AT ₂ Receptor-Mediated Relaxation Is Preserved After Long-Term AT ₁ Receptor Blockade

Abstract

Abstract-Angiotensin II type 2 receptor (AT 2 R) stimulation may cause vasodilation per se and may contribute to the antihypertensive effect produced by Angiotensin II type 1 receptor (AT 1 R) antagonists, given that AT 1 R blockade increases endogenous levels of Ang II, suggesting a physiological role for the unblocked AT 2 R. Thus, we first directly assessed whether or not there is desensitization to AT 2 R-mediated vasorelaxation because this is an important consideration, given the raised Ang II levels and the marked desensitization that is known to occur after AT 1 R stimulation. Second, we examined if AT 2 R-mediated vasorelaxation is preserved after long-term treatment with the AT 1 R antagonist candesartan cilexetil. Consecutive concentration-response curves to AT 2 R stimulation, with either Ang II (with AT 1 R blockade) or the selective agonist CGP42112, were studied in rat isolated mesenteric resistance arteries mounted in an arteriograph. AT 2 R stimulation with Ang II induced a concentration-dependent relaxation without desensitization. Similarly, CGP42112 evoked highly reproducible relaxation, which, like Ang II, was abolished by the AT 2 R antagonist PD123319. By contrast, AT 1 R-mediated contraction exhibited marked desensitization. In rats treated with candesartan cilexetil (2 mg/kg per day for 2 weeks), AT 1 R-mediated contraction was abolished, whereas AT 2 R-mediated relaxation evoked by either Ang II or CGP42112 was highly reproducible, PD123319-sensitive, and of a magnitude similar to that observed in naïve animals. Therefore, this study has provided unequivocal evidence for the reproducible nature of AT 2 R-mediated vasorelaxation during short-term and long-term AT 1 R blockade. (Ang II), including vasoconstriction, aldosterone release, and trophic effects. The physiological role of the AT 2 receptor (AT 2 R), on the other hand, is more controversial. Increasingly, evidence suggests that AT 2 R stimulation opposes the actions of AT 1 R stimulation. 1 However, recent data with AT 2 R knockout mice have provided conflicting data regarding the trophic effects of AT 2 R, in that AT 2 R in fact mediated Ang II-evoked cardiovascular growth, 2,3 as opposed to conventional dogma of a growth-inhibitory effect of AT 2 R. 4 Interestingly, the former studies are consistent with earlier findings in rats with pharmacological AT 2 R blockade. 5 Although the trophic effects of AT 2 R are open to debate, the potential vasodilator signaling pathways of AT 2 R stimulation are much more accepted. AT 2 R are thought to signal through cGMP/nitric oxide and/or bradykinin, at least in the vasculature and kidney. 6 -9 Indeed, it has recently been shown that short-term in vivo AT 2 R stimulation in spontaneously hypertensive rats will lower blood pressure. 10 In addition, AT 2 R-mediated relaxation of isolated mesenteric resistance arteries has been reported, 11-13 as well as AT 2 receptor mRNA and protein expression in this tissue. 11,[13][14][15] In vivo, AT 1 R antagonists are associated with a rise in plasma ...

Angiotensin II-Induced Relaxation of Anococcygeus Smooth Muscle via Desensitization of AT1Receptor, and Activation of AT2Receptor Associated with Nitric-Oxide Synthase Pathway

“…PD123,319 in a concentration-dependent manner attenuates the relaxations without the initial contractions, and losartan has no significant effect on the relaxations. The lack of effect of losartan in these results is in agreement with an earlier suggestion that desensitization to AT 1 -mediated contraction may potentiate relaxation of rat mesenteric artery smooth muscle (Widdop et al, 2002).…”

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

“…The protective effect of 17β‐estradiol is, at least in part, mediated by the AngII type 2 receptor 42. This receptor is counteracting the effect of the type 1 receptor with vasodilator effect not subjected to desensitization,43 although in hypertension, this balance is not necessarily in favor of a vasodilator tone 44, 45. The measurement of blood pressure in mice using plethysmography (tail cuff) can be considered as a limitation, because this technique is less accurate than telemetry.…”

Angiotensin Receptors and Aging

“…2 AT 2 receptor-induced vasodilation has been unequivocally demonstrated in both resistance and capacitance vessels. 3,4 In capacitance vessels, Ang II binding to the AT 2 receptor activates the BK B 2 receptor, stimulating the phosphorylation of endothelial NO synthase at its serine 633 and serine 1177 residues by a protein kinase A-dependent mechanism, inducing NO generation. 4 In mesenteric, uterine, and coronary small resistance arteries, Ang II-induced vasodilation is mediated by the BK/NO/cGMP pathway and is not subject to desensitization, as is AT 1 receptor-mediated vasoconstriction.…”