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.

Chronic administration of sildenafil improves endothelial function in spontaneously hypertensive rats by decreasing COX-2 expression and oxidative stress.

AIMS: Spontaneously hypertensive rats (SHR) exhibit impaired endothelial vasodilation and enhanced vasoconstriction. The phosphodiesterase 5 (PDE5) inhibitor sildenafil (Sild) potentiates the nitric oxide (NO)-mediated effects exerting antioxidative and anti-inflammatory actions. In the present study, we hypothesized that Sild could improve endothelial function in SHR. MATERIALS AND METHODS: Male rats were treated daily for 60 days by oral gavage with Sild (45 mg/kg) before the onset of the hypertensive state (pre-hypertensive protocol). The aortic relaxation to acetylcholine (ACh), sodium nitroprusside (SNP) and the phenylephrine (Phe)-induced contraction was evaluated in SHR. Protein expression of eNOS, p-eNOS, caveolin, COX-1, COX-2, ERK and p-ERK was measured by Western blot. KEY FINDINGS: Resting blood pressure was not modified by Sild administration. Treatment with Sild did not alter the relaxation response to SNP but improved the ACh-induced relaxation and reduced Phe-induced contraction in aortic rings from SHR. This protective effect of Sild could be attributed to reduced superoxide anions (O2-) generation, cyclooxygenase type 2 (COX-2) protein downregulation and increased NO bioavailability. SIGNIFICANCE: Sild improves endothelial function in SHR aorta without affecting resting blood pressure values. These results indicate that PDE5 inhibition has a potential role in the improvement of vascular function and could be an adjuvant in the treatment of essential hypertension.

Hyperglycaemia in pregnant rats causes sex-related vascular dysfunction in adult offspring: role of cyclooxygenase-2.

NEW FINDINGS: What is the central question of this study? Hyperglycaemia during pregnancy induces vascular dysfunction and hypertension in male offspring. Given that female offspring from other fetal programming models are protected from the effects of fetal insult, the present study investigated whether there are sex differences in blood pressure and vascular function in hyperglycaemia-programmed offspring. What is the main finding and its importance? We demonstrated that hyperglycaemia in pregnant rats induced vascular dysfunction and hypertension only in male offspring. We found sex differences in oxidative stress and cyclooxygenase-2-derived prostanoid production that might underlie the vascular dysfunction. These differences, particularly in resistance arteries, may in part explain the absence of hypertension in female offspring born to hyperglycaemic dams. Exposure to maternal hyperglycaemia induces hypertension and vascular dysfunction in adult male offspring. Given that female offspring from several fetal programming models are protected from the effects of fetal insult, in this study we analysed possible differences relative to sex in blood pressure and vascular function in hyperglycaemia-programmed offspring. Hyperglycaemia was induced on day 7 of gestation (streptozotocin, 50 mg kg-1 ). Blood pressure, acetylcholine and phenylephrine or noradrenaline responses were analysed in the aorta and mesenteric resistance arteries of 3-, 6- and 12-month-old male and female offspring. Thromboxane A2 release was analysed with commercial kits and superoxide anion (O2- ) production by dihydroethidium-emitted fluorescence. Male but not female offspring of hyperglycaemic dams (O-DR) had higher blood pressure than control animals (O-CR). Contraction in response to phenylephrine increased and relaxation in response to acetylcholine decreased only in the aorta from 12-month-old male O-DR and not in age-matched O-CR. Contractile and vasodilator responses were preserved in both the aorta and mesenteric resistance arteries from female O-DR of all ages. Pre-incubation with tempol, superoxide dismutase, indomethacin, NS-398, furegrelate or SQ29548 decreased contraction in response to phenylephrine and potentiated relaxation in response to acetylcholine in 12-month-old male O-DR aorta. In this artery, thromboxane A2 release and O2- generation were greater in O-DR than O-CR groups. In conclusion, exposure to hyperglycaemia in utero results in sex-specific and age-dependent hypertension. The fact that vascular function is preserved in female O-DR may in part explain the absence of hypertension in this group. In contrast, the peripheral artery dysfunction associated with increased cyclooxygenase-2-derived production of vasoconstrictor prostanoids could underlie the increased blood pressure in male O-DR.