Angiotensin II- and IV-induced changes in cerebral blood flow roles of AT(1) AT(2), and AT(4) receptor subtypes

Our laboratory has previously reported the discovery of a unique angiotensin binding site (termed AT(4)) specific for angiotensin IV (AngIV) in cultured vascular endothelial and smooth muscle cells. The present investigation employed laser-Doppler flowmetry to examine the effect of angiotensin II (AngII) and AngIV stimulation of these receptors on cerebral microcirculation in anesthetized Sprague-Dawley rats. Internal carotid artery infusion of AngII al a low dose (0.1 pmol min(-1)) revealed a 23% reduction in cerebral blood flow (CBF), while the infusion of AngIV increased CBF ir. a dose-dependent fashion with the highest dose (100 pmol min(-1)) resulting in an elevation of 30%. In a second experiment separate groups of rats were pre-treated with the AT(1) receptor subtype antagonist DuP 753 (Losartan), the AT(2) receptor subtype antagonist PD123177, or a newly synthesized AT(4) receptor subtype antagonist Divalinal-AngIV (Divalinal), followed by AngII or AngIV for the purpose of determining which angiotensin receptor subtype is responsible for mediating these AngII- and AngIV-induced responses. Pre-treatment with Losartan completely blocked subsequent AngII-induced reductions in CBF, while both PD123177 and Divalinal failed to inhibit this response. In contrast, significant increases in CBF were measured due to AngIV stimulation following pre-treatment with Losartan and PD123177, while Divalinal abolished this AngIV-induced response. These results suggest that AngII and IV play opposite roles in cerebral microcirculation, i.e., the AT(1) receptor subtype mediates AngII-induced reductions in CBF, while the AT(4) receptor subtype regulates increases in CBF. (C) 1997 Elsevier Science B.V.