TIPS-Ju~ 1984

III

Calcium antagonists: mechanisms and therapeut ic uses G. Fleckenstein-Griin, M. Frey and A. Fleckenstein hmitute o]" Physiology, Universi~. of Freiburg, FRG.

Two classes of Ca-antagonists with differing potencies and specifit~ties have been identified. These drugs can affect the myocardium, cardiac pacemakers and rascular smooth muscle differentially and therefore have a range of therapeutic apphcatiott~.

Nearly 20 years have passed since the appearance of the filSt report from our laboratory on a new compound (lsoptin, iproveratril, generic name: verapamil) which mimicked the cardiac effects of simple Ca withdrawalS-2: verapamil diminished Ca-dependent contractile force without a major change in the Na- dependent action potential parameters. It also reduced Ca-dependent high energy phosphate utilization of the beat- ing heart, and consequently lowered oxygen consumption in parallel with the depression of contractile activity "a'4. These inhibitory effects of verapamil could promptly be neutralized by addi- tional Ca, 13-adrenergic catecholamines, or cardiac glycosides, i.e. by measures able to restore the Ca supply to the contractile system. Thus, verapamil represented the most interesting proto- type of the new family of 'Ca-antagon- istic' substances. In fact, Ca-antagonism turned out to be a novel pharmaco- dynamic principle clearly distinguishable from [~-reeeptor blockade. These drugs should be subdivided into groups A and B, according to criteria unrelated to their chemical constitution, but corre- sponding to the strength and specificity of their Ca-antagonistic activities.

According to this classification, group A comprises the most potent and specific Ca-antagonists such as nifedipine, niludipine, nimodipine, ryosidine, verapamil, gallopamil and diltiazem. These substances are capable of inhibit- ing Ca-dependent excitation-contraction coupling of the mammalian ventricular myocardium by at least 90% without affecting the fast Na influx associated with the rising phase of the action potential,

Group B, on the other hand, includes prenylamine, fendiSne, terodiline, per- hexiline and caroverine. These drugs

~ 3

are somewhat less potent and specific since, under their influence, a conco- mitant inhibition of the Na-dependent excitatory, process sets in when Ca- dependent contractile tension develop- ment of isolated papillary muscles has been reduced by 50--70%. However, such serious degrees of contractile de- pression can never be observed hz t,ivo as long as the drug concentrations remain in the therapeutic dosage range.

Myocardial effects of calcium antagonists Interference with calcium-dependent excitation-contraction coupling The negative inotropic effects of Ca- antagonists are due to a specific inhi- bition of the slow inward current of Ca z+ ions across the excited myocardial fibre membrane as established by direct measurements using a special voltage- clamp technique -~'6. Ca ~-÷ ions seem to be displaced by Ca-antagonists from specific superficial binding sites at the sarcolemma membrat~e and from the transmembrane Ca-transport system ('slow channels') so that the availability of Ca z+ ions to the contractile system is critically diminished. Consequently, both utilization of ATP by the Ca-acti- vated myofibrillar ATPase and contrac- tile tension development decline.

It is commonly known that the intensity of oxidative cardiac metabolism depends on the rate of ATP-consump- tion. Therefore, Ca-antagonists lower cardiac oxygen requirement in a dose- dependent manner, to the same extent as they reduce Ca-dependent splitting of ATP and tension development. In healthy humans therapeutic doses of C~-antagonists produce only a neglig- ible reduction in heart work and oxygen demand. Nevertheless, adequate doses of Ca-antagonists are of high therapeutic

value in the treatment of patients with a hyperkinetic heart function o r suffering from coronary heart disease, in the latter case, a certain restriction of myo- cardial energy, expenditure obviously also helps to re-establish a balance be- tween reduced coronary oxygen supply and myocardial oxygen requirement.

Cardioprotection As we first showed in I ~ (Ref. 7). heart muscle fibres undergo severe alterations as soon as free Ca -~" ions penetrate excessively through the sarcolemma membrane into the myoplasm, so that Ca-binding capacities or extrusion pro- cesses become insufficient. These alter- ations finally result in necrosis. The crucial event in the development of such lesions is high ener~" phosphate defic- iency which ensues: (1) from excessive activation of Ca- dependent intracellular ATPases. and (2) from Ca-induced impairment of the mitochondria that manifests itself as swell:.n~ vacuolization, cristolvsis and loss of respiratory control and phos- phoD'lation capacity.

