Acute effects of 2-methoxyestradiol on endothelial aortic No release in male and ovariectomized female rats.

The endogenous metabolites of 17beta-estradiol are thought to have protective vascular effects, especially in males and estrogen-deprived females. The present study evaluated the acute in vitro effects of the active metabolite 2-methoxyestradiol on endothelial NO release from ovariectomized female and intact male and female rat aortas. NO was measured electrochemically by differential normal pulse amperometry using carbon fiber microsensors, and also by fluorescence microscopy using 4,5-diaminofluorescein diacetate. 2-Methoxyestradiol alone induced a maintained increase in endothelial NO release in male and ovariectomized rats that was reduced by pretreatment with L-NAME. NO release induced by calcium ionophore alone (A23187) was lower in aortas from ovariectomized rats than from intact females, indicating that estrogen deprivation induces endothelial dysfunction. Pretreatment of aortas with 2-methoxyestradiol potentiated significantly the A23187-induced-NO release in ovariectomized as well as in males, but not in intact females. This potentiation was reduced or abolished by L-NAME. 2-Methoxyestradiol potentiated the vasodilatory effect of A23187 on intestinal arterioles, and also increased intestinal tissular laser-Doppler blood flow signal. These results demonstrate that 17beta-estradiol and its active metabolite 2-methoxyestradiol increase basal aortic endothelial NO production and also cause a potentiation of the calcium ionophore-stimulated NO release in male and ovariectomized, while it has no effects on intact females. 2-Methoxyestradiol appears to be a promising pharmacological agent capable of improving endothelial function in men and postmenopausal women.

N-acetylcysteine exerts protective effects and prevents lung redox imbalance and peroxynitrite generation in endotoxemic rats.

The aim of this study was to determine in endotoxemic rats the effects of N-acetylcysteine on lung redox imbalance and plasma peroxynitrite generation. Eighty male Wistar rats were divided in two sets of five experimental groups. Six hours after vehicle (Control group: isotonic NaCl sterile solution i.p.; n=7), lipopolysaccharide (LPS group: 1 mg/Kg i.p.; n=8), N-acetylcysteine plus LPS (NAC+LPS group, n=8), NAC plus the nitric oxide synthesis inhibitor N(w)-nitro-L-arginine methyl ester plus LPS (NAC+NAME+LPS group; n=8), or NAME plus LPS (NAME+LPS group; n=9), arterial blood and lung samples were taken from each animal under sodium pentobarbital anesthesia. In five additional groups treated as described above, in vivo plasma oxidation of dihydrorhodamine (DRH) 123 to rhodamine (RH)123 was measured as index of peroxynitrite formation. LPS treated rats presented increased plasma lactate, thrombocytopenia and both, decreased reduced thiols and increased lipid peroxidation in lung tissue. Moreover, LPS produced increments in plasma concentration of nitrites/nitrates and DRH 123 oxidation. Pretreatment with NAC prevented all these changes induced by LPS except the increment in plasma concentration of nitrites/nitrates. The protective effects seen in LPS rats pretreated with NAC were not observed in the NAC+NAME+LPS group. In conclusion, the results of this study show that in endotoxemia induced by LPS in rats, NAC produces protective effects on lung redox balance and prevents peroxynitrite anion generation.

Effect of estrogen and angiotensin-converting enzyme inhibitor on vascular remodeling in ovariectomized spontaneously hypertensive rats.

OBJECTIVE: The present study evaluated whether estrogen influences the effect of angiotensin-converting enzyme inhibition in preventing the vascular remodeling induced by hypertension and also investigated the signal mechanism involved in that effect. DESIGN: Ten-week-old female spontaneously hypertensive rats were ovariectomized (OVX) and randomly assigned to the groups: untreated OVX and treated with 17beta-estradiol (estradiol, 1.5 mg) and/or captopril (5 mg/kg/day). Evolution of systolic blood pressure was determined until 18 weeks. At that time, the heart and mesentery were excised. Structural changes in coronary vessels were quantified by an image analyzer. Inmunoblotting was performed on mesenteric arteries for determination of phosphorylated (ERK1/2). RESULTS: Estradiol treatment enhanced the antihypertensive effect of captopril in OVX rats. Treatment with captopril slightly modified the media cross-sectional area and wall-to-lumen of myocardial arterioles from OVX spontaneously hypertensive rats, whereas coadministration of captopril and estradiol significantly reduced the media cross-sectional area, wall-to-lumen ratio, and perivascular fibrosis in OVX spontaneously hypertensive rats. Captopril alone did not significantly inhibit extracellular signal-regulated kinase 1/2 phosphorylation, whereas coadministration of captopril and estradiol significantly attenuated this parameter. CONCLUSIONS: These results indicate that estrogen may enhance the angiotensin-converting enzyme inhibition-mediated improvement of vascular remodeling in hypertension, which may be partly mediated via inhibition of extracellular signal-regulated kinase 1/2.

