Angiotensin Type 2 Receptor in Resistance Arteries of Type 2 Diabetic Hypertensive Patients

Abstract

Abstract-The role of angiotensin type 2 receptor (AT 2 R) on vascular responses to angiotensin II in humans remains unclear. In this study we explored whether AT 2 R is expressed and functionally active on peripheral resistance arteries of hypertensive diabetic patients treated for 1 year with either the angiotensin receptor blocker valsartan or the ␤-blocker atenolol. Twenty-six hypertensive type 2 diabetic patients treated with oral hypoglycemic and antihypertensive agents (not receiving angiotensin receptor blockers or ␤-blockers) were randomly assigned to double-blind treatment for 1 year with valsartan or atenolol once daily added to their previous therapy in a clinical trial that we reported recently and compared with 10 normal subjects. Resistance arteries dissected from gluteal subcutaneous tissues were assessed on a pressurized myograph. Vasomotor response curves to angiotensin II (1 nmol/L to 1 mol/L) were performed on norepinephrine precontracted vessels in the presence of valsartan (10 mol/L) with or without the AT 2 R inhibitor PD123319 (1 mol/L). AT 2 R expression was evaluated by confocal microscopy. After 1 year of treatment, systolic and diastolic blood pressure was controlled and comparable in the valsartan and atenolol groups. Angiotensin II evoked a significant vasodilatory response only on resistance arteries from patients treated with valsartan, effect blocked by PD123319. AT 2 R expression was 4-fold higher in small arteries of valsartan-treated patients. A ngiotensin II (Ang II) is the main biological effector of the renin-angiotensin system, which plays a major role in cardiovascular and renal homeostasis. Most of the physiological and pathophysiological effects of Ang II are mediated by the angiotensin type 1 receptor (AT 1 R), which is widely expressed by most cell types. Expression of the angiotensin type 2 receptor (AT 2 R) is more limited and occurs predominantly in fetal tissues where it may play a role during development. 1,2 Recent studies, mostly in cellular and adult animal models, mapped the distribution of AT 2 R in certain areas of the brain, 3 kidneys, 4 coronary arteries, cardiomyocytes, ventricular myocardium, 5 and the vasculature. 6,7 Increased AT 2 R expression has been observed under pathological conditions, such as vascular injury, 8 hypertension, 6,7 myocardial infarction, 9,10 congestive heart failure, 11 renal failure, 12 and brain ischemia. 13 Few studies have investigated the functional expression of AT 2 R in humans. AT 2 Rs are expressed in the human skin (throughout the epidermal and dermal structures) 14 and are markedly upregulated in incisional cutaneous wounds. 15 AT 2 Rs have been demonstrated in the human coronary microcirculation, where they may contribute to vasodilation. 16 Studies in cellular and animal models suggest that AT 2 R counteracts many AT 1 R actions by inducing vasodilation, antiproliferation, and apoptosis. 2 We showed recently in animal models of hypertension that AT 2 R is upregulated and mediates vasodilation only when AT 1 Rs are bl...

Stimulation of angiotensin AT2 receptors by the non‐peptide agonist, Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats

“…In that study, Compound 21, given for 7 days after myocardial infarction, improved systolic and diastolic function and reduced infarct size (Kaschina et al, 2008), thus illustrating the potential use of this non-peptide compound in a number of cardiovascular settings. Indeed, our current findings suggest additive effects of AT1 receptor blockade and AT2 receptor stimulation would be beneficial for BP reduction, and fit with clinical findings of increased vascular AT2 receptor expression after long-term sartan treatment (Savoia et al, 2007), highlighting the need for future determination of the chronic effects of Compound 21 in hypertensive settings.In conclusion, we have established that Compound 21 evoked vasorelaxation in mouse and SHR aortae or rat mesenteric arteries, and vasodepressor responses in conscious SHR, via AT2 receptor stimulation. The BP-lowering effect of Compound 21 was additive to candesartan when the latter compound was given at a dose that itself lowered BP.…”

“…Chronic treatment with AT1 receptor antagonists is associated with increased AT2 receptor expression in aortae from SHR (Cosentino et al, 2005;Savoia et al, 2005), and human subcutaneous gluteal arteries (Savoia et al, 2007), as well as in mesenteric arteries from SHR, which normally exhibited decreased AT2 receptor expression under basal conditions (You et al, 2005). Indeed, sartan-induced up-regulation of AT2 receptors unmasked ex vivo AT2 receptormediated vasorelaxation in otherwise unresponsive vessels (Yayama et al, 2004;Cosentino et al, 2005;Savoia et al, 2005;Savoia et al, 2007). Therefore, it is conceivable that enhanced in vivo sensitivity of untreated SHR, compared with WKY rats, to Compound 21 was due to higher AT2 receptor expression, although elevated MAP per se could still contribute to AT2 receptor-mediated depressor activity in vivo.…”

Blood pressure and renal hemodynamic effects of angiotensin fragments

“…AT 2 receptors were reported to be upregulated and to contribute to Ang II-induced vasodilation in resistance arteries of hypertensive type 2 diabetes patients treated with AT 1 receptor blockers. 80 AT 2 (À/À) mice have elevated basal blood pressure and exaggerated pressor responses to exogenous Ang II as compared with wild-type litter mates, which is line with the hypothesis that AT 2 receptors counteract AT 1 receptor-mediated responses. 46,75,76,81,82 Moreover, AT 2 (À/À) mice have increased prostaglandin E2 and prostacyclin levels, suggesting that these vasodilator prostanoids might be important in preventing hypertension in this model.…”

Effects of Angiotensin Metabolites in the Coronary Vascular Bed of the Spontaneously Hypertensive Rat

“…11 AT 2 receptor upregulation and/or AT 1 receptor downregulation (resulting in a relative AT 2 receptor upregulation) is generally believed to induce protective effects under pathophysiological conditions. [12][13][14] However, such beneficial effects have not been found consistently by all of the investigators. For instance, AT 2 receptors mediate constriction in the renal medulla of 2-kidney, 1-clip rats 15 and in mesenteric arteries of spontaneously hypertensive rats (SHRs), 16 and the AT 2 receptor-induced natriuresis by Ang III no longer occurs in SHRs.…”