Table I sho~,.x the various pathogenetic circumstances under which intracellular Ca-overload proved to be the decisive etiological factor in the production of myocardial fibre damage. In all these

T A B L E 1. ( 'au.~s of calcium-o~ erioad leading to

myocardial netarotization

( 1 ) Overdose.,, of 13-adrenergic catcchotammc~ 12) Oxerdt~cs of ~atamin D~ or dih~drotach~-

qero[ (AT 1(|1 (3~ Mimenta~ Mg- or K-dcficienc~ (4~ Genetic defects Lheredita~ cardiom.~opath~

of S.vnan hamsters) (5) .~noxic or tschemic m~ocardial fibre

membrane damage

cases, Ca-antagonistic comlxmnds are capable of protecting structural and functional intem-ity by pre~enting abun- dant transmembrane Ca influx. In m~o- cardial hypoxia or ischemia an eark indication of myocardial necrosis is the observed alteration of the sarcolemma membrane which leads to a precipitous upwke of excessive amounts of Ca. Ca- anta,gonists are able to prolong the time of ~urvival of anoxic or i~hemic hearts, thus mitigating the harmful influence of oxygen deprivation. Because ~.hev afford better myocardial preservation it is not surprising that Ca-antagonists have recently proved to be useful additives to cardioplegic solutions in cardiac surge~'.

Dampbzg influence on calcium-depe,'e- aent nomotopic or ectopic pacemaker dctivi~, and on atrioventricular tachyarrhythmias The fundamental processes of sinoatrial

28.~ TIPS- ~ 1984

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Ftg ! Relamnon t~ ) of K-depolarized ~ig coronan, strips by various Ca-antt.~gont,~: comparison of the relaxing po;encie~ o] these drugs administered to K-depolarized fully contracu~red pig coronam.' strips. Nifed~pine is approximately 3 (,00 times gallopami1300 times, rerapamil and dihiazem 50 to IO0 thnes uronger than papaverine ~'. Ni~oldlpine. a derirative of nifedipine, is even 15 000 times more efficient than paparenne.

and atrio~entricular node automaticity, as well as atrioventricular conduction are obligatorily linked with a trans- membrane influx of Ca ~+ ions as elec- tric charge carriers. This applies even more to ec~opic pacemaker activity aris- ing from altered atrial or ventricular fibres which, in this state, are liable to excessive transmembrane Ca-i~atrusian. The Ca-transport systems operating in spontaneously firing nomotopi,c or ec- topic cells resemble the 'slow membrane channels" of ordinary myocardial fibres. This means that cardiac auton~aticity is also susceptible to the inhibito,ry action of Ca-antagonists. Accordingly, most Ca-antagonists can exert not only nega- tive inotropic effects on the myocardium, but can also reduce the rates of SA node discharge and AV conduction. The on- set of ec~opic auton'mticity ill altered atrial or ventricular myocardium, is caused fundamentally by a drop in membrane potential so that the excita- toq,' process turns trom its regular Na- dependent form into the slow-channel- mediated Ca-dependent type, char~er- istic of partially depola~:ed myo- cardium. Thus, Ca-antagot~ists ('the fourth class" of amidysrhythmic drugs) preferentially extinguish such Ca-depen- dent atrial or ventricular extopic foci. They also block Ca-dependent slow- channei-med'ated re-entry pathways in altered myocardium, leaving normal Na-dependent atrial or ve,tricular exci- tation and con~ :orion unaffected. According to clinit~d observations,

verapamil is particularly useful for the suppression of reciprocating atrioven- tricular tachyarrhythmias (associated with the Wolff-Parkinson-White-syn- drome). This anomaly is based on exci- tatory atrioventricular circus-movements through the AV node (anterograde pathway) and an accesso D' (retrograde) bypass track for return. Verapamii, by

slowing down impulse conduction through the AV node, can dramatically interrupt such atrioventricular rc-entry loops ~.

