Interaction Between Hydralazine and Nitrovasodilators in Vascular Smooth Muscle

Abstract

The combination of hydralazine and nitrates has been shown to provide long-term benefit in congestive heart failure, despite a nitrate dosage that should induce tolerance. To assess the interactions between hydralazine and nitroglycerin, aortic rings were isolated from male Wistar rats. In rings precontracted with phenylephrine, hydralazine incubation (10 microM and 0.1 mM) potentiated the responses to nitroglycerin (p < 0.05) but not to sin-1 (a direct activator of guanylate cyclase), 8-bromocyclic guanylate monophosphate, and forskolin (an adenylate cyclase activator). In similar conditions, the incubation of isoniazid (0.1 mM, used as a pyridoxal-sequestering agent without direct vasoactive properties) also potentiated the dose-response curve to nitroglycerin (p < 0.05). In aortas isolated from rats rendered nitrate tolerant in vivo (50 mg/kg subcutaneously twice daily during 4 days), hydralazine partially attenuated tolerance (p < 0.05). Our results suggest that the observed interaction between hydralazine and nitroglycerin may involve an inhibition of pyridoxal-dependent reactions, such as the catabolism of methionine and cysteine. This may enhance the availability of sulfhydryl-containing compounds, and therefore potentiate the responses to nitroglycerin.