RESUMO
Diminazene aceturate (DIZE) has been described as an angiotensin-converting enzyme 2 (ACE2) activator. We aimed to investigate DIZE effects on blood pressure (BP) of spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats. BP was recorded in awake and unrestrained rats 24 hours after femoral artery catheterization. DIZE (15 mg/kg, s.c.) produced a fast BP decrease only in SHR (P < .01). Pre-treatment with L-NAME (10 mg/kg, iv) did not change the hypotensive effect on systolic BP whereas mitigated the DIZE effect on diastolic BP (∆ Emax: -31 ± 5 DIZE vs -15 ± 1 mm Hg DIZE + L-NAME, P < .05). BP changes after DIZE remained unchanged after the treatment of rats with A-779 (50 ug/kg, iv), a Mas receptor blocker. Vasodilatation curves to DIZE (10-9 to 10-4 mol/L) in mesenteric arteries confirmed the NO-mediation on DIZE effects in SHR, as L-NAME (300 µmol/L) reduced the vascular sensitivity (∆EC50: -5.12 ± 0.09 CONTROL vs -4.66 ± 0.08 L-NAME, P < .05) and the magnitude of DIZE effect (area under the curve (AUC), 357.5 ± 8.2 DIZE vs 424.7 ± 11.6 L-NAME; P < .001), whereas A-779 (1 µmol/L) enhanced DIZE response (AUC, 357.5 ± 8.2 DIZE vs 309.8 ± 14.7 A-779, P < .05). Our findings indicate that DIZE acutely reduces the BP in SHR possibly by a mechanism other than Mas receptor activation. This effect seems to be mediated, at least partially, by NO.
Assuntos
Diminazena/análogos & derivados , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Óxido Nítrico/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Diminazena/farmacologia , Hipertensão/metabolismo , Masculino , RatosRESUMO
Triorganotins, such as tributyltin (TBT), are environmental contaminants that are commonly used as antifouling agents for boats. However, TBT is also known to alter mammalian reproductive functions. Although the female sex hormones are primarily involved in the regulation of reproductive functions, 17ß-estradiol also protects against cardiovascular diseases, in that this hormone reduces the incidence of coronary artery disease via coronary vasodilation. The aim of this study was to examine the influence of 100 ng/kg TBT administered daily by oral gavage for 15 d on coronary functions in female Wistar rats. Findings were correlated with changes in sex steroids concentrations. Tributyltin significantly increased the baseline coronary perfusion pressure and impaired vasodilation induced by 17ß-estradiol. In addition, TBT markedly decreased serum 17ß-estradiol levels accompanied by a significant rise in serum progesterone levels. Tributyltin elevated collagen deposition in the heart interstitium and number of mast cells proximate to the cardiac vessels. There was a positive correlation between the increase in coronary perfusion pressure and incidence of cardiac hypertrophy. In addition, TBT induced endothelium denudation (scanning electron microscopy) and accumulation of platelets. Moreover, TBT impaired coronary vascular reactivity to estradiol (at least in part), resulting in endothelial denudation, enhanced collagen deposition and elevated number of mast cells. Taken together, the present results demonstrate that TBT exposure may be a potential risk factor for cardiovascular disorders in rats.