Vascular effects of calcium antagonists Relaxation o f coronary smoo th muscle, and reduction o f sys temic f l o w resistance Both tonic and phasic contraction of arterial smooth muscle also depend on the availability of free Ca "~+ ions. They are either supplied from extracellular sources through potential-dependent or receptor-operated Ca-channels that are opened by electrical, mechanical, or pharmacological stimuli, or are alternat- ively released from cellular storage sites by non-electrical mechanis,.ms. The Ca- antagonists block directl~ (and most effectively) potential- or receptor-depen- dent transmembrane Ca-supply, but also impair transmembrane replenish- ment of the cellular stores, an effect that appears ofte, with some delay. Under the influence of Ca-antagonists, every kind of contractile vascular smooth muscle activity can be damped in a dose-related manner 9-~ ~.

Contractile performance of vascular smooth muscle is even more responsive to Ca-antagonists than is myocardial tension develc,pment. Thus, under the influence of Ca-antagonists, any restric- tion of the mechanical energy expendi- ture of the m~rocardium - even of slight degree - is always accompanied by a

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Fig. 2. The two histological sections on the left demonstrate the excessive calcium accumulaJion in the wall of rat coronary artery branches 4 days after one single intramuscular injection of 300 000 I. U. v;tamin D.~ kg-z body wt. Tissue calcinosis is visualized in the form of black areas with V. Kossa'~ histt ~hemical slaining technique. In contrast, calcinosis is totally absent in the two sections on the right originating from rats that had received ddtiazem (2 x 500 mg kg -I orally with a stomach tube) for 4 consec~aive days a{ter the injection of 300 000 L U. vitamin D3 kg -I body wt. This treatment completely neutralizes the vitamin D ~ effects ~ ~.

T I P S - July 1984

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more or less pronounced decrease of arterial vascular tone, particularly on the coronary stem arteries. For instance, relaxation of the coronary vasculature by Ca-antagonists usually occurs in an experimental dosage range which is only 1/3 to 1/10 of that required to produce negative inotropic effects on heart muscle. In fact, the highly specific Ca- antagonists of group A proved to be the most effective coronary vasodilators ever discovered (see Fig. 1).

In humans, the vasodflatory actions of Ca-antagonists manifest themselves most significantly on the coronary bed. Furthermore, they exert this action at the 'fight' place, that is to say, on the great extramural coronary stem arteries (including collaterals and anastomoses). Interestingly, more than 95% of the stenosing atherosclerotic processes are located in this particular part of the coronary system. Circulator), improve-

285

imposed to eccentric atheromatous lesions o! may even occur without angiographic evidence of structural obstacles.

In additmn, Ca-antagonists possess distinct antihypertensivc effects in both animals and humans, by reducing Ca- dependent smooth muscie tone of peripheral resistance vessels ~3. Con~- quenfly Ca-antagonists, particularly those of group A. are increasingly used fi~r therapeutic purposes in cases of acute hypertensive crises, and for the treatmeat of chronic h)pertension, par- ticularl~ in elderly patients.

ment is most evident in cases of Prinzmetars vasospastic "variant" angina and other forms of functional coronaD" constriction which is frequently super-

Therapeutic prospects-: anticalcwu~tic vascular protection by cah'ium antagonisL~ For more than 50 years human path- ology has emphasized the decisive role of arterial lipid accumulation, particu- lath' cholesterol, in the pathogenesis of arteriosclerosis. The concomitant cal- cinc~sis has mostly been comidered a phenomenon of secondary importance. However. our observations on the pri- mary pathogenetic role of Ca~twerload in myocardial necrotization leave little doubt that the accumulation of Ca in the arterial walls is by no means a negligible factor. Thus. for several years, our interest has focussed on the p~thogenetic con~quences of excessive Ca-uptake into the arterial smooth muscle cells. and on the vascular protection that various Ca-antagonists may pro', :de.

Experimentally, ~vere calcinosis of the a~tenal media in rats can be induced ~Athin a few days b 3 administration of overdoses of dihvdrotach~terol ( AT 11)) or vitamin D~. Histologically. the vas- cular alterations brought atxmt by this treatment care quite similar to M6nckeberg's t}lae of calcifying arterio- sclero,,is in humans. As already pointed

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Fig. 4. Scope of Ca-antagonistw drug responses.

