Indian J f'kysiol f'hlrmacol 1991; 35(4): 211-231

CALCIUM CHANNELS AND CALCIUM CHANNEL BLOCKERS

S. D. SETH· AND SANDEEP SETH**

Departmcnts of Plwrmacology" Mcdicinc ....All fndia fnstilUlc of Medical Scienccs,New Delhi - 110 029

INTRODUCTION

Calcium channel blockers (CCB) have been usedextensively in various C<.lrdiov<.lscular conditionsincluding ischemic heart disease, supraventriculararrhythmias, systemic hypertension, pulmonary llypcr­tension, congestive heart failure ~lOd hypertrophiccardiomyopaLhy. They may have :t role in many non­cardiac diseases like bronchial asthnJ:l, esoph:lge:llspasm, migraine, Raynaud's phenomenon and prcmn­lure labor (I).

Hass and H:.tnfelder reponed in 1%2 th,lIverapamil, a coron:.try vasodil;.l1or, h,ld a neg,Hiveinolropic action. Subsequently, Fleckenstein suggesledlhJL this was due to inhihilion of CXeiL;llion-contmctioncoupling vi,] a reducLion of movement of calcium ionsinto enrdiuc muscle cells (2). Rougier et al 0),presented evidence suggesting thai fast and slowchannels were involved in lhe gencsis of ,ltri;lldepolarization. When the lr.lnSlllemhr;me potclllial ofa cardiac cell exceeds threshold, lhe 'f,lSl channel' for'Na' innux' opens up. A second inward current tllleto Cal' innux takes much longer 10 re:1(::h ma:<.imumvalues and is termed the 'slow channel' or 'Cal,channel'.

Calcium and Calcium Channc{~': Calcium in thecells can scrve two functions. One, i! can carr)' chargeresulting in depolarization which cun serve us aregul:.ltor of pncemaker activity or conduction veloci!y.The sinoatrial and the mriovenlri<.:ular nodes in theheart arc cxamples of the depoJarizmion funclion of acalcium current. Two, lhe culciulll influx can serve asan intracellular messenger. Example" of lhis effecl inthe cardiovascular system include contractile clementactivation by the binding of cakium to troponin inthe heart and binding of calcium to calmodulin to

'Com:Jpondin& AUUlor

activate myosin light-chain kinase in vascular smoothmuscle.

In the study of va"culnr smooth muscle, two c1as­sine:llions of mechllOisms regulating calcium innuxwere the voltage-dependent Hnd receptor-o~rated

medmnisms. The fonner was often swdled by depo­briz.1tion of vascular smOOlh musclc with potassium(e.g. 60mM) and the l:ltler b)' stimulation of calciuminllux by norepinephrine binding 10 post-junctionala-receptors. Now, it is recognizcd th,1t voltage-depen­denl and receptor-o[1Cr:.lled mechanisms for increasingintracellu!:lr Cllkium eonccnlI<llion arc not as discreteand simple as previously lhought but arc rather morecompk'.x. 11lis ha.~ become increasingly apparent as therole of calcium ;IS an intr:.Jcellubr messenger has beendefined in a number of non-c:mliovaseular tissues.Lots of inform:ttion has been galhered regarding theregulation of intr,lcellular calcium ion concenlr,ltion bysludying stimulus-secretion cOt/pling of neural andendocrine celts and the lIleehaniS1llS involved in rccep·tor-regul:Heti mewbolic processes in non-eltciwbieorg:ms.

CfJlciWII CJumne/s: The \'olt:Jge dependent and re­ccptor-olx:raled processes form twO ends of :L spce­lmlll. TIlere arc pure vollage-depemlcnt calcium chan­nels <Ind also a variety of receptor-regututed mecha­nisms.

Receptor-,lgonist interaction can c<luse Cal.concentration to increase in the following ways: I)receptor ~timt/l;J!ion IC:lds to the liberation or allintr:lcellular messenger lending to relea<;e of calciumfrom inlIm.:ellul:lr storage sites, 2) reccptor stimulationfacili1..11es calcium innux through a voltage·depcndeOil:<1lcium dUUlllel :mel 3) rcteplOr stimulation resultS inthe coupling LO :lIld aClivalion of a calcium ch.1nnel.

218 &Ih and Seth Indfan I I'hysiol Plurmlcol 1991; 35(4)

Calcium channels arc divided into 3 groups:Receptor operated. stretch opcrnlcd and vollage regu­lated calcium channels.

(i) Receptor opera/cd channels: TIlcsc chan­ncls increase calcium innux in responselO various hannoncs and ncuro-hormones.

(ii) StreIch operated channels: These arcpresent in blood vessels and increasecalcium innux on being slrCtchcd.

(iii) Vollage-regulated calcium channels:These arc innucnced by high K' levels ordepolarizing external stimuli. Voltagesensitive calcium channels containdomains or subunits of homologoussequence thaI arc arranged in tandemwithin a large subunit. These domainscontain several hydrophilic regions span­ning the cell membrane. Besides thismain subunit termed at' other associatedsubunilS include !Xz. ~1' Y and 0 (4).

Calcium Channel Structures

!Receptor- regulated I-,~===:::C~==_~,

L

+

----{AC.j--t;I,

!voltage - sensitive I~L N T

P

~ATP

cAMp·DAG

Fig. I ; Diagmnmatic representation of Calcium Channcls. Ca" - lntf1lcclluln Calcium, ,.. (Tnomiem). 1'1 (Neuronal), and L (Long last·ing) Voltage regulated Qarmels. AC·Adenyl Cyclase, G·G l'rOlcin, I'K·I'rutein Kinase; I·-I'hospllorylation.alagoniS!, a, agonist, ~, agQllistPL- Phospholipase C; I'll'l -1'l1osphatidylinositol bipho5phatc; DAG -Diacylglyccrol, I'K, -Protein Kinasc; IPI-Inositoltriphosphate.

