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

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) 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.

Enalapril Treatment Alters the Contribution of Epoxyeicosatrienoic Acids but Not Gap Junctions to Endothelium-Derived Hyperpolarizing Factor Activity in Mesenteric Arteries of Spontaneously Hypertensive Rats

“…Previous studies in large, elastic, superior mesenteric arteries of SHRs also described decreases in endothelial Cxs and associated these changes with diminished EDHF responses, both reversed by candesartan treatment (Kansui et al, 2004). A causal link between EDHF and endothelial Cx expression in these arteries was also made after chronic treatment with angiotensin II (Dal-Ros et al, 2009). In contrast, we found no association between reduced endothelial Cxs40 and 43 and EDHF relaxation in the downstream muscular branches of the superior mesenteric artery.…”

Losartan Normalizes Endothelium-Derived Hyperpolarizing Factor–Mediated Relaxation by Activating Ca2+-Activated K+ Channels in Mesenteric Artery From Type 2 Diabetic GK Rat

“…The finding that these responses could be restored by an ACEI, by an ARB, or by a combination of the two has been taken as an indication of the negative influence of the RAS on EDHF-mediated responses (54,55). Indeed, in a very recent study, Dal-Ros et al (56) demonstrated in the rat that Ang II-induced hypertension is associated with selective impairments of EDHF-mediated relaxation and hyperpolarization in the mesenteric artery. In the present study, two-week treatment with losartan improved the EDHF-mediated relaxation in mesenteric arteries from GK rats even though the treatment was begun when the rats were already in the established phase of type 2 diabetes (i.e., at 32 -36-week-old).…”

Effect of angiotensin II-induced arterial hypertension on the voltage-dependent contractions of mouse arteries

“…Both in AngII [6] and in other hypertensive models [2,40], AHT is associated with depolarized membrane potentials of the VSMC. This depolarization may be due to attenuated basal NO release and (partial) removal of the hyperpolarizing effect of NO [2].…”

“…Because this might result in a reduction of the hyperpolarizing effect of NO on the VSMCs [2,6], this would shift the window current induced contraction curves to lower K + concentrations without affecting the functional properties of the L-type Ca 2+ channels [8]. In order to exclude that the shift of the window current induced contraction curves in aortic segments of mice with AngII-induced AHT was due to attenuated NO availability and the subsequent depolarization of VSMCs, aortic segments from saline-and AngIItreated mice were studied before and after inhibition of basal NO release with 300 μM L-NAME (Fig.…”