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.