Intf1lccllular calcium conccntr:lliOfi incrt.asci by innux through l1\ernbr~"c during aClivDtiQll of T, N or L voltagc regulatcd chan·nch. Rcceptor aaivalion increases intracellular calcium hy Of\C of the following mechanisms depending uPon the type of receptorslimulated. ~,.aglllliSl binds wilh adenyl cyclase by G protein. The l'Csulting increasc in cyclic AMP activates a protein kinase tophosphorylate an L-<:hannel, which facilitates intraedlular calcium innu•. AflOIhcr agonist (cr., receptor agonist) activates receptorlinked by G.protcin to channel through which c.alcium CI" ~~,t"r cell. 'Illis is .l.Ug&eucd to be the L channel regulated directly byUr·reeeptor. The receptor regulalcd by a, agonist activates phospholipue C, resulting in brcakdown of phosphatidylinositolbiphosplille. This IC.Jds to the relc;l$C or diacylglyccrol, lcading 10 activation of prOtcin kin3$c C and inositol tripllosphate whiChserves as intf1lccllular second mcucngcr. Binding or inositol uiphO'Sphate to re«:plors on sarcoplasmic reuculum leads to thc re·lease of calcium (modified (ron, 'l..c1is & Moore, Circulluon, 1989; 80 suprl IV, IV-14-IV·16).

Indian J Physiol Pharmacol 1991; 35(4)

The voltage sensitive channels are further dividedinto subtypes L (long lasling or 'slow' channel), N(neuronal) and T (transient or 'fast') channels, basedon their voltage sensitivity and conductance (5.6). TheT and L channels are found in cardiac and vascularsmooth muscles. These tissues are devoid of Nchannels which arc sccn only in nerves. Calciumconduclance is low in the T channel, high in L chan­nel and intermediate in the N channel (7). In neuronaltissue, the T channels arc activated casily when lhetransmembrane potential becomes less negativethan -70mV (8). The N and the L channels are moredifficult to activate. Transmembrane vollage must bereduced by a grei.llcr extcnt, requiring a potential ofabout -lOmV before activation occurs (8). The tmn­sient or T channels are mpidly inactivated, this is whycalcium conductance is low. The long lasting or Lchannels are morc slowly inactivated, thus allowingfor a greatcr net conduCl:lnce. The N channels arcintermediate (7,8).

The three channels arc specifically blocked bydifferent agents. The T channels are resistant to

blockade by most agents. Only nickel can inhibitcalcium conductance. Both Nand L channels can beblocked by cadmium and the venom of marine snailConus gcographicus (w-conotoxin). It is only the Lchannel that is sensitive to blockade by the organiccalcium amagonislS such us diltiazcm, ver<lpllmil andnifedipine.

In the neuronal tissues, both Nand L c1mnnelsexist The organic calcium channel blockers can inhibitthe calcium innux mediated by L channels but havevery little effect on neuroscnetory coupling (8,9),suggesting lhereby that calcium innux can be compart­mentalized within the celt.

Clusters of N channels have been found aroundarcas of membrane fusion points where synaptic ves­icles fuse with the mcmbmne to relc~lsc their contentsinto the neurocffcctor junction. Furthcr, (O-conotoxininhibits L chnnncls in neuronal tissues but not else­where (7). This suggests that there might be morethan one species of L channels.

ReceplOr - regulated calcium channels: Themechanism by which intracellular concenlnltion of

Calcium Channels and Calcium Channel Blacken 219

calcium is incrc.1SCd is presented in Fig. 1. Three typesof reccptors arc shown with three different types of ag­onisls, coupled by a G-protein to a specific mecha­nism. The T and N regulated channels represent a purevohage-sensitive mechanism to increase intracellularcalcium concentration from an eXlTaccllular source, thereceptor opemtcd mechanism that works by causingintfilCellular calcium concentration to rise by releasefrom imracctlular storage sites. This is the mechanismwhen ai-adrenergic receptors are stimulated.

(X,-receptor stimulation activates phospholipase C,which hydrolyses phosphatidylinositol biphosphate,cleaving it into two active components, diacylglyccrol,which activates protein kinase C, and inositoltriphosphate (IP:J. IP, serves as an intracellular mcs­senger that interacts with reccptors on the sarcoplas­mic reticulum to cause calcium release from this intra­cellular organelle.

A rcceptor-opcnued mechanism that can modulateC<llcium innux by a voltage regulated channel is de­picted in Fig. I. Here a receptor llgonist results in thephosphorylation of an L channel by a cycliC-AMPdependent protcin kinase. In the phosphorylated state,the L channels arc more likely to open in response tomembrane depoillri ....ation and whole cell conductanceincreases. A prototype of this mechanism is that acti­vated by the PI-adrenergic agonist in the heart. In addi­tion to the phosphorylation of the L-typc voltage-sen­sitive channel, the protein kinase activated by cyclicAMP nlso phosphorylates a protcin in the sarcoplas­mic rcticulum, which enhances cntcium uptake by thisorganelle. Thc result of activating this mechanism isan intcnse cnlcium pulse of shoner duration.

