Cardiovascular Effects of Trans-4-Methoxy-β-Nitrostyrene in Spontaneously Hypertensive Rats: Comparison With Its Parent Drug β-Nitrostyrene

Abstract

We previously reported that trans-4-methoxy-β-nitrostyrene (T4MN) evoked higher vasorelaxant effects in small resistance arteries from spontaneously hypertensive rats (SHRs) in comparison with its parent drug, the β-nitrostyrene 1-nitro-2-phenylethene (NPe). To further our knowledge of the influence of insertion of an electron-releasing group such as methoxy in the aromatic ring of NPe, we investigated the cardiovascular responses to intravenous (i.v.) injection of T4MN in SHRs and compared with those of NPe. In anesthetized SHRs, i.v. treatment with T4MN (0.03–0.5 mg/kg) and NPe (0.03–3 mg/kg) induced dose-dependent bradycardia and hypotension, which were biphasic (named phases 1 and 2). Magnitude of these responses was significantly higher for T4MN compared with NPe. Phase 1 cardiovascular responses to both T4MN (0.3 mg/kg) and NPe (3 mg/kg) were prevented by cervical bivagotomy or perineural treatment of both cervical vagus nerves with capsaicin, but was unchanged by i.v. pretreatment with capsazepine or ondansetron. After injection into the left ventricle, NPe and T4MN no longer evoked phase 1 responses. In conscious SHRs, NPe (3 mg/kg, i.v.), and T4MN (0.3 mg/kg, i.v.) evoked monophasic hypotensive and bradycardiac effects which were suppressed by i.v. pretreatment with methylatropine. It is concluded that i.v. administration of NPe and T4MN in SHRs induced a vago-vagal hypotensive and bradycardic reflex that did not involve the activation of vanilloid TRPV1 or 5-HT3 receptors located on vagal pulmonary sensory nerves. With respect to its parent drug, T4MN was more potent in inducing this reflex. Phase 2 hypotensive response to i.v. NPe and T4MN seems partially resulting from a direct vasodilatory action. It seems that insertion of a methoxy group into the aromatic ring stabilized NPe, which in turn increases its cardiovascular effects.

Vasodilatory action of trans‐4‐methoxy‐β‐nitrostyrene in rat isolated pulmonary artery

“…A similar profile was recently reported in isolated small resistance arteries from SHRs, in which T4MN was 22 times more potent as a relaxing agent than NPe 25 . Furthermore, both T4MN and NPe elicited vago‐vagal bradycardia and hypotension, and T4MN was about 30 times more potent at recruiting chemosensitive pulmonary vagal afferent fibres than NPe 16 . Thus, it seems that introduction of a methoxy group into the aromatic moiety stabilizes NPe, thereby enhancing both its potency and its interaction with sGC.…”

“…Previous in vitro experiments using aortic rings from normotensive rats showed that the methoxy derivative, trans ‐ 4 ‐ methoxy ‐ β ‐ nitrostyrene (T4MN; Figure 1B), exerts vasorelaxant activity by stimulating the sGC/cGMP pathway independently of endothelial NO 15 . Interestingly, the vasorelaxant potency of T4MN in resistance arteries from SHRs was 22‐fold greater than that of its parent drug, NPe 16 . To better understand the influence of insertion of the electron‐releasing methoxy group in the aromatic ring of NPe, we investigated vasorelaxant effects of T4MN in isolated pulmonary artery from normotensive rats, and compared them with those of its parent drug, NPe.…”

Vasorelaxant effect of trans‐4‐chloro‐β‐nitrostyrene, a synthetic nitroderivative, in rat thoracic aorta

“…Finally, it is suitable to assess the cardiovascular effects of T4CN in conscious rats. Previously, we showed that intravenous administration of 1‐nitro‐2‐phenylethane [47,48], NPe [49], T4MN [49], and T4MeN [50] elicited hypotensive and bradycardiac responses from vago‐vagal origin in rats.…”