Inhibition of myocardial Ca²⁺ channels by three dihydropyridines with different structural features: potential‐dependent blockade by Ro 18–3981

Abstract

depolarized (to + 10 mV) from a holding potential (Vh) of -20 mV (IC50 = 2.3 nM) than at -50 mV (IC50 = 100 nM).3 The three dihydropyridines caused a concentration-dependent reduction in contractile force of isolated, electrically-stimulated left atria of the guinea-pig. Elevation of the extracellular K+ concentration from 5.9 to 24 mM resulted in a significant reduction in negative inotropic IC50 values for Ro 18-3981 (137 fold), darodipine (8 fold) and nifedipine (20 fold). 4 The affinity of these drugs for the high-affinity (+ )-(3H]-PN 200-110 binding site was determined in guinea-pig cardiac membranes. The KD value of Ro 18-3981 (1.0 nM) was similar to the IC50 value for blockade of ICa at a Vh of -20 mV (2.3 nM), i.e. at a level of near-maximal depolarization. 5 Thus, structurally-different dihydropyridines exert potential-dependent inhibition of myocardial Ca2`channel activity consistent with the modulated receptor hypothesis. These results demonstrate that blockade of myocardial excitation-contraction coupling by Ca2+ entry blockers is also potentialdependent.

Frequency‐ and Potential‐Dependency of the Negative Inotropic Action of Various Dihydropyridine and Non‐Dihydropyridine Calcium Antagonists

“…(compare Holck & Osterrieder 1987;Robertson & Lumley 1989, Ravens & Schopper 1990. Thus, quantitative differences exist between the extent of potential-dependency among various dihydropyridines.…”

“…On the other hand, in the case of dihydropyridines, calcium channel inhibition can exhibit voltage-and even frequencydependency as shown for at least some of the derivatives (Bean 1984;Sanguinetti & Kass 1984;Nelson & Worley 1989). Furthermore, contrasting results have been obtained with different dihydropyridines, with changes in the K + concentration between 5 mM and 24 mM having marked effects (factor ten or more, Holck & Osterrieder 1987), or no effects (Robertson & Lumley 1989;Ravens & Schopper 1990). Furthermore, contrasting results have been obtained with different dihydropyridines, with changes in the K + concentration between 5 mM and 24 mM having marked effects (factor ten or more, Holck & Osterrieder 1987), or no effects (Robertson & Lumley 1989;Ravens & Schopper 1990).…”

Isradipine—A Review of Its Antihypertensive and Other Properties

“…The action of calcium antagonists is also dependent on the membrane potential and it is conceivable that this is the most important factor explaining the tissue selectivity of calcium antagonists. It is becoming increasingly clear that the membrane potential infiuences the action of individual drugs differently (37,41,65,77,114). Activation of the L channel increases the binding of isradipine (23).…”