Assuntos
Vasos Coronários/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Estradiol/farmacocinética , Compostos de Trialquitina/toxicidade , Vasodilatação/efeitos dos fármacos , Animais , Vasos Coronários/fisiologia , Interações Medicamentosas , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/ultraestrutura , Estradiol/administração & dosagem , Feminino , Ratos , Ratos WistarRESUMO
Although progesterone has the ability to promote dilation of vascular smooth muscle, its role in coronary circulation is still poorly characterized, especially in essential hypertension and in a model of endogenous deficiency of ovarian hormones. Thus, this study evaluated the effect of progesterone treatment on endothelium-dependent coronary vascular reactivity in hypertensive (SHR) and ovariectomized rats. Adult SHR aged 8-10 weeks were divided into: SHAM, Ovariectomized (OVX) and Ovariectomized + treatment with 2 mg/kg/day of progesterone for 15 days (OVX-P4). Coronary vascular reactivity was investigated using the modified Langendorff method. After stabilization, baseline coronary perfusion pressure (CPP) was recorded and vascular reactivity to bradykinin (BK, 0.1-1000 ng) were assessed before and after infusion, either individually or in combination, with Nω-nitro-l-arginine methyl ester (l-NAME), indomethacin or clotrimazole. Scanning electron microscopy was used for qualitative analysis of the endothelium. OVX and OVX-P4 groups had a higher baseline CPP compared to that of the SHAM group. BK was able to promote vasodilation in all groups. However, relaxation to BK was less pronounced in the OVX group when compared to SHAM, with architecture loss and areas of cell atrophy having been observed. Progesterone treatment prevented this injury. Perfusion with l-NAME induced greater damage to the SHAM group, while the use of indomethacin led to a significant reduction in the vasodilator response to BK in the OVX-P4 group. Taken together, our results show that progesterone modulates endothelium-dependent coronary vasodilation in SHR ovariectomized, preventing damage caused by ovarian hormonal deficiency through a mechanism that involves prostanoid pathway.
Assuntos
Vasos Coronários/patologia , Endotélio Vascular/patologia , Hipertensão/patologia , Progesterona/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Bradicinina/farmacologia , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/ultraestrutura , Endotélio Vascular/efeitos dos fármacos , Feminino , Tamanho do Órgão/efeitos dos fármacos , Perfusão , Ratos Endogâmicos SHR , Sístole/efeitos dos fármacos , Útero/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
BACKGROUND: The protective effect of estrogen on the vasculature cannot be explained only by its action through the receptors ERα and ERß. G protein-coupled estrogen receptors (GPER)-which are widely distributed throughout the cardiovascular system-may also be involved in this response. However, little is known about GPER actions in hypertension. Therefore, in this study we evaluated the vascular response mediated by GPER using a specific agonist, G-1, in spontaneously hypertensive rats (SHR). We hypothesized that G-1 would induce a relaxing response in resistance mesenteric arteries from SHR of both sexes. METHODS: G-1 concentration-response curves (1 nM-10 µM) were performed in mesenteric arteries from SHR of both sexes (10-12-weeks-old, weighing 180-250 g). The effects of G-1 were evaluated before and after endothelial removal and incubation for 30 min with the inhibitors L-NAME (300 µM) and indomethacin (10 µM) alone or combined with clotrimazole (0.75 µM) or catalase (1,000 units/mL). GPER immunolocalization was also investigated, and vascular hydrogen peroxide (H2O2) and ROS were evaluated using dichlorofluorescein (DCF) and dihydroethidium (DHE) staining, respectively. RESULTS: GPER activation promoted a similar relaxing response in resistance mesenteric arteries of female and male hypertensive rats, but with the participation of different endothelial mediators. Males appear to be more dependent on the NO pathway, followed by the H2O2 pathway, and females on the endothelium and H2O2 pathway. CONCLUSION: These findings show that the GPER agonist G-1 can induce a relaxing response in mesenteric arteries from hypertensive rats of both sexes in a similar way, albeit with differential participation of endothelial mediators. These results contribute to the understanding of GPER activation on resistance mesenteric arteries in essential hypertension.
RESUMO
Progesterone seems to play a role in cardiovascular physiology since its receptors are expressed on endothelial cells from both sexes of mammals. However, little is known about its role on the coronary circulation. Thus, this study aims to evaluate the effect of acute administration of progesterone on the coronary bed and the endothelial pathways involved in this action in normotensive rats of both sexes. A dose-response curve of progesterone (1-50 µmol/L) in isolated hearts using the Langendorff preparation was performed. Baseline coronary perfusion pressure (CPP) was determined, and the vasoactive effect of progesterone was evaluated before and after infusion with Nω-nitro-L-arginine methyl ester (L-NAME), indomethacin, catalase, and Tiron. The analysis of nitric oxide (NO) and superoxide anion (O2 · -) was performed by DAF-2DA and DHE, respectively. Female group showed higher CPP. Nevertheless, progesterone promoted a similar relaxing response in both sexes. The use of L-NAME increased vasodilatory response in both sexes. When indomethacin was used, only the males showed a reduced relaxing response, and in the combined inhibition with L-NAME, indomethacin, and catalase, or with the use of Tiron, only the females presented reduced responses. NO and O2 ·- production has increased in female group, while the male group has increased only NO production. Our results suggest that progesterone is able to modulate vascular reactivity in coronary vascular bed with a vasodilatory response in both sexes. These effects seem to be, at least in part, mediated by different endothelial pathways, involving NO and EDH pathways in females and NO and prostanoids pathways in males.
