Inhibition of myocardial Ca 2+ channels by three dihydropyridines with different structural features: potential‐dependent blockade by Ro 18–3981

1 Inhibition of myocardial Ca 2+ channels was investigated for three dihydropyridines with different structural features: Ro 18–3981, darodipine (PY 108‐068) and nifedipine. Ro 18–3981 contains a sulphamoyl acetyl side‐chain. 2 In voltage‐clamp experiments with isolated cardiac myocytes of guinea‐pig, Ro 18‐3981 caused a concentration‐dependent inhibition of the Ca 2+ current, which was influenced by the membrane holding potential. A markedly greater inhibition by Ro 18‐3981 was observed when myocytes were depolarized (to + 10 mV) from a holding potential (V h ) of −20 mV (IC 50 = 2.3 n m ) than at −50 mV (IC 50 = 100 n m ). 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 m m resulted in a significant reduction in negative inotropic IC 50 values for Ro 18‐3981 (137 fold), darodipine (8 fold) and nifedipine (20 fold). 4 The affinity of these drugs for the high‐affinity (+)‐[ 3 H]‐PN 200‐110 binding site was determined in guinea‐pig cardiac membranes. The K D value of Ro 18‐3981 (1.0 n m ) was similar to the IC 50 value for blockade of I Ca at a V h of − 20 mV (2.3 n m ), i.e. at a level of near‐maximal depolarization. 5 Thus, structurally‐different dihydropyridines exert potential‐dependent inhibition of myocardial Ca 2+ channel activity consistent with the modulated receptor hypothesis. These results demonstrate that blockade of myocardial excitation‐contraction coupling by Ca 2+ entry blockers is also potential‐dependent.