The vascular smooth muscle docs not contain anL channel that C<ln he phosphorylated by a p-reccptormedimcd activation of adenylate cyclase. Rather insmooth muscle, ~-rcccptor stimulmion leads to activationof a cyclic AMP dependcnt protein kinase. Inin-vitro systems, phosphorylation of myosin light-Chainkinase ren<tcrs it less sensitive 10 activation by thecalcium-calmodulin complex - a mechanism proposedto cxplain v,lsculnr smooth muscle reluxation byp-rcceptor stimulation. Howcver, reccm evidence sug­gests that the myosin light-chain kinase phosphoryla­tion sites required for en....yme dcscnsitii'.mion are not

220 Seth and Seth Indian J I'hysiol Plmmacol 1991; 35(4)

lhc sites !.hal arc phosphorylated in-vivo. The middlereceptOr seems to be direcLly coupled by a G proteinto a calcium channel (7). With recepLor activation. aninOux of calcium occurs through this channel. Theevidence lhat such a channel exists is bascd on theobservation lhat certain rcccplor-opcr.ltcd mechanismsarc vcry sensitive to inhibition by organic calciumchannel blocking agents. The post junctional L-rcccp­tor in vascular smOOth muscle would be a proLOtypeof this mechanism (7). This might represcnt anotherspecies of L-typc channel.

The evidence presented above suggests lhat anumber of different L-Iypc channels exist, all of whichcan be blocked by Ihe org:mic CeB (9). In nerves, theL channels can also be blocked by C1}-conotoxin. SomeL-lypc channels, such as Lhosc ill cardi:IC musdc, C,lllbe phosphorylated by a cydic AMP dependent proleinkinase, a process that facililUtes c:lkillm innu.'I( (7). Invascular smooth muscle, it is possible that L·typcchannels can be linked lO Ct-:l(tr~ncrgic Slimulation,and can increase calcium innux. In skclet:JI muscle,the T tubules arc a rich source of dihydropyridincreceptors, which bind to organic CCB with highaninity (10). Bascd on reconstitution studies, thesedihydropyridine receptors closely resemble and mighl,infact, be a form of lhc L channel. These dihydropyr­idine receplors arc clearly involved in excitation-con­traction coupling. Howevcr, lhcir exatt function inexcitation-contraction coupling is unclear. Many of theT tubular dihydropyridine receptors arc found in closephysical association with fcct StrUClUres on lhe sarco­plasmic reticulum. These feet structures arc thought(0 represent the sarcoplasmic reticular Cal> -releasechannel and the ryanodine receptor (11).

In skeletal muscle exciwtion-contruClion coupling,whether these dihydropyridine rct:;epLOrs cause voltage­sensitive Ca2• release by a dircct conformntion,,1 ef·feet on the ryanodinc receptor, is nOI yet seuled.

In nerves, calcium innux through N-lypc channelscauses neurosecretory coupling, whereas L ch:lllnelaClivation (and inhibilion) affecls nerve function onlyunder exueme conditions. Calcium innux through acardiac L channel being phosphorylated by a cyclicAMP dependcnt kinase, can potentiate contractility inthe hearl by a calcium mechanism acting :It thc level

of this filamcnt. When the receptor stimulation insmOOlh muscle incre:lses Ca2• , the increase in vaso­motor tone is caused by a myosin regulated mecha­nism. Thus, whcn symp:llhclic ncrves arc activatcd andthe physiological neurotransmitter norepinephrine isreleased, nil the stimulatory effeCl'i on the cardiovas­cular system arc mediated by increasing intracellularcalcium depending whether norepinephrine is interact­mg wilh a ~l-' (X2-' or (II· adrenergic receptor.

Ciani/ica/ion of CCB: Nayler et al (12) havedivided CeB into 3 groups.

(,,) The organic b{ocker.~ including ver:lpamil,galJop:lmil, nifedipine. nlludipine. nimodipine,:unlodipine, isr'ldipine nicardipine, nitrendip­inc, dillhlzcm, prcnylamine, fendiline.

(b) Inorganic bioc.kers e.g. cmions like La" ,1'...1112., C0 2•• Nu·.

(c) Energy dependent blockers e.g. cy:mide, dini­lrophenol.

The org:lllic CCB include all lhe clinicallyrelevant drugs and have been further subdi­vided by Fleckenstein (9) into :-

(i) l/igllly potenl &. specific sub.wunces likeverapamil. diltiazem, nifedipinc (and re­lated dihydropyridines).

(ii) Less specific sulmances like prenylaminc,fendiline, cinnarizine, perhexiline andcaroverine.

(iii) Non-sflecific agcnfs e.g. phenytoin,chlorpromnzinc. indomethacin and highdoses of some hew blockers.

They C<tO also be divided by their chemical struc­lures into:

Gr. I: Dihydropyridine CO!1lfl0lUlds e.g. nifedip­ille, nirnodipinc, nisoldipine, niludipinc,Py 108-068, nicardipine.

Gr. 2: Bcnwlhiau.!flin compounds e.g. diltiazem.

Gr. 3: Phcnylaikylamincs e.g. ventpamil, gallo­pmnil, li:lp:unil.

