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.

The present investigation aimed to characterize the effect of a short‐time treatment with a new thiazolidinedione (TZD) derivative, GQ‐130, on metabolic alterations in rats fed a high‐fat diet (HFD). We investigated whether metabolic alterations induced by GQ‐130 were mediated though a mechanism that involves PPARβ/δ transactivation. Potential binding and transactivation of PPARα, PPARβ/δ or PPARγ by GQ‐130 were examined through cell transactivation, 8‐anilino‐1‐naphthalenesulfonic acid (ANS) fluorescence quenching assays and thermal shift assay. For in vivo experiments, male 8‐week‐old Wistar rats were divided into three groups fed for 6 weeks with: (a) a standard rat chow (14% fat) (control group), (b) a HFD (57.8% fat) alone (HFD group), or (c) a HFD associated with an oral treatment with GQ‐130 (10 mg/kg/d) during the last week (HFD‐GQ group). In 293T cells, unlike rosiglitazone, GQ‐130 did not cause significant transactivation of PPARγ but was able to activate PPARβ/δ by 153.9 folds in comparison with control values (DMSO). Surprisingly, ANS fluorescence quenching assay reveals that GQ‐130 does not bind directly to PPARβ/δ binding site, a finding that was further corroborated by thermal shift assay which evaluates the thermal stability of PPARβ/δ in the presence of GQ‐130. Compared to the control group, rats of the HFD group showed obesity, increased systolic blood pressure (SBP), insulin resistance, impaired glucose intolerance, hyperglycaemia, and dyslipidaemia. GQ‐130 treatment abolished the increased SBP and improved all metabolic dysfunctions observed in the HFD group. Oral treatment with GQ‐130 was effective in improving HFD‐induced metabolic alterations probably through a mechanism that involves PPARβ/δ activation.

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