Potentiation by isoniazid of relaxation induced by nitrovasodilators in rat aorta

The influence of isoniazid (ISO) preincubation on the relaxant effects of a group of nitrovasodilators was examined in norepinephrine-contracted rat aortic rings with and without endothelium. ISO displaced to the left the dose-response curves to all nitrovasodilators and increased the negative logarithm of their median effective concentration (EC50) values. Potentiation was minimal with sodium nitrite and increased progressively with sodium nitroprusside, nitroglycerin (NTG), and isosorbide dinitrate. The phenomenon occurred in rings with and without endothelium and was not seen with the nitric oxide-releasing agent acetylcholine or with the nonspecific vasodilator hydralazine. These results confirm previous observations of potentiation of NTG vasorelaxation by ISO and extend them to other nitrovasodilators. Potentiation is attributed to the previously postulated inhibition by ISO of pyridoxal-requiring enzymes involved in the breakdown of homocysteine, leading to its intracellular accumulation. Increased availability of this sulfhydryl donor would lead in turn to enhanced bioactivation and vasorelaxant effects of nitrovasodilators. The different degrees of potentiation observed would be related to the sulfhydryl requirement of each compound for bioactivation. Alternatively, enhanced bioactivation of the nitrovasodilators could be due to induction by ISO of P-450 enzymes involved in this process.