Indi:lfl J Pby~iol Pharmacol 1991; 35(4)

Effects of Calcium Chilnnel Blockers on Elec/rophY~'i­

oJogical Activity of Ileart

(l) S-A node, A-V node and atria: Calcium chjn·nel blockers cause rcduction ill the nlte of sinus nodedischarge (negative chronolfopic) and decrease in thevclocity of conduClion of electrical impulse throughAN nodc (negative dromolropic) (12). In-vitro andin-vivo effects of calcium channel blockers on thesedepressant effects differ considembly. In isolated prepa­ration of atrial tissue. jlmost all calcium channelblockers have been shown to slow the nlte of S-Anode discharge and prolong the A-V conduction time,the latter being evident by a prolonged effective re­fraclory period in the action potential. On the otherhand. in conscious anim:lls, an inUlct autonomic nerv­ous system considerably modifies these electrophysi­ological effects of the calcium channel blockers. Asignificant reOex sympaLhctic action due to peripheralvasodilatation nullifies or evcn reverses the dcpressantaction of nifedipine on the hearl (13). This is not en­countered wiLh verapami! and dilLim~em due to theirnonspecific antagonism (14). Re-enlrunl A-V nodaltachycardia is prevented by ver..tpamil which is due toits property of prolonging the A- V nodal refr..tctOriness(15).

(II) Effect on verllricular electrical activity: E!TccL~

of calcium ch::mnel blockers on the elcclrophysiologyof the venlricular tissue and venLricular arrhythmi;lshave also been investigated. Verupamil suppresses Lhespontaneous and elcclrically <lctivaLed rhythm of LItePurkinje fibres while depressing the exciL.ability (16).Autom:lliciLy of ventricular muscle fibre is markedlyresiSUlnl to calcium chnnnel blockers. Experimel1l:11ventricular arrhythmias caused by myocardial ischemiahave been found to be responsive to calcium e1mnnclblockers (17).

(III) Effect of Calcium Channel Blockers on tri~­

gered activity causing cardiac arrhythmias: The pre­cise eleClrophysiologic:l1 mechanism of triggereu acti­vity at phase 4 of cardiac action potential giving riseto different Lypes of canli:lc arrhythmias. is not kllown.

However, oscillmory increase in the intr:H.:cllul;lrCal> concenlration has been found to pby some rolein their genesis (18). Ver:lpamil and g:lllopamil ha\'e

Calcium Channels and Calcium Channcl Blockers 221

been found to prevenL or correCl such triggered activ­ity (19).

Calcil/m Channel Blockers and Vascular SmoothMuscle: Chronic systemic hypertension is now gener­ally considered LO be caused by an increased pcriph·eml vascular resistance. willi cardiac OUlpUI remainingun:lItered (20). The cLiology of this raiscd peripheralvascular resistance is multiple. Augmented sympathcticouttlow has been found to play an importanl role inits pathogenesis. TllCre is now ample evidence, basedon informmion gathered from animal ellperiments, thatseveral oLher factors c:ln act independently or jointlyto cause :1JI increased syrnp.:llhetie OUlnOw. These are:(i) stress induced increased central sympathetic outOow(21), (ii) abnormally l<lrge release of norepinephrin~

(NE) from nerve endings (22), (iii) resetting of thebaroreceplOrs which normally supervise the homeo­stalic control of blood pressure (23). Apa.rt from NE.Olher circulating substances which can augment theVllSCU);U responsiveness arc angiotensin II, 5-hy­drollytrypt:tmine (5·Hn (24) and an endogenous Na:'K' ATPase inhibitor (naLriuretic hormone) (25). Allthese f;1Ctors C:lllse an increased vascular resistance.Because the onset of hypcrtcnsion is chronic ,lIldsympLomless, by the time it is detcctcd, the etiologi­c,,1 factors can be d:unpcned secondnry LO adaptationsdue to chronic rise of bl()()(l pressure.

Cal. and Vascular Smooth Muscle: Cal> consti­tutes the link between differem factors causing llUg­mented vuscular responsiveness and vasculllr spasm.AcLin anu myosin inLeraction in smooth mllscle cclldepends on u1e phosphoryJ:llion of myosin light chainkinase, activlllcu by calmodulin-Cal. complell (26,27).

Both yoHugc-opcmletl :md recepLor-operated chan·nels l>ring :Iboul an uligmenLed inllux of extracellularCal -. In the volLage-dependent Cn2' innux, depolarisa­tion of the membrane plays an important role. 'Recep­tor-operated' influll of activator Cal> stimulated bysome v,lsoconstrictor agents, e.g. norepinephrine, his­t:1I111ne. 5-HT etc., provides a bypuss pathway Lhatworks unrcl~lled Hl bioelecLric membrane ellcit,lIion(28).

The following sections denl wiLh the effects ofc:ill.:ium channel blockers on two types of vessels,

222 Seth and Seth Indian J Physiol I'hannacol 1991; :35(4)

(i) extramural coronary arteries and (ii) olher systemicarteries.

Extramural coronary smooth muscle relaxation byCalcium Channel Blockers: The properly of calciumchannel blockers to dilate the coronary.vessels andthus increase the coronary blood now, is one of theirmost important circulatory effeclS. These drugs causean interruption of transmembrane Cal> influx and thusblock two processes, (a) lhc 'voltage-operated' trans·membrane Cal. supply. thus inhibiting excitation­contraction directly and (b) !.he transmcmbronc refill­ing of intracellular ea!' pools. From these latter sitesaclivalOr Cal. is released 'non-electrically' by vasocon­Slrictor subsumecs. c.g., NE, histamine and 5-HT.These Cal> pools are mainly (i) superficial, looselymembrane bound Cal•• (ii) tightly membrane boundCal', (iii) Cal. stored in sarcoplasmic reticulum and(iv) Ca1• stored in the internal surface of the mem­brane. It is presumed on the basis of some experi­mental data thal in coronary smooth muscles lhecellular Cal~-pools are· less rich and require a regularand rapid lransmembrane replenishmenl of Cal. thanperipheral vascular smooth muscle. Thus, calciumchannel blockers apart from blocking 'voltage-depend-

ent' contractile activmion of coronary smooth muscle,also diminish the Calo replenishment needed forvasoconstrictor substance which induces phasicconlJ1lClions.

