Effects of Ca++-Agonistic and Ca++-Antagonistic 1,4-Dihydropyridine Compounds on Tonic and Phasic Activation of Extramural Coronary Vasculature

Abstract

The administration of calcium antagonists as antiangmal, antiarrhythmic, antihypertensive or cardioprotective drugs, makes use of the different manifestations of one and the same elementary membrane action, i.e. inhibition of transmembrane Ca++ entry in myocardial fibres, nomotopic and ectopic cardiac pacemakers, as well as in various types of vascular smooth muscle cells1 (Fig. 1). How ever, it must be emphasized, that these particular effects are differently accentuated, depending on the individual calcium antagonist used. For instance, the classical calcium antagonists verapamil and D 600 (the generic name of D 600 is gallopamil) exert their damping influence on myocardium, pacemakers, and arterial smooth muscle with comparable intensity. On the other hand, the BAYER compound nifedipine and further dihydropyridine calcium antagonists preferentially suppress Ca++-dependent smooth muscle functions, whereas, at least in humans, the influence of such dihydropyridines on cardiac tension development and pacemaker activity in situ is rather modest. The fundamental Ca++-antagonistic potency of the prototypical substance nifedipine on isolated myocardium and vascular smooth muscle has first been established by Fleckenstein and his group in the years 1969–1972 [5–11]. Since that time, a considerable number of further 1,4-dihydropyridine derivatives were synthesized in the BAYER laboratories and also elsewhere. All these compounds, listed in Table 1, share their preferential Ca++-antagonistic action on the vascular system with the prototypical substance nifedipine. This is true of nimodipine, nisoldipine, nitrendipine, ryosidine, niludipine, felodipine, nicardipine and PY-108-068. However, with the recent discovery of other nifedipine-derivatives (”Calcium-Agonists”) which promote transmembrane Ca++ entry (see Table 2), it became clear that 1,4-dihydropyridine compounds may exert a “Januslike” influence on passive transmembrane Ca++ transport.KeywordsCalcium AntagonistContractile ResponseDihydropyridine Calcium AntagonistCoronary Smooth MuscleCoronary ConstrictionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.