30. Deth R, van Breemen C. Relative contributions of Ca’+ influx and cellular Ca”+ release during drug-induced activation of the rabbit aorta. Pflugers Arch 1974;348:13-22. 31. Meisheri KD, Hwang 0, van Breemen C. Evidence for two separate Ca’+ pathways in smooth muscle plasmalemma. J Memb Biol 1981;59:19-25. 32. Karaki H, Hatano K, Weiss GB. Effects of magnesium on ““Ca uptake and release at different sites in rabbit aortic smooth muscle. Pflugers Arch 1983;398:27-32. H Ilraknwn 33. Knraki .-_._D_..-__, -_-__-..- N . Cnmnnmtive d_.__ __.- - __of -_ ____-_._ H __, .Naknmwn r------ - effects

34.

35.

36.

37;

GASTROENTEROLOGY

WEISS

verapamil and sodium nitroprusside on contraction and 45Ca uptake in the smooth muscle of rabbit aorta, rat aorta and guinea pig taenia coli. Br J Pharmacol 1984:81:393-400. Karaki H. Weiss GB. Inhibitors of mitochondrial Ca++ uptake dissociate potassium-induced tension responses from increased %a retention in rabbit aortic smooth muscle. Blood Vessels 1981;18:28-35. Karaki H. Suzuki T, Ozaki H, Urakawa N, Ishida Y. Dissociation of K’-induced tension and cellular Ca’+ retention in vascular and intestinal smooth muscle in normoxia and hypoxia. Pflugers Arch 1982;394:118-23. Nakagawa H, Karaki H, Urakawa N. Effects of antimycin A (AA] on smooth muscle contractions (abstr). Abstracts of the Ninth International Congress on Pharmacology, 1984. Itn K. Knrnki Jraknwa N. The mode of contractile action _._ _., _.___... H. __, I____._.._

of palytoxin on vascular smooth muscle. Eur J Pharmacol 1977:46:9-14. 38. Kalsner S, Nickerson M, Boyd GN. Selective blockade of potassium-induced contractions of aortic strips by p-diethylaminoethyldiphenylpropylacetate (SKF525A). J Pharmaco1 Exp Ther 1970;174:500-8. of 39. Van Breemen C, Hwang 0, Meisheri KD. The mechanism inhibitory action of diltiazem on vascular smooth muscle contractility. J Pharmacol Exp Ther 1981;218:459-63. 40. Thorens S, Haeusler G. Effects of some vasodilators on calcium translocation in intact and fractionated vascular smooth muscle. Eur J Pharmacol 1979;54:79-91. 41. Golenhofen K. Weston AH. Differentiation of calcium activation systems in vascular smooth muscle. In: Betz E. ed. Ionic actions on vascular smooth muscle. Berlin: Springer Verlag. 1976;22-5. 42. Freer RJ. Calcium and angiotensin tachyphylaxis in rat uterine smooth muscle. Am J Physiol 1975;228:1423-30. 43. Golenhofen K. Theory of P and T systems for calcium activation in smooth muscle. In: Bulbring E. Shuba MF. eds. Physiology of smooth muscle. New York: Raven, 1976:4659. K. Differentiation of calcium activation process 44. Golenhofen in smooth muscle using selective antagonists. In: Bulbring E, Jones AW, Tomita T. eds. Smooth muscle: an assessment of current knowledge. London: Edward Arnold, 1981:157-70. 45. Golenhofen K, Hermstein N. Differentiation of calcium activation mechanisms in vascular smooth muscle by selective suppression with verapamil and D600. Blood Vessels 1975;12:21-37. 46. Watkins RW. Davidson IWF. Comparative effects on nitroprusside and nitroglycerine: actions on phasic and tonic components of arterial smooth muscle contraction. Eur J Pharmacol 1980;62:191-200. 47. Karaki H, Murakami K, Nakagawa H, Urakawa N. Nitroglycerine-induced biphasic relaxation in vascular smooth muscle of rat aorta. Br J Pharmacol 1984;81:387-92. 48. Rapoport RM, Murad F. Effects of ouabain and alterations in potassium concentration on relaxation induced by sodium nitroprusside. Blood Vessels 1983;20:255-64. 49. Ito Y, Suzuki H, Kuriyama H. Effects of sodium nitroprusside on smooth muscle cells of rabbit pulmonary artery and

Vol.