Calcium Channel Blockers and peripheralvascular smooth muscle: Vascular smooth musclerelaxation by calcium channel blockers is quiteindistinguishable from that of coronary smoothmuscle, described in the previous section, i.e. directrelaxation by inhibition of transmembrane Calo

influx through 'voltage-dependent' channels orthrough some 'receptor-operated' channels and indirectrelaxation by depletion of cellular Cal·-pools wherecontractile response is due partly to Ca'·-releasingvasoconstrictor substances. But, unlike coronarysmooth muscle cells, the cellular Calo-pools arerather rich in Cal' and do not require a rapid replen­ishment by transmembrane Calo innux. Severalexperimental observations have confirmed thatcalcium channel blockers prevent the increasein Ca 20 permeability of the membrane due todepolarisalion, but is less effective in anlagoni­sing the release of activator Cal. from Ch-poolsby vasoconstrictor agents, e.g., norepinephrine (29,30).

TABLE I : Phannacokinclics or !.he Calcium Channel £lIockc~.

Agenl.S Synonym AbsQrplion Uioavailabilily I'rutcin Volumc of '. Qcuancchinding distrihulioo.. .. .. '" mVrnin/kg

Niledipine S, 10 mg Cllcigard >90 65 " 1.:32 -5 500""'"Tab. capsule Ocrin, Nifclal

Myogard. Nifedine

Nifcdipine rel.ardSR Tab.

500·600Diltiaz.em (30, 60 Dilgina, Nengil >90 35-<>0 78 5.0 4.1-5-6 15mg Tlb.)

Diltiaz.em SR (90, Diltime SR > '0 35-<>0 78 5.0 15120mg SR Tab.)

Venpamil (40, SO, Cordilelt. Isoplin > '0 10.-20 '0 4.3 6±4 (~v.) 13±7120 ml Tal>.) lnj. S mglml Vuopten, Venmil .,. (p.o)

Verapamil SR > '0 10.-20 '0 4.3 13±7

Indian J Physiol Phannaool 1991; 35(4)

Calcium channel blockers and stretch-induced au­toregulalory vasoconstriction: Biedl and Reiner in1900 (32) and Bayliss in 1902 (33) firsl pos!Ulmed lhephenomcnon of vasoconsU"iclive autoregulation ofblood supply. Whcn the pressure wiLhin a blood ves­sel increases, lhe vascular wall lcnds lO constricl tomaintain a conSlaflt blood flow through an organ in­spite of changes in arterial perfusion pressure. Thisphenomenon has been found 10 be presem in renal,cerebral, coronary. intestinal and skelewl anerics (34).As vascular conlraclile responses require Ca1 ', thisevent is also responsive to lhe aClion of cakiumchannel blockers.

Apart from its physiological role, Lhe autO-regu­lalOry vasoconstriction might also pl:ly a signific.ullrole in the pathophysiology of essential syslemich)1JCrtension.

C~kium Channcl$ and Catcium Channel Blockers 223

induced relensc of lysosomal enzymes and Ca1'-acti­vntcd phospholipascs leading to proSL.1glandin synthe­sis, are twO other eJGl.mples of calcium interactions insecretory cells.

The following table shows some organs whcreCa1 • regulates the stimulntion·sccretion coupling proc­ess. So the ubiquitous role pla}'cd by Cal. in activa­tion of diffcrcnt excilablc cells suggests the potentialof calcium channel blockers in the U"caUllent of somenon-cardiovascular discases ns well.

Cells

l. Adrenal medulla Stimulation of catccholaminerelease.

2. l11Alaglomcrutar app.:lrlllUS Inhibition of renin Iccretion.

3. t'ancreas Stimulation of glucose-inducedinsulin sce""tiQll.

TABLE IT : Tissue selectivity of Calcium AnligonislS.

Drug Myocardi,,] Vasculature CQIlducting andContractility Nodal tissue

Ver:>pamil ... ... +H

Diltia1A:m .. ++~. ++

Nifedipine <+ +<.. +

Pharmacokinerics: The absorption of CCB isnearly complcle after oral administration. Bioavailabil­ity may be reduced bccau~e of firSI pass hepaticmewbolism. First pa~s hepmic metabolism is extensivefor vemp:lInil and diltiazem. The effects of drugs aremunifcstcd within 30-60 min_ of an oral dose. Peakcffe(,;t of intravenous verapamll is evidcnt within 15minutes. Plasma protcin binding is significant(70-99%). The elimination half-life is 1.5-5 hours.Nifcdipine and verapamil nre excreted primarily inthe urine and diltiazem in thc feces. RcpC<ltcd orallldministration may lead 10 an increase in bioavail­:lbility and half-lifc because of saturation of hepaticmetabolism. In paticnts wilh hepatic cirrhosis, thebioavailabilily and half·Jives of the CCB arc increased(44,4S) (Table· II).

