Novel pyridyl-substituted nitronyl nitroxides as potential antiarrhythmic and hypotensive agents with low toxicity and enhanced stability in aqueous solutions

Abstract

This study explores the antiarrhythmic and hypotensive potential of pyridyl-substituted nitronyl nitroxides derivatives, uncovering the crucial role of a single carbon moiety of the pyridine cycle alongside radical and charged oxygen centers of the imidazoline fragment. Notably, the introduction of fluorine atoms diminished the antiarrhythmic effect, while the most potent derivatives featured the nitronyl nitroxide pattern positioned at the third site of the pyridine cycle. Gender-dependent responses were observed in lead compounds L^CF3 and L^Me, with L^Me inducing temporary bradycardia and hypotension specifically in female rats, and L^CF3 causing significant blood pressure reduction followed by rebound in females compared to milder effects in males. Mechanistic insights point towards β₁ adrenoceptor blockade as an underlying mechanism, supported by experiments on isolated rat atria. This research underscores the interplay between structure, cardiovascular effects and gender-specific responses, offering insights for therapeutic strategies for treating free radical-associated cardiovascular disorders.

Keywords: Animals; Antiarrhythmics; Cardiovascular diseases; Drug effects; Nitronyl nitroxides; Rats.