286

out in 1929 by Hertenberg. the process of vitamin Dfinduced calcification affects particularly the smooth muscle cells and the elastic fibres”. According to more recent electron microscopic observations. the arterial media of vitamin-DJ-poisoned animals contains intracellular C&deposits in the form of electron-dense granules in the cyto- pJasm, C&overloaded mitochondria, mineralized elastic fibres. calciferous plaques. etc. In addition, the arterial intima cells are heavily damaged and parietal microthrombi develop. HOW- ever. as we first reported in 1971172’” and 1978”, suitable oral or S.C. doses of certain Ca-antagonists are capable of JWecting the arterial walls from deWuc- t rvc calcinosis produced by dihydro- tirchysterol or vitamin De3 respectively. JGgure 2 demonstrates the tremencdous anticakinotic efficacy of the Ca-antag- onist diltiazem. In further experiments on rats. we studied arterial Ca overload due to hereditary spontaneous h>pr- tkmion. iulwmed age. alloxan-diabetes. anJ - as recently established - nicrdine intoxication I’*‘“. In all &se different vascular disease mod&, we found par- Ocular Ca-antagonists were able to pfc- vest deleterious Ca overload and damage of the arterial walls.

Vascular cakinosis. whether symp tomattc or not. is an inevitable come- quence of advanced age. In fact. the aging process of human arteries is refkcted in a pogressive augmentation of sheir Ca content, whereas the Mg concentration remains more or less unchanged. Aczording to our obser- vations, age-induced arterial Ca over- load is dramatically speeded up in dia- betics and heavy smokers. Conversely, Ihe normal myocardial t&es are exempt from any age-induced change in absoJute Ca content or CazMg ratio. In dogs and rats. the Ca content of the arterial tissue also ruses Iconsid::rab)y with increasing age, but without attaining destructive concentratmns (fig. 3). E.xtrapolation from our experiments with vitamin D suggests &at in humans, the degree of Ca accumulation reaches, or even sur- passes, the critical range at which struc- tural integrity is jeopardized at an age of about 60 years. Our results suggest that the steady rise in arterial Ca content during J&z is not only a characteristic of age, but also represents rhe decisive inherent risk factor which predisposes SenfSXnt arteries to WerioscJelotic degeneraffion_ Thus, apart from aug-

mentation of wall cholesterol. progress- ive age-dependent Ca overload appears to he an important latent precursor of overt arteriosclerosis. All these obser- vations, particularly the data of Fig. 3. point to the possibility of an event- ual retardation of the C&dependent arterial aging process (and of secondary circulatory complications) by suitable &antagonist prophylaxis. Hence. a definite clarification of the pibie sig- nifica~~ of Ca-antagonists as anti-arterio sclerotic drugs, also in human therapy. is certainly one of the most fascinating topics of future cardiovascular research.

c@JncJudJng rrmprb; The large scope of Ca-antagonistic

drug responses is summarized in Fig. 4. However, it must be emphasized that the particular effects on myocardium. cardii -makers and vascular smoolh muscle are differently accentuated &pending on the individual Ca-antag- orrist used. Verapamil and gallopamil exert their influence on myocardium. pacemakers and vasculature with com- parable intensity. On the other hand. nifedipine and further 1 &dihydropyri- dine derivatives preferentially suppress vascular contractility, whereas, at least in humans, their influence cm cardiac contractility and pacemaker function it1 sim is rather modest. In comparison with these features of verapamil and nifedipine. the profile of the cardiovas- cular actions of diltiazm keeps an inter- mediate position.

ReadJngJJst 1 Fleckenstein. A. (MU) Circ. Res. Suppl. 52.

%lh 2 J%ekett%tein. A. (1977) Annu. Rev. Pharmacol.

Toxicof, 17. 149-166 3 Fleckenstein. A. (1968) V&I. Dtreh. Ger.

Kreisfauffo~ch 34. EL34 4 J?eckenstein. A. (1970) Arzneim. Forwh. 20,

13174322 5 !%cJcenstcin, A. (1971) in Cafcium rard rhe

Hean (Harris. P. and opie. L.. eds). pp_ 135-188. Ac8demic J’ress. London

6 JCoJtlhardt. M.. Bauer. B.. Krause. H. and Ffeckemrein. A. (1972) p/liiers Arch_ GeslzmU l%ysiof. Mtn&cn ITi?re 335. -322

7 Fleckenstein. A. (1%8) in VI. Symposium Herzinfurks und Schock (HeiJmeyer, L. and HoJtmeier, H. 1.. eds). pp, 9&Jf!9. Georg TJtieme verfag. s1uttgall

