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 LCF3 and LMe, with LMe inducing temporary bradycardia and hypotension specifically in female rats, and LCF3 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.
摘要：
本研究探讨了吡啶基取代的硝酰基硝基氧衍生物的抗心律失常和降压潜力，揭示吡啶环的单个碳部分以及咪唑啉片段的自由基和带电氧中心的关键作用。值得注意的是,氟原子的引入减少了抗心律失常作用，而最有效的衍生物具有位于吡啶循环第三位置的硝酰硝基氧模式。在先导化合物LCF3和LMe中观察到性别依赖性反应，特别是在雌性大鼠中，LMe会诱发暂时性心动过缓和低血压，与男性相比，LCF3导致女性血压显着降低，然后反弹。机制见解指出β1肾上腺素受体阻断是一种潜在机制，由离体大鼠心房实验支持。这项研究强调了结构之间的相互作用，心血管效应和性别特异性反应，为治疗自由基相关心血管疾病的治疗策略提供见解。