87, No. 4

portal vein. J Pharmacol Exp Ther 1978;207:1022-31. T. Actions of nitroglycerine on smooth muscles 50. Karashima of the guinea-pig and rat portal veins. Br J Pharmacol 1980;71:489-97. 51. Haeusler G. The effects of sodium nitroprusside on vascular smooth muscle. Experientia 1978;31:729. 52. Karaki H, Hester RK, Weiss GB. Cellular basis of nitroprusside-induced relaxation of graded responses to norepinephrine and potassium in canine renal arteries. Arch Int PharThor 148n.7A6.1 marndvn “‘uyv..JII -.--. Iyvv,1 .“.___an_2?0. C. The effect of sodium 53. Zsoter TT, Henein NF, Wolchinsky nitroprusside on the uptake and efflux of ‘%a from rabbit and rat vessels. Eur J Pharmacol 1977;45:7-12. 54. Itoh K, Kuriyama H, Ueno H. Mechanisms of the nitroglycerine-induced vasodilation in vascular smooth muscles of the rabbit and pig. J Physiol (Lond) 1983:343:233-52. 55. Kreye VAM. Baron GD. Luth JB, Schmidt-Gayk H. Mode of action of sodium nitroprusside on vascular smooth muscle. Naunyn Schmiedeberg Arch Pharmacol 1975;288:381-402. 56. Katsuki S, Arnold WP, Murad F. Effects of sodium nitroprusside, nitroglycerine, and sodium azide on levels of cyclic nucleotides and mechanical activity of various tissues. J Cyclic Nucleotide Res 1977:3:239-47. 57. Ignarro LJ, Lipton H. Edward JC, Baricos WH, Hyman AL, Kadowitz PI af ,~~sc&ar s_~_got.h. _ ,’ Cnlettar -. yy..y _ C-A -. _. &&nis.q. muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiol as active intermediates. J Pharmacol Exp Ther 1981;218:739-49, 58. Kukovetz WR. Poch G. Holzmann S. Cyclic nucleotides and relaxation of vascular smooth muscle. In: Vanhoutte PM, Leusen I, eds. Vasodilatation. New York: Raven, 1981:33953. 59. Diamond J, Janis RA. Increase in cyclic GMP levels may not mediate relaxant effects of sodium nitroprusside. verapamil and hydralazine in rat vas deferens. Nature 1978;271:472-3. J. Relationship between cyclic nucleo60. Janis RA, Diamond tide levels and drug-induced relaxation in smooth muscle. J Pharmacol Exp Ther 1979;211:480-7. Ibrr7nin MR Mn~rarl V Snrlixlm nitmnril
Ozaki H. Shibata S. Kitano H, Matsumoto P. Ishida Y. A comparative study on the relaxing effects of nitroprusside and verapamil on human umbilical vessels. Blood Vessels
N. Effects of vanadate on mechanical 65. Uzaki H, Urakawa response and Na-K pump in vascular smooth muscle. Eur J Pharmacol 1980;68:339-47. 66. Kishimoto T. Urakawa N. Effects of ouabain induced contractions in various smooth muscle the guinea pig. Jpn J Pharmacol 1982;32:551-61.

on high-K tissues in

67. Massingham R. A study of compounds which inhibit vascular smooth muscle contraction. Eur J Pharmacol 1973;22:7582. T. Dieu 68. Godfraind norepinephrine-evoked