Ca2< -regulated processes in non-cardiovasculartis.tues: Apart from cardiovascular system, Ca2'-de­pendent smooth muscle contr.:lction plays u key role innormal and paLhological condiLions of olher organs inthe body. Thcsc arc listed below:

Ca" -regulated process Physiological Of rathol"llie:~1

e:oodiLion

I. Bmnc:hial smooth musde (lr\)tlchial tone: or Bronchospasm.(35-38)

2. Uterine Smooth muscle !'al1uritiQll. Dysmenorrhea.(39, 40)

3. Gallroimeninal smooth C.1. Spasm. C.1. MoLility.muscle (41) Esophageal spasm.

4. Genitourinary smooth U""terie spasm.muscle (42)

Cah also plays a key role in the stimulation­secretion coupling phcnomenon in non-motile cells.Exocytosis from these cells have been found lO beinitiated by an increased Icvel of cylOsolic Cal-'concentration and to a considerable extcnt requiresttansmembrane Cal. influx through the calcium chan­nel (43). So it is quile evident th:ll a~ in the ca..~e ofstimulaLion-contraction coupling, Calo play~ the role ofthe second messengcr also in excitation-secrclioncoupling. Calmodulin, a eylOsolic high-affinily calcium­binding protein, binds lhe calion and triggcrs lhecellular event, as in the case of smooth mu~'(:le. Cal'

4. MaSl cells

5. Pbtelcts

StimulaLion of histamine relcase.

Stimulation of IGJ:rcgaLioo.

lndiNi J Physiol Ph.nn'eoI 1991; 35(4)

orally in combination with digoxin in treating acuteand chronic atrial fibrillation (77).

Atrial Fluller: Imravenous verapamij controls theventricular response in atrial flutter by increasing theA- V block. (77, 78). Il may cause the development ofatrial fibrillation with a cor.trolled ventricular response(77).

Paroxysmal Supra-Ventricular Tachycardia(PSVT): Most cases of SVT are due to intranodalrccnuy or circus movements and two-thirds of ectopicatrial tachycardias convert LO sinus rhythm withverapamil (77). Vempamil may be preferable overother agents especially if there is an urgent need toteminare the PSVT (action within 3 minutes) or inpatients of coronary artery disease or peripheralvascular disease (77). Il can also be used for preven­tion of PSVT (79).

Systemic Hypertension: CCB arc effeclive asantihypertensive agents because of pcriphera.! vasodila­union, antiadrcncrgic and natriuretic actions (80) anddirect negative inotropic aClions. CCB reduce bothsystolic and diastolic blood pressures with minimumside effects (81). They do not affect !he blood pres­sure in nonnotensive persons (81). They may be mostuseful in patients with low renin hypertension (82).CCB have also been found to be beneficial in severehypertension and hypertensive crises (81, 82) by theoral, sublingual or intravenous route (81).

l1ypenrophic Cardiomyopathy (lICMP): The rca­sons for the beneficial effects of verapamil in HCMPare not clear. Verapamil reduces left ventricular out­now obstruction (83) but nOt a<; a result of reductionin left ventricular hypcrcontractility (84).

Improvement in diastolic function results inincreased end-diastolic volume which decreases theventuri forces moving thc mitral valve leaflet towardsthe septum (84). This in tum may decrea~e the ob­struction and reduce myocardial stress (83) Vcrapamilhas proved to be effective in patienls refractory (0

propranolol (84).

Congestive Heart Failure: The clinical experiencewith CCB in heart failure is limited. Vasodilatationcauses a reduction in after-load but the negative

Calcium Olanncls and Cl.lcium Olanncl Blockel'll 225

inotropic action of CCB counters lheir cffect on thcafter load (85).

Hemodynamic studies have shown significantreductions in systemic vascular resistance along withthe in;::r('3se in cardiac output (86).

PatiCnl with left ventricular dysfunction and nor­mal levels of left vcntricular after-load and those withoutf1ow obstructions are more lik.ely to have unfavo­rable effccts (87). The present evidence suggests thatCCll should be used in CHF only if additional indi­cmions exist c.g. angina or systemic hypertension.

Anti Alherogenic {'roperlies: Studies in severaltypes of nnimal modcls especi:llly cholesterol fedrabbits, have shown that calcium antagonisls canreduce the accumulation of atherogcnic lesion com­ponenl~ and decrease the progression of lesions. Theymay do this by a combinztion of decreasing calciumaccumulation within artcrial wall cells and by altcringcalcium channel independent met.1bolie aClivities,which affeCl thc development of the lesion (88,89).

(B) Non-Cardiac uses of CCB

Neurological disorders: Thc usc of CCB in neuro­logical disorders has been limited because of their mildinhibition of the eNS Ca1 ' channel activity. Nimodip­inc and flunarizine arc the drugs which have beentried.

Migraine Prophylaxis: The effect of CCB inmigraine prophylnxis is now wcll established. CCOprevent vasoconstriction by inhibition of Cal> innuxvia voltage and receptor channels. The onset of actionis delayed, L'tking urto two wccks and it leads to areduction in both the frequency and severity of atlack..<;.Sludies have shown lhat 80-90% of patients wilhvascular headaches benefit from nimodipine (90).While verapamil and nifedipine are also effectivc asprophylactic drugs, thcy have more systcmic side ef­fects being less selective for cephalic vessels (91).Some patients experience all initial exncerbation onfirst taking CCB and later find relief (92).

Sub Arachnoid Hemorrhage: Vasospasm followingsubarachnoid hemorrhage (SAH) is a major cause ofmorbidity due to the resulting cerebral ischemia. Vari-

226 Seth lUld Seth

ous studies involving nimodipillc have been publishedshowing its efficacy in reducing !.he scverity of postSAH vasospasm and its resultant morbidity (93,94).Nimodipine reduces !.he frequency and severity ofischemic defects. penetratcs !.he blood brain barriereffectively and has no significant side effects. Themechanism of action may be related to vasodilatationor to blocking a calcium ion dependent 'cascade' ofbiochemical processes leading to cell damage, prevent­ing a calcium induced decrease in red blood celldcfonnity and improving cell energy production (95).

Cerebro Vascular Accidents (CVA): Born nimodip­ine and nunarizine have been shown to have someeITcct on the course of CVA (96).

