Angiotensin II-Induced Hypertension Is Associated with a Selective Inhibition of Endothelium-Derived Hyperpolarizing Factor-Mediated Responses in the Rat Mesenteric Artery

Département de Pharmacologie et Physicochimie, Unité Mixte de Recherche 7175 Centre National de Recherche Scientifique/Université Louis Pasteur (Strasbourg I), Faculté de Pharmacie 74, Illkirch, France.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 12/2008; 328(2):478-86. DOI: 10.1124/jpet.108.145326
Source: PubMed


Hypertension has been shown to be associated with impaired endothelium-derived hyperpolarizing factor (EDHF)-mediated arterial relaxation and hyperpolarization. Treatments of hypertensive rats with inhibitors of the renin-angiotensin system have been shown to restore both EDHF-mediated responses and the expression of connexins involved in the intercellular transfer of the hyperpolarization in mesenteric arteries. The present study was designed to determine whether chronic treatment of rats with angiotensin II impairs EDHF-mediated responses and the expression of connexins in the mesenteric arterial wall. Male Wistar rats were treated with angiotensin II (0.4 mg/kg/day) for 21 days using osmotic minipumps. Arterial pressure was measured by tail-cuff plethysmography. Contractile responses and membrane potential were measured in isolated mesenteric arteries. The expression of the three connexins (Cxs), Cx37, Cx40, and Cx43, was quantified in segments of mesenteric arteries by immunohistochemistry and quantitative real-time reverse transcriptase-polymerase chain reaction. Angiotensin II administration increased the mean systolic blood pressure. EDHF-mediated relaxation and hyperpolarization to acetylcholine and red wine polyphenols were significantly impaired in mesenteric arteries from angiotensin II-treated rats in comparison with control animals, whereas nitric oxide-mediated relaxation was unaltered. The expression of connexins Cx37, Cx40, and Cx43 was significantly decreased in the mesenteric artery from angiotensin II-treated rats. These findings indicate that angiotensin II-induced hypertension is associated with a selective impairment of EDHF-mediated relaxation and hyperpolarization in the rat mesenteric artery. The inhibition of EDHF-mediated responses is due, at least in part, to a decreased expression of connexins Cx37, Cx40, and Cx43 in the arterial wall.

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    • "We have previously shown that prenatal T exposure leads to endothelial dysfunction with specific impairments in the EDHF function [17]. An endothelial dysfunction involving a selective blunting of EDHF-mediated relaxation in the mesenteric artery has also been observed in spontaneously hypertensive rats [46] and in Ang II-treated rats [21]. In the present study, we observed that treatment with the ACE inhibitor enalapril prevented endothelial dysfunction in T rats, as indicated by normal EDHF-mediated relaxations in mesenteric arteries, suggesting that Ang II may to be a causal factor contributing to the underlying impairment of the EDHF-mediated response observed in T rats. "
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    ABSTRACT: Prenatal exposure to elevated testosterone levels induces adult life hypertension associated with selective impairments in endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation in mesenteric arteries. We tested whether the angiotensin-converting enzyme inhibitor enalapril restores EDHF function through regulating the activities of small (Kcnn3) and intermediate (Kcnn4) conductance calcium-activated potassium channels in the mesenteric arteries. Pregnant Sprague-Dawley rats were injected with vehicle or testosterone propionate (0.5 mg/kg/day from Gestation Day 15-19, subcutaneously), and their 6-mo-old adult male offspring were examined. A subset of rats in these 2 groups was administered enalapril (40 mg/kg/day) for 2 wk through drinking water. Blood pressures were assessed through carotid arterial catheter and endothelium-dependent mesenteric arterial EDHF relaxation using wire myograph. Ace and Kcnn3 and Kcnn4 channel expressions were also examined. Renal and vascular Ace expression and plasma angiotensin II levels were increased in testosterone offspring. Blood pressures were significantly higher in testosterone offspring compared to controls, and treatment with enalapril significantly attenuated blood pressure in testosterone offspring. EDHF relaxation in testosterone offspring was reduced compared to controls, and it was significantly restored by enalapril treatment. Kcnn4 channel expression and function were similar between control and testosterone rats, but it was not affected by enalapril treatment. The relaxations mediated by the Kcnn3 were impaired in testosterone offspring, and it was normalized by enalapril treatment. Furthermore, enalapril treatment restored expression levels of Kcnn3 channels. These findings suggest that enalapril has a positive influence on endothelial function with improvement in EDHF relaxation through normalization of Kcnn3 expression and activity. Copyright 2015 by The Society for the Study of Reproduction.
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    • "Moreover, the present study investigated the long-term (6 weeks after the last injection) effects of doxorubicin, whereas previous studies reported an endothelial dysfunction in response to a shorter duration (within 12 h or 7 days) of doxorubicin IP injection. An endothelial dysfunction involving a selective blunted EDH-mediated relaxation in mesenteric artery rings has also been observed in spontaneously hypertensive rats [27] and in angiotensin II-treated rats [28]. In healthy arteries, EDH-mediated relaxations involve activation of SKCa and IKCa channels leading to the hyperpolarization of the endothelium, which is then transmitted to the underlying vascular smooth cells, in part, via myoendothelial gap junctions formed by Cx37, Cx40, and Cx43 to cause vasorelaxation [12]. "
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    • "Indeed, both an angiotensin-converting enzyme inhibitor and an AT1 receptor antagonist have been shown to prevent the aging-related endothelial dysfunction [10], [17]. In addition, angiotensin II, which is a potent inducer of vascular oxidative stress via the AT1 receptor-dependent upregulation of NADPH oxidase [18], has also been shown to induce a severe inhibition of EDHF-mediated relaxations in the mesenteric artery [19]. "
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