Efeitos cardiovasculares do trans-4-metil-β-nitroestireno em ratos normotensos

Abstract

The mechanisms involved in the vasorelaxant effects of trans-4-methyl-β-nitrostyrene (T4MeN) were studied in rat aortic rings in in vitro experiments, and the mechanisms related to the cardiovascular effects of T4MeN were investigated in normotensive rats in vivo. In the in vitro protocols, T4MeN completely relaxed phenylephrine (PHE) -induced contractions (IC50 = 61.41 [35.40-87.42] mmol/L) and KCl (IC50 = 83.50 [56.63- 110.50] mmol/L) in preparations with intact endothelium. The vasorelaxant effect of T4MeN was not altered by the removal of the endothelium by pretreatment with L-NAME, indomethacin, tetraethylammonium, ODQ or MDL-12,330A. Under Ca2+ free conditions, T4MeN significantly reduced PHE (but not caffeine) induced contractions, CaCl2-induced contractions in PHE-stimulated aortic preparations (in the presence of verapamil) or high KCl as well as those contractions evoked by the reestablishment of external Ca2+ levels after depletion of intracellular Ca2+ stocks in the presence of thapsigargin. In contrast, T4MeN was more potent in inhibiting contractions induced by the tyrosine phosphatase inhibitor, sodium orthovanadate, than on contractions induced by the PKC activator, phorbol-12,13-dibutyrate. In pentobarbital-anesthetized rats, intravenous (i.v.) injection of T4MeN (0.03-0.5 mg/kg) induced bradycardia with rapid onset (1-2 s) and hypotension which were dose-dependent. These cardiovascular responses to T4MeN were abolished by bilateral cervical vagotomy or by selective blockade of the neural conduction of vagal C-fibers afferent by perineural treatment of both cervical nerves with capsaicin. Hypotension and bradycardia were also recorded when T4MeN was injected directly into the right ventricle, but not into the left ventricle. In addition, both hypotension and bradycardia responses to i.v. T4MeN were significantly reduced by i.v pretreatment with capsazepine but remained unchanged by ondansetron or suramin. In conscious rats, dose-dependent hypotension and bradycardia evoked by T4MeN (i.v.) were abolished by i.v. pretreatment with methylatropine. It can be concluded that T4MeN induces endothelium-independent vasorelaxation that appears to occur intracellularly through the inhibition of contractions that are independent of Ca2+ influx from the extracellular medium, but involve the phosphorylation of tyrosine residues. In anesthetized rats, bradycardia and hypotension responses induced by T4MeN have a vago-vagal reflex origin resulting from the stimulation of vagal pulmonary afferents. The mechanism of transduction seems to involve the activation of vallinoid TRPV1, but not purinergic (P2X) or 5-HT3 receptors located on vagal pulmonary sensory nerves.