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

Abstract

Abstract-Because angiotensin (Ang) metabolites mediate functions independent of Ang II, we investigated their effects on coronary flow in spontaneously hypertensive rats (SHRs). Results were compared with those in the iliac artery and abdominal aorta and the coronary circulation of the Wistar rat. Ang II, III, and IV decreased coronary flow in SHRs and Wistar rats, with Ang III and IV being Ϸ10 and Ϸ1000 times less potent than Ang II. Ang-(1-7) decreased coronary flow at concentrations Ͼ1 mol/L in SHRs. The Ang II type 1 receptor antagonist irbesartan blocked the effects of Ang II, III, and IV, whereas the Ang II type 2 receptor antagonist PD123319 blocked the effects of Ang-(1-7 Key Words: angiotensin III Ⅲ angiotensin (1-7) Ⅲ AT 2 receptor Ⅲ spontaneously hypertensive rat Ⅲ Wistar rat A ngiotensin (Ang) I and II are metabolized by a whole range of peptidases, 1 resulting in the generation of Ang III, Ang IV, and Ang-(1-7). Ang II exerts its effects via Ang II type 1 (AT 1 ) and type 2 (AT 2 ) receptors, whereas Ang III, Ang IV, and Ang-(1-7) mediate functions of their own by stimulating AT 1 , AT 2 , and/or newly discovered receptors. [2][3][4][5][6][7] For instance, Ang III appears to be the preferred agonist of the AT 2 receptor both in the heart and kidney, inducing, respectively, coronary vasodilation 8 and natriuresis. 5 In addition, Ang III regulates blood pressure via central AT 1 receptor activation. 9 Ang IV mediates relaxant effects via Ang II type 4 receptors, 10 whereas Ang-(1-7) activates vasodilatory Mas receptors. 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. 12-14 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. 17 Interestingly, blood pressure-lowering in SHRs restored the vasodilatory function of the AT 2 receptor. 18 Chronic treatment of apolipoprotein E knockout mice with Ang IV reversed vascular dysfunction, possibly by enhancing NO bioavailability in an AT 2 and/or Ang II type 4 receptor-dependent manner. 7 Finally, Ang-(1-7) exerts vasodepressor 19,20 and antiremodeling 21 effects under pathological conditions. Although this has been attributed to its capacity to activate Mas receptors, 22 it may also involve AT 2 receptor activation, 20 ACE inhibition, 23 and/or AT 1 receptor blockade. 8,24 Given the conflicting data regarding the endogenous agonist and effect(s) of the AT 2 receptor under pathophysiological conditions, here we compared the effects of Ang II, Ang III, Ang IV, and Ang-(1-7) in the coronary vascular bed, iliac artery, and aorta of the SHR under carefully standardized conditions, both with and without blockade of AT 1 or AT...

Compound 21 Induces Vasorelaxation via an Endothelium- and Angiotensin II Type 2 Receptor-Independent Mechanism

“…1,2,11,12,22 Simultaneously, we were able to confirm that C21 binds with high affinity to AT 2 receptors.…”

“…In addition, in a previous study we were unable to detect AT 2 receptor-mediated vasodilation in the SHR coronary vascular bed. 11 Thus, a non-AT receptordependent mechanism must underlie the coronary relaxant effect of C21.…”

“…As such, it seems to counteract Ang II type 1 (AT 1 ) receptor-mediated effects. 10 However, opposite findings have been reported as well, and according to some studies, Ang II type 2 (AT 2 ) receptor effects mimic those of the AT 1 receptor (eg, inducing vasoconstriction 11,12 and hypertrophy 13 ). Our knowledge on AT 2 receptor function is largely based on the use of the AT 2 receptor antagonist PD123319, AT 2 receptor-deficient (AT 2 R Ϫ/y ) animals, and the peptidic AT 2 receptor agonist CGP42112A.…”

“…We made use of preparations that, in previous studies, displayed clear AT 2 receptor-mediated vasodilation. 1,2,11,12,22 …”

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

“…21 However, whether Ang II receptors are involved in Ang-(1-7)-stimulated effects is still under debate because some of the stimulated pathways are also affected by co-treatment with AT 1 blockers 22,23 or AT 2 blockers. 24,25 To further characterize the impact of Ang II receptor subtypes on Ang-(1-7) mediated vascular relaxation, we investigated the cardiovascular response to acute Ang-(1-7) infusion in recently generated mice lacking one, two or all three Ang II receptor subtypes. 26 …”