17beta-estradiol exerts a beneficial effect on coronary vascular remodeling in the early stages of hypertension in spontaneously hypertensive rats.

OBJECTIVE: Estrogens may induce cardioprotective effects and prevent neointima formation in response to vascular injury in vivo. The present study evaluated the effect of 17beta-estradiol on myocardial arterial remodeling and on vascular mitogen-activated protein kinase expression in experimental hypertension. DESIGN: The experiments were performed in intact female spontaneously hypertensive rats (SHR), in SHR that were ovariectomized at 10 or 25 weeks of age, and in ovariectomized SHR that were supplemented with 17 beta-estradiol (OVX + E2, 1.5 mg every 8 weeks, subcutaneous pellets). RESULTS: At 18 weeks of age, in all myocardial arterioles and small arteries studied, we found significant increases in wall-to-lumen ratio in ovariectomized rats as compared with intact animals. 17beta-estradiol significantly reduced the wall-to-lumen ratio in OVX + E2 rats. Perivascular fibrosis of small coronary arteries was significantly increased by ovariectomy, and this effect was prevented by long-term treatment with 17beta-estradiol. Phosphorylated extracellular signal-regulated kinase 1/2 significantly increased in mesenteric arteries from ovariectomized animals and this effect was prevented by 17beta-estradiol. Wall-to lumen ratio and perivascular fibrosis were significantly higher in older intact animals at 33 weeks of age. However, neither ovariectomy nor estradiol replacement had any effect on long-term hypertension-induced vascular remodeling. CONCLUSIONS: These data suggest that estradiol may exert a beneficial effect by protecting the vasculature from hypertension-induced myocardial arterial remodeling in the early stages of hypertension, but not when chronic alterations are established after a long-term period of hypertension.

Effects of oestrogen treatment and angiotensin-converting enzyme inhibition on the microvasculature of ovariectomized spontaneously hypertensive rats.

We investigated the role of oestrogen in the function and structure of the microcirculation of female spontaneously hypertensive rats (SHRs), and evaluated the effect of 17beta-oestradiol on their cardiovascular response to pharmacological agents that block the formation of angiotensin II. Ten-week-old SHRs were randomly assigned to the following groups: intact, ovariectomized, and ovariectomized treated with 17beta-oestradiol (1.5 mg delivered over 60 days) and/or captopril (5 mg kg(-1) day(-1) for 8 weeks). Systolic blood pressure was determined from the time of ovariectomy up to 18 weeks of age, at which time endothelial function and microvascular density in skeletal muscle were evaluated. Both 17beta-oestradiol and captopril prevented development of hypertension in ovariectomized rats. Furthermore, coadministration of both drugs had a greater antihypertensive effect than either one alone. Acetylcholine-induced vasodilatation was impaired in ovariectomized SHRs, and the response was improved by treatment with 17beta-oestradiol and/or captopril. In addition, 17beta-oestradiol replacement in ovariectomized rats enhanced the effect of captopril on acetylcholine-induced vasodilatation. Ovariectomized rats also showed lower microvascular density than intact rats, an effect that was prevented by 17beta-oestradiol replacement or captopril treatment and, to a significantly larger extent, by coadministration of both. We concluded that both 17beta-oestradiol and captopril attenuated the development of hypertension and improved the impairment in microvascular density of ovariectomized SHRs. Moreover, when simultaneously administered, oestradiol and captopril had an additive effect on blood pressure and the microvasculature.

17Beta-oestradiol enhances the acute hypotensive effect of captopril in female ovariectomized spontaneously hypertensive rats.

The objective of this study was to investigate whether the acute haemodynamic effects of angiotensin-converting enzyme inhibition with captopril could be enhanced by oestrogen administration, and then to evaluate the mechanisms involved in this enhancement. All experiments were performed in 18-week-old female spontaneously hypertensive rats arranged in three experimental groups: intact; ovariectomized (OVX); and ovariectomized plus treatment with 17beta-oestradiol (OVX + E2). These groups were used to evaluate the effects of captopril administration alone, or following bradykinin B2 receptor blockade or nitric oxide synthase inhibition, on a number of haemodynamic parameters (mean arterial pressure, cardiac index, vascular resistance and heart rate). The drop in mean arterial pressure and vascular resistance index in response to captopril was more pronounced in intact and ovariectomized rats treated with 17beta-oestradiol than in ovariectomized animals. Blockade of bradykinin B2 receptors or inhibition of nitric oxide synthesis attenuated the synergy between 17beta-oestradiol and captopril. It is concluded that ovariectomy blunted the blood pressure and vascular resistance index drop observed in intact rats in response to captopril. Treatment with 17beta-oestradiol prevented the blunted response to captopril in ovariectomized rats. Kinins and nitric oxide may be involved in the mechanisms of 17beta-oestradiol potentiation of the haemodynamic effects of captopril.