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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 4, 2008; DOI: 10.1124/jpet.108.145326
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Received for publication August 27, 2008.
Revised October 29, 2008.
Accepted for publication October 30, 2008.

Angiotensin II-induced hypertension is associated with a selective inhibition of EDHF-mediated responses in the rat mesenteric artery

Stephanie Dal-Ros 1, Christian Bronner 1, Christa Schott 1, Modou O. Kane 1, Marta Chataigneau 1, Valerie B. Schini-Kerth 1, Thierry Chataigneau 1*

1 Faculte de Pharmacie

* Address correspondence to: E-mail: thierry.chataigneau{at}pharma.u-strasbg.fr

Abstract

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) during 21 days using osmotic mini-pumps. 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 Cx37, Cx40 and Cx43 was quantified in segments of mesenteric arteries by immunohistochemistry and quantitative real time RT-PCR. 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 NO-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 partly, to a decreased expression of connexins Cx37, Cx40 and Cx43 in the arterial wall.


Key words: Connexins, EDHF, Endothelium, Gap junctions, Hyperpolarization, Relaxation




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