8 Krikkr. D. and S~U&Y. R. A. (1974) Posr- grnd Med. /. SO. 447453

9 Griin, G. and Fleckenswi~~. A. (1972) Arzneim. Forsdt 22.334-344

JO J=leckenst&Griin. G. (1!%2) in c;oldwn .~odulmon (Godbind. I-., AJ&rtini. A. and Pad& R.. eds), pp_ J41-154. E&evier Bio-

II

12

13

15

14

lc:

T..PS - hi-y I984

medical J’ress. Amsteniam Fieckenstein-Grijn. G. and Heckenstein. A. (l!Xl~ in CaItium-Antq&smur (Fleckenstein. A. and Roskamm. H.. eds). pp. 191-2017. Springer Verlug. J3crlin Fleckenstcin-Griin. G. and Fleckenstein. A. (J9U3) in Gallopamil, phormukologiwhes und klinisches Wirkungspribrip eines Kal:ium- unfugoniwen (Kaltenbach, M. 8nd Hopi. R.. eds). pp. 3.~Sl , Springer Verlag. Berlin Reckensteim. A. and Reckenstein-Grim. G. (1980) Eur. Heun J. 1 (SuppI. B) IS-21 Herzenbeq, H. (1929) Beitr. Parhal. Anew Allg. Pa!hol. 82. 27-57 Janke. 1.. Ilein, B., Pachinger. 0.. Lcder. 0. and Fleckensteb. A. (1972) in Vawiar Smoorh MrLFcIp (Bet+. E., cd.). Pp. 71-72. Sprinwr Verlae. Berlin Frey. M., Keidel. J. and Fleckenstein. A. ( 19t@) in C&wn-Art&?guniimur (Fkckenstein. A. and Roskamm. H., eds). pp. 258-264. Springer Vcrlap. BerJin

17 neckenstein. A.. Frey. M. and Lcder. 0. (MJ3) in New Calcium Anragonirrr Becenf Developmenrs and Prosperrr (Rcckenstem. A.. Hashimoto. K.. Herrmann. M.. Schwartz. A. and Seipel, J.. eds). pp. I-S-31. Gustav Fiiher Verlag. Stuttgart

1% JXxkenstein. A.. Frey. M. and v. Witzleben. H. ( 1983) in Proceedings of the 5rh Adular Symposium (Kaltenbach. M. and Ncufeld. H. N.. eds). pp_ .X%X!. Excerpta Medica. Amsterdam

Far further information and references. see Fleckenstein. A. (1983) Calcium Antagorurm in Hear! and Smoortr Muscle, Experimental Fac&s and 7hpIIpeu~ic Prospect. John Wiley and Sons, New York

Dr Gisa Fleckensrein-Griin wus (I medical student. and lafer a research rrrsiranl at the Physiological Minue of the Unive&y of Freiburg. FUG. Sub- sequenily. she became Assoctie Proffisor at this in&ution. Her mujor research interest ha been the eiuci&tion of the mtx hunism of action of calcium awgonim in uterine and oscular smooth muscle, land the heart.

Ilk Markus Fw is a .%nior _&search Worker a! the YJhysio!ogiud In&we of the Lhaivenriry of Fkilwg. I%% reseamh huewsts concern rhe pa!hogeneriic ~@dfican~ of insrace~l~ar Ca overload. boih in i~mr and vawukw smooth muwle, and the pro&c- rive pffpcp of cdabn ontagottkL9.

Dr Albmzht E&c* WPF a medical auden~ 01 the Univers&ies of W-burg (Bovarkt) ad Vienna (Asuwia). He huer became a lrdurer a~ the Uni- versity of Hekie&erg’s Phormacologiral In&we and a Bridsh Council Exchange Lecturer in the Deparbwu of Pharmacology as Odotri Univers@ His many publicmions i&h&= the monographs Me&u&m!5ofP8inJidTiiIrrit8tionandJxal e Eaergetifs of Soditnn-Pc@&un E&at&fin!tX?Uly,C&UmAttt8gCVnbi8 Heari and smooth Mm&, rrpnscrlring un q&?e of h P hmtWngresea&workon~new plimnrocodyMmit princ@&_ He ir curmuty Pro- fasor of phvJiotogy and Hcvrd of rise Phys~ogical Ins&& at the Uniiwshy of Fm-burg.