The chronic blockade of angiotensin I-converting enzyme eliminates the sex differences of serum cytokine levels of spontaneously hypertensive rats

Sex hormones modulate the action of both cytokines and the renin-angiotensin system. However, the effects of angiotensin I-converting enzyme (ACE) on the proinflammatory and anti-inflammatory cytokine levels in male and female spontaneously hypertensive rats (SHR) are unclear. We determined the relationship between ACE activity, cytokine levels and sex differences in SHR. Female (F) and male (M) SHR were divided into 4 experimental groups each (n = 7): sham + vehicle (SV), sham + enalapril (10 mg/kg body weight by gavage), castrated + vehicle, and castrated + enalapril. Treatment began 21 days after castration and continued for 30 days. Serum cytokine levels (ELISA) and ACE activity (fluorimetry) were measured. Male rats exhibited a higher serum ACE activity than female rats. Castration reduced serum ACE in males but did not affect it in females. Enalapril reduced serum ACE in all groups. IL-10 (FSV = 16.4 +/- 1.1 pg/mL; MSV = 12.8 +/- 1.2 pg/mL), TNF-alpha (FSV = 16.6 +/- 1.2 pg/mL; MSV = 12.8 +/- 1 pg/mL) and IL-6 (FSV = 10.3 +/- 0.2 pg/mL; MSV = 7.2 +/- 0.2 pg/mL) levels were higher in females than in males. Ovariectomy reduced all cytokine levels and orchiectomy reduced IL-6 but increased IL-10 concentrations in males. Castration eliminated the differences in all inflammatory cytokine levels (IL-6 and TNF-alpha) between males and females. Enalapril increased IL-10 in all groups and reduced IL-6 in SV rats. in conclusion, serum ACE inhibition by enalapril eliminated the sexual dimorphisms of cytokine levels in SV animals, which suggests that enalapril exerts systemic anti-inflammatory and anti-hypertensive effects.Univ Fed Espirito Santo, Dept Ciencias Fisiol, BR-29042755 Vitoria, ES, BrazilInst Fed Espirito Santo, Vitoria, ES, BrazilCtr Univ Vila Velha, Dept Farm, Vila Velha, ES, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Biofis, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Biofis, São Paulo, BrazilWeb of Scienc

Endothelial relaxation mechanisms and oxidative stress are restored by atorvastatin therapy in ovariectomized rats.

The studies on hormone replacement therapy (HRT) in females with estrogen deficiency are not conclusive. Thus, non-estrogen therapies, such as atorvastatin (ATO), could be new strategies to substitute or complement HRT. This study evaluated the effects of ATO on mesenteric vascular bed (MVB) function from ovariectomized (OVX) female rats. Female rats were divided into control SHAM, OVX, and OVX treated with 17β-estradiol (EST) or ATO groups. The MVB reactivity was determined in organ chambers, vascular oxidative stress by dihydroethidine staining, and the expression of target proteins by western blot. The reduction in acetylcholine-induced relaxation in OVX rats was restored by ATO or EST treatment. The endothelium-dependent nitric oxide (NO) component was reduced in OVX rats, whereas the endothelium-derived hyperpolarizing factor (EDHF) component or prostanoids were not altered in the MVBs. Endothelial dysfunction in OVX rats was associated with oxidative stress, an up-regulation of iNOS and NADPH oxidase expression and a down-regulation of eNOS expression. Treatment with ATO or EST improved the NO component of the relaxation and normalized oxidative stress and the expression of those signaling pathways enzymes. Thus, the protective effect of ATO on endothelial dysfunction caused by estrogen deficiency highlights a significant therapeutic benefit for statins independent of its effects on cholesterol, thus providing evidence that non-estrogen therapy could be used for cardiovascular benefit in an estrogen-deficient state, such as menopause

Effect of atorvastatin treatment on EDHF- and prostanoid-mediated relaxation in the MVBs.

<p>MVBs from the control (SHAM), ovariectomized (OVX) and ovariectomized treated with 17β-estradiol (EST) or atorvastatin (ATO) groups were contracted with noradrenaline (NE) in presence of N^G-nitro-L-arginine methyl ester (L-NAME) plus indomethacin. The inset shows the area under the concentration-response curves (AUC%) after this double blockade, which represents the magnitude of EDHF-mediated relaxation (A). The role of prostanoids in MVB relaxation is represented by the difference in the area under the curve (dAUC%) between the groups in the presence of L-NAME and after inhibition with L-NAME plus indomethacin (B). The responses are expressed as the percentage of reduction in the perfusion pressure relative to the contractions induced by NE. Each point represents the mean of 6 experiments ± S.E.M. </p

Atorvastatin treatment improves oxidative stress in the mesenteric arteries from ovariectomized rats.

<p>Representative DHE staining in mesenteric arteries from the control (SHAM) (A), ovariectomized (OVX) (B) and ovariectomized treated with 17β-estradiol (EST) (C) or atorvastatin (ATO) (D) groups (upper panel). The fluorescent intensity was quantified based on the red signal (magnification x40, lower panel). Each column represents the mean of 6 experiments ± S.E.M., and the results are expressed as the percentage of the SHAM group. *P<0.05 vs. the SHAM group by one-way ANOVA followed by Tukey’s test.</p

Effect of atorvastatin treatment on endothelium-dependent relaxation caused by acetylcholine in ovariectomized rats.

<p>The mesenteric vascular beds (MVBs) from control (SHAM), ovariectomized (OVX) and ovariectomized treated with 17β-estradiol (EST) or atorvastatin (ATO) groups were contracted with noradrenaline (NE) in the absence (A) or presence of aminoguanidine (B) or N^G-nitro-L-arginine methyl ester (L-NAME) (C). The inset shows differences in the area under the concentration-response curves (dAUC%). The responses are expressed as the percentage of reduction in the perfusion pressure relative to the contractions induced by NE. Each point represents the mean of 6 experiments ± S.E.M. **P<0.01 and *P<0.05 vs. the SHAM group by two-way ANOVA followed by Tukey’s test.</p