D. The inhibition of flunarizme of the contraction and calcium influx in

October

1984

rat aorta and mesenteric arteries. J Pharmacol Exp Ther 1981:217:510-15. 69. Kreye VAW, Kern R. Schleich I. ““Chloride efflux from noradrenaline-stimulated rabbit aorta inhibited by sodium nitroprusside and nitroglycerine. In: Casteels R. Godraind T. Ruegg JC. eds. Excitation-contraction coupling in smooth muscle. Amsterdam: ElsevieriNorth Holland Biomedical Press, 1977:145-50. LJ. Griebel L, Wende W. Activation of vascular 70. Peiper smooth muscle of rat aorta by noradrenaline and depolarization: two different mechanisms. Pflugers Arch 1971;330:7489. 71. Bilek I. Lawen R. Peiper U. Regnat K. The effect of verapamil on the response to noradrenaline or to potassium-depolarization in isolated vascular strips. Microvasc Res 1974:7: 181-9 TM. Effects of sodium nitroprusside and 8-bromo 72. Lincoln cyclic GMP on the contractile activity of the rat aorta. 1 Pharmacol Exp Ther 1983:224:100-7. 73. Lammel E. ‘“<:a uptake of stomach smooth muscle during different modes of activation. In: Casteels R, Godfraind T. Ruegg JC. eds. Excitation-contraction coupling in smooth muscle. Amsterdam: ElsevieriNorth Holland Biomedical Press. 1977:273-7. 74. Golenhofen K, Wagner B, Weston AH. Calcium systems of smooth muscle and their selective inhibition. In: Casteels R. Godfraind T. Ruegg JC, eds. Excitation-contraction coupling in smooth muscle. Amsterdam: ElsevieriNorth Holland Biomedical Press, 1977:131-6. 75. Ishizawa M. Miyazaki E. Prostaglandin Fz,,(PGF,,,)-induced contraction and calcium movement in longitudinal muscle of guinea-pig isolated stomach. Prostaglandins 1978;16:591a. ‘I. Nakajima H. Kiyomoto A. Effects of diltia76. Magaribuchi zem and lanthanum ion on the potassium contracture of isolated guinea pig stomach muscle. Jpn J Pharmacol 1977: 27:333-g. 77. Golenhofen K. Weiser HF. Siewert R. Phasic and tonic types of smooth musr.le activity in lower esophageal sphincter and stomach of dog. Acta Hepato-Gastroenterol 1979;26:227-34. K. Lukanow J. Selective suppression of 78. Boev K. Golenhofen phasic and tonic activation mechanisms in stomach smooth muscle. In: Bulbring E, Shuba MF. eds. Physiology of smooth muscle. New York: Raven 1976:203-8. T, Karaki H, Urakawa N. High K-induced 79. tleda F. Kishimoto contractions in rabbit and monkey tracheal smooth muscle. Jpn J Smooth Muscle Res 1983:19:541-Y. K. Kurihara J, Takata Y. Kato H. Selective inhibi80. Nakayama tion by nicardipine of the contractile response to 5-hydroxytryptamine in cerebral artery (abstr). Abstracts of the Eighth Congress on Pharmacology. 1981. page 802. H), Gorlitz BD, Wagner J. Influence of papaver81. Schumann me. I)600 and nifedipine on the effects of noradrenaline and calcium on the isolated aorta and mesenteric artery of the rabbit. Naunyn Schmiedebergs Arch Pharmacol 1975: 289:409-18. G. Differential effects of verapamil on excitation82. Haeusler contraction coupling in smooth muscle and excitation-secretion coupling in adrenergic nerve terminals. 1 Pharmacol Exp Ther 1972:180:672-81. C. Siegel B. The mechanism of u-adrenergic 83 Van Breemen activation of the dog coronary artery. Circ Res 1980:46:4269. T. A comparison of the different effects of 84 lmai S. Kitagawa nitroglycerine. nifedipine and papaverine on contractures induc;ed in vascular and intestinal smooth muscle by potassium and lanthanum. lpn 1 Pharmacol 1981:31:193-Y.

