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

We previously reported that trans-4-methoxy-ß-nitrostyrene (T4MN) evoked higher vasorelaxant effects in small resistance arteries from spontaneously hypertensive rats (SHRs) in comparison with its parent drug, the ß-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.

Mechanisms underlying the vasorelaxant effect of trans-4-methoxy-ß-nitrostyrene in the rat mesenteric resistance arteries.

Mechanisms underlying the vasorelaxant effects of the synthetic nitro compound, trans-4-methoxy-ß-nitrostyrene (T4MN) were studied in isolated small resistance arteries from spontaneously hypertensive rats (SHRs). T4MN caused vasorelaxation in endothelium-intact third-order branches of the mesenteric artery pre-contracted with noradrenaline (NA). This effect was unchanged by indomethacin and atropine but was significantly reduced by endothelium removal, L-NAME, LY294002, glybenclamide, TEA, apamin, TRAM 34, or by the association of apamin and TRAM 34. Pretreatment with the sGC inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reduced the T4MN-induced relaxation in endothelium-intact, but not in denuded preparations. Incubation of small resistance arteries with T4MN increased nitric oxide (NO) production, an effect that was blocked by L-NAME. In Ca2+-free medium, T4MN inhibits the contractions induced by (i) NA, (ii) exogenous calcium through receptor- or voltage-operated Ca2+ channels and (iii) those evoked by Ca2+ influx through stores-operated Ca2+ channels activated by thapsigargin-induced Ca2+ store depletion. In contrast, T4MN was inert against the transient contraction induced by caffeine in Ca2+-free medium. In conclusion, T4MN induced effective vasorelaxant effects in isolated small resistance arteries from SHRs. This vasorelaxation seems to be mediated partly by an endothelium-dependent mechanism involving activation of Akt/eNOS/NO pathway and partly by an endothelium-independent mechanism through activation of sGC/cGMP/PKG pathway in vascular smooth muscle, leading to inhibition of Ca2+ influx from the extracellular milieu and IP3-sensitive intracellular Ca2+ release as well as activation of potassium channels.

Cardiovascular Effects of the Essential Oil of Croton argyrophylloides in Normotensive Rats: Role of the Autonomic Nervous System.

Cardiovascular effects of the essential oil of Croton argyrophylloides Muell. Arg. (EOCA) were investigated in normotensive rats. In saline-pretreated anesthetized or conscious rats, intravenous (i.v.) injection of the EOCA induced dose-dependent hypotension. Dose-dependent tachycardia was observed only in conscious rats. In anesthetized rats, cervical bivagotomy failed to enhance EOCA-induced hypotension but unmasked significant bradycardia. In conscious rats, i.v. pretreatment with methylatropine, but not with atenolol or L-NAME, reduced both hypotensive and tachycardiac responses to EOCA. However, hexamethonium pretreatment reverted the EOCA-induced tachycardia into significant bradycardia without affecting the hypotension. In aortic ring preparations precontracted with phenylephrine, EOCA induced a concentration-dependent relaxation that was significantly reduced by vascular endothelium removal and pretreatment with atropine, indomethacin, or glibenclamide but remained unaffected by pretreatment with L-NAME or TEA. It is concluded that i.v. treatment with EOAC decreased blood pressure probably through an active vascular relaxation rather than withdrawal of sympathetic tone. Muscarinic receptor stimulation, liberation of the endothelium-derived prostacyclin, and opening KATP channels are partially involved in the aortic relaxation induced by EOCA and in turn in the mediation of EOCA-induced hypotension. EOCA-induced tachycardia in conscious rats appears to be mediated reflexly through inhibition of vagal drive to the heart.

Cardiovascular effects of a labdenic diterpene isolated from Moldenhawera nutans in conscious, spontaneously hypertensive rats.

CONTEXT: The labdenic diterpene labd-8(17)-en-15-oic acid (labd-8) isolated from a methanolic extract of Moldenhawera nutans Queiroz & Alkin (Leguminosae) has hypotensive and tachycardiac properties in normotensive rats. A part of the hypotensive effect was due to a reduction in the sympathetic nerve drive to vessels, an event admittedly enhanced in spontaneously hypertensive rats (SHRs). OBJECTIVES: We assessed whether the cardiovascular effects induced by labd-8 could be enhanced in SHRs. MATERIALS AND METHODS: For in vivo experiments, arterial and venous catheters were implanted under anesthesia for blood pressure recording and drug administration, respectively. For in vitro experiments, thoracic aorta rings were suspended in organ baths containing warm (37 °C) perfusion medium that was continuously bubbled with carbogen. RESULTS: Intravenous injection of labd-8 (1, 3, 5, and 10 mg/kg) induced similar dose-dependent hypotension and tachycardia in both SHRs and Wistar-Kyoto rats (WKY). In SHRs, only the tachycardia response to labd-8 was significantly reduced by pretreatment with methylatropine or propranolol. However, both cardiovascular effects of labd-8 were reduced by hexamethonium while remained unchanged by l-NAME. In isolated aortic preparations from SHRs, labd-8 (1-1000 µg/mL) relaxed potassium-induced contractions with an IC50 (geometric mean [95% confidence interval]) value (536.5 [441.0-631.9] µg/mL) significantly greater than that (157.6 [99.1-250.5] µg/mL) obtained in preparations from WKY rats. CONCLUSION: In SHRs, the hypotension induced by labd-8 is associated with a reflex tachycardia and seems mediated partly through withdrawal of sympathetic vasomotor tone and partly through an active vasorelaxation. Its magnitude was not enhanced when compared with WKY rats likely because of impaired vasorelaxant effects of labd-8 in preparations from SHRs.