Vertebro Basilar Insufficiency: Nimodipine andnunarizine reduce venebrobasilar insufficiency thoughit is not clear whether this is the result of a directvestibular action or via increased regional blood now(95).

Vertigo: Deka (97) has reported beneficial effectsof cinnarizine. a selective calcium channel antagonistin Meniere's disease, cervical spondylosis, suddendeafness and vestibular neuronitis.

Epilepsy: Aunarizine has been found to be usefulin reducing seizure activity in experimenlai settings asweB as in patients not responding to conventionaltherapy (96). Whether CCB can function as independ­ent anti-epileptics is under investigation.

Psychiatric Disorders: CCB have been round tobe useful in manic depressive psychosis. depression,schizophrenia and tardive dyskinesia. Verapamil, whenused in mania. was found to have significant benefi­cial effccts (98).

PheochroffwcYlOma: Symptomatic relief occurcd ina patient wirn a noradrenaline secreting pheochromocy­toma while on nifedipine treatment Studies suggestthat nifedipine interferes wirn the myocardial action byacting directly on vascular smooth muscle (99).

Pufnwnary lIypertension (PUn: TIle treatment ofPHT continues to be unsatisfactory. The main focusof attention is on vasodilator drugs. Most drugs havebeen shown to have favorable acute benefits with

Indian J PhYlioJ Pbannacol 199t; 3:5(4)

reduced pulmonary vascular resistance and increasedcardiac output but the increased stroke work of theright ventricle ultimately leads to worsening of rightventricular function. CCB given in high doses titratedto the hemodynamic response have caused dramaticreductions in pulmonary artery pressure and pulmonaryvascular resistance along with regression of rightventricular hypertrophy. However, less than half of thep3tients respond to this rcgimen, especially ones withearly and less advanced disease. Responses of thepulmonary vasculature to prostacycline may be prcdic·live of response to CCB according to some prelimi­nary studies (100,101).

GastroifllestifllJl Diseases

Achalasia: Thcre are a number of reports suggest­ing lhe role of CCB especially nifedipine in themedical m3l\3gement of achalasia. The lower esoph­ageal sphincter pressure is reported to decrease by asmuch as 50% without any significant side effects. Thiseffect is believed to be due to the spasmolytic actionof CCB on smooth muscle cells (102).

Diffuse Esophageal Spasm: Nifedipine is knownto improve the symptoms related to diffuse esophagealspasm though at the cost of significant side effects(102).

Gynecological Disorders: Verapamil has beenfound to have relaxant effects on isolated humanmyometrium though in-vivo studies failed to reveal anyaction at tolerable therapeutic dosages.

Nife<lipine has been shown to have a considerableinhibitory effcct on uterine hypcrcontraetility which isbelieved to be a major mechanism of pain in primarydysmenorrhea (99).

Oncology: The calcium channel anwgonisls vera­pamil, nifedipine, nitrendipine and caroverine havebeen found to increase the antineoplastic action of thedrugs like vincristine, daunorubicin and adriamycin. IIis mooted that they increase the cellular drug accumu·Imion by blocking drug efflux (103).

Urinary Incontinence: Urinary incontinence due todetrusor inSL:lbility can occur with damage to inhibitoryneural pathways traveling along the lateral and ventral

226 Scih and Scih

ous studies involving nimodipinc have been publishedshowing its efficacy in reducing the severity of poSlSAH vasospasm and ilS resulrant morbidity (93.94).Nimodipine reduces the frequency and severity ofischemic defects, penetrates the blood br:lin barriereffectively and has no significanl side effeelS. Themechanism of action may be related lO vasodilatationor LO blocking a calcium ion dependent 'cascade' ofbiochemical processes leading to cell damage, prevent­ing a calcium induced decrease in red blood celldeformity and improving cell energy production (95).

Cerebra Vascular Accidents (CVA): Both nimodip­ine and nunarizine have been shown to h:!Ve someeffeCl on the course of eVA (96).

Vertebro Basi/ar Insufficiency: Nimodipine andnunarizine reduce vertebrobasilar insufficiency thoughit is not clear whether this is the result of a directvestibular action or via increased regional blood now(96).

Vertigo: Deb (97) has reported beneficial effecLSof cinnarizine, a seleclive ealcium channel antagonislin Meniere's disease, cervical spondylosis, suddendeafness and vestibular neuronitis.

Epilepsy: Aunarizine has been found to be usefulin reducing seizure activity in experimental settings aswell as in patients not responding to conventionallherapy (96). Whether CCB can function as independ­ent anti-epileptics is under investigation.

Psychialric Disorders: CCB have been found tobe useful in manic depressive psychosis, depression,schizophrenia and tardive dyskinesia. Verapamil, whenused in mania, was found to have· significant benefi·cial effecLS (98).

Pheochromocytoma: Symptomatic rclief occurcd ina patient wilh a noradrenaline secreting pheochromocy­toma while on nifedipine treatment Studies suggesllhat nifedipine interferes with the myocardial action byacting directly on vascular smooth muscle (99).

Pulmonary Hypertension (PlI1]: 111e treatment ofPHT continues to be unsatisfactory. The main focusof anention is on vasodilator drugs. Most drugs havebeen shown to have favorable acute benefits with

Indian J Physiol Phannaool 1991; 35(4)

reduced pulmonary vascular resistance and increasedcardiac output but the increased stroke work of theright ventricle ultimately leads to worsening of rightventricular function. CCB given in high doses titratedto the hemodynamic response have caused dramaticreductions in pulmonary artery pressure and pulmonaryvascular resistance along with regression of rightventricular hypertrophy. However, less than half of thepatients respond to this regimen, especially ones withearly and less advanced diSease, Responses of thepulmonary vasculature to prostaeycline may be predic­tive of response to CCB according to some prelimi­nary studies (100,101).