CALCIUM

CHANNELS

IN SMOOTH

MUSCLE

969

85. Walus KM, Fondacaro JD. Jacobson ED. Effects of calcium and its antagonists on the canine mesenteric circulation Circ Res 1981:48:692-700. 86. Verhaeghe RH. Shepherd JT. Effects of nitroprusside on smooth muscle and adrenergic nerve terminals in isolated blood vessels. J Pharmacol Exp Ther 1976;199:269-77. 87. Shepherd JT, Vanhoutte PM. Veins and their control. Philadelphia: WB Saunders 1975. 88. Ishida Y. Ozaki H. Shibata S. Vasorelaxant action of caroverine fumarate (a nuinoxaline derivative), a calciumblockin~ agent. Br J Pharmacol 1980;71:343-8. 89. Hester RK. Weiss GB. Comparison of degree of dependence of canine renal arteries and veins on high and low affinity 1 calcium for responses to norepinephrine and potassium. Pharmacol Exp Ther 1981:216:239--46. 90. Lowe DA, Matthews EK, Richardson BP. The calcium antagonistic effects of cyproheptadine on contraction, membrane electrical events and calcium influx in the guinea-pig taenia coli. Br J Pharmacol 1981:74:652-63. 91. Johnishi J. Sunano S. The role of membrane electrical activities and extracellular calcium in high-K-induced cou1978;28:1-16. tracture in guinea pig ureter. Jpn 1 Physiol 92. Riemer J. Dofler F. Mayer CJ. I_Jlbrecht G. Calcium antagonistic effects on the spontaneous activity of guinea pig taenia coli. Pflugers Arch 1974:351:242-58. 93. Mayer CJ. van Breemen C, Casteels R. The action of lanthanum and D600 on the calcium exchange in the smooth muscle cells of the guinea-pig taenia coli. Pflugers Arch 1972;337:333-50. 94. Rosenberger LB. Ticku MK, Triggle DJ. The effects of Ca’ ’ antagonists on mechanical responses and Ca” movements in guinea pig ileal longitudinal smooth muscle. Can J Physiol Pharmacol 1979:57:333-47. 95. Triggle CR, Swamy VC, Triggle DJ. Calcium antagonists aud contractile responses in rat vas deferens and guinea pig ileal smooth muscle. Can J Physiol Pharmacol 1979;57:804-18. 96. Jim K, Triggle DJ. The actions of praziquantel and l-methyladenine in guinea pig ileal longitudinal muscle. Can J Physiol Pharmacol 1979;57:1460-2. 97. Clement JG. BaCl,-induced contractions in the guinea pig ileum longitudinal muscle. Role of presynaptic: release of neurotransmitters and Ca2+ translocation in the postsynaptic membrane. Can J Physiol Pharmacol 1981;59:541-7. 98. Hay DWP. Wadsworth RM. Effects of some organic calcium antagonists and other procedures affecting Ca” translocation on KCl-induced contractions in the rat vas deferens. Br J Pharmacol 1982:76:103-13. 99. Shimodan M, Sunano S. The initiation of phasic and tonic contraction by potassium and the effect of calcium, multivalent cations and Ca-antagonists on potassium contracture in guinea-pig vas deferens. Jpn J Physiol 1981;31:15-27. 100 Farley JM, Miles PR. The sources of calcium for acetylcholine-induced contractions of dog tracheal smooth muscle. 1 Pharmacol Exp Ther 1978:207:340-6. 101 Goodman FR. Calcium-channel blockers and respiratory smooth muscle. In: Weiss GB. ed. New perspectives on calcium antagonists. Baltimore: Williams & Wilkins, 1981: 217-22. 102 Jetley M. Weston AH. Some effects of sodium nitroprusside. methoxyverapamil (D600) and nifedipine on rat portal vein. Br J Pharmacol 1980;68:311-20. K. Golenhofen K. Activation 01 gastro-intestinal 103 Mandrek smooth muscle induced by the calcium ionophore A 23187. In: Worcel M, Vassort G. ed. Smooth muscle pharmacology and physiology. INSERM 50, 1976:343-S 1. 104 Burnstock G. Holamn ME, Prosser CL. Electrophysiology of smooth muscle. Physiol Rev 1963;43:482-527.

970

105.

106.

107.

KARAKI

AND

WEISS

Karaki H, Urakawa N. Ikeda M. Influences of external magnesium, bicarbonate and phosphate on potassium-induced contracture of guinea pig taenia coli. Jpn J Pharmacol 1966;16:423-37. Nasu T. Karaki H. Ikeda M. Urakawa N. Effect of histamine on calcium movement in guinea pig taenia coli. Jpn J Pharmacol 1971;21:597-603. Hurwitz L. Characterization of calcium pools utilized for contraction in smooth muscle. In: Worcel M. Vassort G, eds. Sm~ooth mmsc1e =-~ nharmarnlnov and r”,I~-~ nhvsinlnuv_b,. _..-INSF’RM _... _ 50 __. _-.- __I_._ b: ____ 1976;369-80.

108.

109.

110.

111.

112:

Urakawa N, Holland WC. Ca’” uptake and tissue calcium in K-induced phasic and tonic contraction in taenia coli. Am J Physiol 1964:207:873-6. Ohashi H, Takewaki T, Okada T. Calcium and the contractile effect of carbachol in the depolarized guinea-pig taenia caecum. Jpn J Pharmacol 1974;24:601-11. Casteels R, van Breemen C, Mayer CJ. A study of the calcium distribution in smooth muscle cells of the guinea pig taenia coli using La3+. Arch Int Pharmacodyn Ther 1972:199:1934. Fox JET, Daniel EE. Role of Ca” in genesis of lower esophageal sphincter tone and other active contractions. Am J Physiol 1979;237:E163-71. Gnval RK. Rattan S. Effects nf s&ium nitr~nrusside and m-,-----,

