title: Inhibition of myocardial Ca2+ channels by three dihydropyridines with different structural features: potential-dependent blockade by Ro 18-3981.
abstract: Inhibition of myocardial Ca2+ 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. In voltage-clamps experiments with isolated cardiac myocytes of guinea-pig, Ro 18-3981 caused a concentration-dependent inhibition of the Ca2+ 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 (Vh) of -20 mV (IC50 = 2.3 nm) than at -50 mV (IC50 = 100 nM). 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). 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. 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 potential-dependent.
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007473:Ion Channels / Q000378:metabolism; D017275:Isradipine; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D009543:Nifedipine / Q000031:analogs & derivatives / Q000494:pharmacology; D010069:Oxadiazoles / Q000378:metabolism / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D007473:Ion Channels; D010069:Oxadiazoles; D011725:Pyridines; C052934:Ro 18-3981; D009543:Nifedipine; C034600:darodipine; D011188:Potassium; D017275:Isradipine