Gastrointestinal Diseases

Achalasia: There are a number of reports suggesl­ing the role of CCB especially nifedipine in themedical management of achalasia. The lower esoph­ageal sphincter pressure is reported 10 decrease by asmuch as 50% without any sij,.rnificant side effecLS. 1l1iseffect is believed to be due to the spasmolytic actionof CCB on smooth muscle cells (102).

DijJuse Esophageal Spasm: Nifedipine is knownto improve the symptoms related to diffuse esophagealspasm though at the cost of significant side effects(102).

Gynecological Disorders: Verapamil has beenfound to have relaxant effects on isolated humanmyometrium though jn~viyo studies failed to reveal anyaction at tolerable therapeutic dosages.

Nifedipine has been shown to have a considerableinhibitory effect on uterine hypercontractilily which isbelieved to be a major mechanism of pain in primarydysmenorrhea (99).

Oncology: The calcium channel antagonists vcra+pamil, nifedipine. nitrendipine and carovcrine havebeen found to increase the antineoplastic action of thedrugs like vincristine, daunorubicin and adriamycin. Itis mooted that they increase the cellular drug accumu·lation by blocking drug efnux (103).

Urinary Incontinence: Urio.-uy incontinence due todetrusor insttlbility can occur with damage to inhibitoryneuml pathways traveling along the lateral and ventral

lndi." J Ph)'sioll'halmacol 1991: 35(4) Calcium OlJnneh and Calcium OIannel Blockers 21:1

TAllLE 1tI: Incidence of common side effects of CalciumChannel Blockcrs.

wilh occa~ional worsening of angina. headache. flush­ing and vertigo.

Negative inoLrOpic action and conduction blocksarc of concern in coronary ancry disease, cardiomegalyand inLIaClablc heart failure (44). (Table IJI).

8 12

,3

Percenl IncidenceVef1lf'll",il Dihil1,erT1 Nifcdipine

8 2 ,

Flushing

Hcadachc

Side effect

Asthma: CCB are an important contribUlion to lhedrugs available to U'Cal heart disease in patients withassociated reactive airway disease. CCB do not causebronchoconslriclion unlike drugs like propranolol. Theyalso inhibit exercise or allergen induced bronchospasm.Clinical trials have not shown any effect on restingbronchial tone in asthmatics. They arc useful lhereforcmainly in the management of heal1 disease in asthmat­ics even though lhey do not cause bronchodilatation(l05).

rcticulospinal trocks, resulting in unpredictablc invol­untary voiding. Nifcdipinc by reducing dcLIusor con­tractions can improve continence (104).

Hiccups: Hiccups not responding to conventionallherapy responded to nifedipine 20 mg TID in onepatient (99).

Constipalion 30

2

22

TABLE [V: Drug [nleractions "'ilh Calcium Channel Blockcrs.

Propranolol when given in combinalion wilhnifedipine blunts the renex tachycardia due to vaso­dilatalion (45). Other interactions also occur and arcgiven in Table IV.

Interactions: Digoxin doses need 10 be reducedbecause of an increase in plasma concentration ofdigoxin by as much as 75% when combined withverapamil.

Renal Transplant: Paticnts of renal transplanttre<lted wilh diltiazem had improved gmn function 'Jfter6 monlhs as compared to controls. Incrc:lscd levels ofcyclosporin also allowed reduction of cyclosporindosage (106).

Raynaud's PheTUJmenon: CCB have found a placein lhe management of Raynaud's phenomenon (107)oocuuse of their ability 10 cause smoolh muscle relWla­tion. Nifedipine is lhe drug of choice showing asignificanl reduction in vasospastic attacks aftertherapy for lhree weeks. Verapamil has not beenfound to be effective. Diltiazem has also been used(30-90mg TID).

Ankle edema

Taeh)'cardia

2 ""

Malaria: Malarial p;m.lsites have an obligmecalcium requirements for intracellular growlh anderythrocyte invasion. Verapamil, its analog RO 11­2933 and desipramine cause a dose dependent increasein Ihe accumulation of chloroquine in human andmouse hepalocytCS, thus breaking chloroquine resis­tance (108).

O1go)\i1\ Incrcase digoxin leveh particularl)' "'ithveupamil fall ",ith nifedipine

Alpha·blockers Additive/s)'nergic effect on blood premll'l:

BCla·blockcrs Reduce rent.'( lach)'cardia of nifedipine(caution "'ilh i.v. vcrapamil)

Amiarrhylhmia.l Avoid combinalion

Side Effects: The risk of side effeCls depends onthe route of administralion, underlying disease ;mddoses used. The side effects occur mainly due (Q

vasodilatation. negative inOlropic action and con­duction delay. Vasodilatation leads to sodiumretention, edema, weight gain. renex tachycardia

111- anllgonisls Inereasc calcium channel blockcr tevel

Drugs increasing Reduce CCB levelhqulie microsomalol\idasc lIClivily

Anesthelics Il)'plXcns;on. lach)'cardia

228 Seth and Seth lndian J Physiol Phannacol 1991: 35(4)

Conclusion: Calcium channel blockers representan important breakthrough in lhc history of medicaltherapeulics. Wilh lhe ever increasing role of CCB in

both cardiac and non cardiac conditions, and wilh theavailabilily of more selective agents their potential isendless.

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