Effect of 4-aryl-2-methyl-5-nitro-1,4-dihydropyridine-3-carboxylates on the guinea pig papillary muscle and isolated human vena saphena magna that is used for coronary artery bypass grafting

Abstract

Background The goal of this study was to estimate: (i) the action of 5-nitro-substituted 1,4-dihydropyridines as well as Bay K 8644 (CAS [71145-03-4]) and CGP 28392 (CAS [89289-93-0]) on cardiac action potential duration (APD) and isometric contraction in the isolated guinea pig papillary muscles; (ii) whether the effects of 2-propoxyethyl 4-(2-difluoromethoxyphe-nyl)-2-methyl-5-nitro-1,4-dihydropyridine-3-carboxylate on the lengthening of cardiac APD were related to certain potassium channels (e.g., I K1, K ATP and I K); and (iii) the modulation of the contraction-relaxation effects on isolated human vena saphena magna samples using three 5-nitro-substituted 1,4-dihydropyridine derivatives, displaying the positive inotropic and AP duration effects. Methods The experiments were conducted on isolated human vena saphena magna samples and papillary muscles from adult guinea pigs. Isometric contractions and APs were recorded using a force transducer and microelectrode technique, respectively. Results 2-Propoxyethyl 4-(2-difluoromethoxyphenyl)-2-methyl-5-nitro-1,4-dihydropyridine-3-carboxylate significantly increased APD and isometric contractions in a concentration-dependent manner. Its effects were suppressed by dl-sotalol. Other derivatives tested, such as Bay K 8644 and CGP 28392, showed either negligible effects or increased the contraction force but did not influence the APD. Compounds possessing positive inotropic properties at a concentration of 10 −7 to 10 −4 M significantly relaxed the isolated vessel samples pre-contracted with phenylephrine (10 −4 M). The weakest response was shown by 2-propoxyethyl 4-(2-difluoromethoxyphenyl)-2-methyl-5-nitro-1,4-dihydropyridine-3-carboxylate. Conclusion These results show that 5-nitro-substituted 1,4-dihydropyridine derivatives with positive inotropic action significantly relaxed isolated vein samples that were pre-contracted with phenylephrine in a dose-dependent manner. 2-Propoxyethyl 4-(2-difluoromethoxyphenyl)-2-methyl-5-nitro-1,4-dihydropyridine-3-carboxylate prolongs the cardiac APD, which could be determined by the rapid component I Kr of the delayed potassium current I K blocker.