verapamil on lower esophageal sphincter. Am J Physiol 1980;238:G40-4. 113. Polidro JH, Savino EA. Responses of the rat tail artery to high external potassium concentration. Arch Int Pharmacodyn Ther 1982;256:36-48. 114. Flaim SF. Comparative pharmacology of calcium blockers based on studies on vascular smooth muscle. In: Flaim SF. Zelis R, eds. Calcium blockers, mechanism of action and clinical applications. Baltimore: Urban & Schwarzenberg. 1982:155-78. 115. Nakajo S. Shimizu K. Kometani A, et al. Inhibitory effect of bassianolide, a cyclodepsipeptide, on drug-induced contractions of isolated smooth muscle preparations. jpn J Pharmaco1 1982;32:55-64. 116. Nakajo S, Shimizu K. Kometani A, Suzuki A, Ozaki H. Urakawa N. On the inhibitory mechanism of bassianolide. a cyclodepsipeptide. in acetylcholine-induced contraction in guinea-pig taenia coli. Jpn J Pharmacol 1983:33:573-82. 117. Evans DHL. Schild HO, Thesleff S. Effects of drugs on depolarized plain muscle. J Physiol (Land] 1958:143:47485. 118. Edman KAP, Schild HO. The need for calcium in the contractile responses induced by acetylcholine and potassium in the rat uterus. J Physiol (Lond] 1962:161:404-11. 119. Westfall DP. The effects of denervation, cocaine, B-hydroxy-

GASTROENTEROLOGY

120.

121.

122.

123.

124.

125.

126. 127. 128.

129.

130.

131.

132.

133.

134.

Vol.

87, No. 4

dopamine and reserpine on the characteristics of druginduced contractions of the depolarized smooth muscle of the rat and guinea pig vas deferens. J Pharmacol Exp Ther 1977;201:267-75. Benham CD, Bolton TB. Do smooth muscle stimulants acting through receptors open similar ion channels in taenia of guinea-pig caecum? J Physiol (Lond) 1981;319:61P-2P. Karaki H, Nakagawa H. Urakawa N. Different characteristics of calcium channels in smooth muscles (abstr). Abstracts of the Ninth International Congress on Pharmacology, 1984. Fleckenstein A. Fundamental actions of calcium antagonists on myocardial and cardiac pacemaker cell membranes. In: Weiss GB. ed. New perspectives on calcium antagonists. Baltimore: Williams & Wilkins, 1981:59-82. Baker PF. Meves H. Ridgway EB. Effects of manganese and other agents on the calcium uptake that follows depolarization of squid axons. J Physiol (Lond) 1973;231:511-26. Nachsem DA, Blaustein MP. The effects of some organic “calcium antagonists” on calcium influx in presynaptic nerve terminals. Mol Pharmacol 1979;16:579-86. Pinto JEB, Trifaro JM. The different effects of D600 (methoxyverapamil) on the release of adrenal catecholamines induced by acetylcholine. high potassium. or sodium deprivation. Br J Pharmacol 1976:57:127-32. Matthews

EK, Sakamoto

Y. Electrical

characteristics

of pan-

creatic islet cells. J Physiol (Lond) 1975;246:421-37. Thorn NA, Russel JT, Torp-Pederson C, Treiman M. Calcium and neurosecretion. Ann NY Acad Sci 1977:307:618-39. Rubin RP. Actions of calcium antagonists on secretory cells. In: Weiss GB, ed. New perspectives on calcium antagonists. Baltimore: Williams & Wilkins, 1981;147-58. Vanhoutte PM, Verbeuren TJ, Webb RC. Local modulation of adrenergic neuroeffector interaction in the blood vessel wall. Physiol Rev 1981:61:151-247, Haeusler G. The effect of verapamil on the contractility of smooth muscle and on excitation-secretion in adrenergic nerve terminals. Angiologica 1971;8:156-60. Karaki H, Nakagawa H, Urakawa N. Effects of organic calcium antagonists on release of [“Hlnorepinephrine in rabbit aorta. Eur J Pharmacol 1984;101:177-83. Van Der Kloot W. Calcium and neuromuscular transmission. In: Weiss GB. ed. Calcium in drug action. New York: Plenum. 1978:261-87. Asai F. Nishimura M. Urakawa N. Effects of verapamil and manganese on potassium-induced transmitter release in rat diaphragm muscles. Arch Int Pharmacodyn Ther 1982: 255:191-s. Nishimura M, Asai F. Urakawa N. Verapamil-induced transmitter release in rat diaphragm muscle. Jpn J Pharmacol 1982;32:231-5.