Assuntos
Progesterona/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Feminino , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Fatores Sexuais , Superóxidos/metabolismo , Esfregaço VaginalRESUMO
AIM: An imbalance between antioxidant and pro-oxidant factors, with a predominance of the latter, characterises oxidative stress and is indicative of a loss of vascular function. The beneficial vascular effects of oestrogen may be related to its ability to stimulate the G protein-coupled oestrogen receptor (GPER) and produce antioxidant activity. This study evaluated the GPER-dependent relaxation response in the mesenteric resistance arteries of female and male rats and measured the contributions of pro-oxidant and antioxidant enzymes in this response. MAIN METHODS: The relaxation response was characterised in third-order mesenteric arteries using concentration-response curves of the selective GPER agonist G-1 (1â¯nM-10⯵M), target protein levels were measured using Western blots, and vascular superoxide anion (O2-) and hydrogen peroxide (H2O2) levels were measured using dihydroethidium (DHE) and dichlorofluorescein (DCF) staining, respectively. KEY FINDINGS: The GPER agonist induced concentration-dependent vasorelaxation without showing differences between sexes. However, GPER expression was greater in male rats. No sex differences were detected in the expression of antioxidant proteins (catalase, SOD-1, and SOD-2). The basal vascular production of O2- and H2O2 was similar in the studied groups, and stimulation with G-1 maintained this response. SIGNIFICANCE: Together, our results show that the expression of GPER is greater in male mesenteric arteries, despite of the lack of a difference in vascular response. Nevertheless, antioxidant enzyme expression levels and the generation rates of pro-oxidants were similar between the studied groups. These results offer a new perspective for understanding GPER expression and functionality in resistance arteries.
Assuntos
Antioxidantes/metabolismo , Endotélio Vascular/metabolismo , Artérias Mesentéricas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Vasodilatação/fisiologia , Animais , Endotélio Vascular/citologia , Feminino , Masculino , Artérias Mesentéricas/citologia , Ratos , Ratos Wistar , Fatores Sexuais , Transdução de SinaisRESUMO
Gender-associated differences in the development of cardiovascular diseases have been described in humans and animals. These differences could explain the low incidence of cardiovascular disease in women in the reproductive period, such as stroke, hypertension, and atherosclerosis. The cardiovascular protection observed in females has been attributed to the beneficial effects of estrogen on endothelial function. Besides estrogen, sex hormones are able to modulate blood pressure by acting on important systems as cardiovascular, renal, and neural. They can have complementary or antagonistic actions. For example, testosterone can raise blood pressure by stimulating the renin-angiotensin-aldosterone system, whereas estrogen alone or combined with progesterone has been associated with decreased blood pressure. The effects of testosterone in the development of cardiovascular disease are contradictory. Although some researchers suggest a positive effect, others indicate negative actions of testosterone. Estrogens physiologically stimulate the release of endothelium-derived vasodilator factors and inhibit the renin-angiotensin system. Although the cardioprotective effects of estrogen are widely appreciated, little is known about the effects of progesterone, which is commonly used in hormone replacement therapy. Progesterone has both vasodilatory and vasoconstrictive effects in the vasculature, depending on the location of the vessel and the level of exposure. Nevertheless, the mechanisms through which sex hormones modulate blood pressure have not been fully elucidated. Therefore, the characterization of those could lead to a better understanding of hypertension in women and men and perhaps to improved forms of therapy.