Angiotensin II- and IV-induced changes in cerebral blood flow. Roles of AT1, AT2, and AT4 receptor subtypes.
Our laboratory has previously reported the discovery of a unique angiotensin binding site (termed AT4) 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 at a low dose (0.1 pmol min-1) revealed a 23% reduction in cerebral blood flow (CBF), while the infusion of AngIV increased CBF in 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 AT1 receptor subtype antagonist DuP 753 (Losartan), the AT2 receptor subtype antagonist PD123177, or a newly synthesized AT4 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 PD 123177, while Divalinal abolished this AngIV-induced response. These results suggest that AngII and IV play opposite roles in cerebral microcirculation, i.e., the AT1 receptor subtype mediates AngII-induced reductions in CBF, while the AT4 receptor subtype regulates increases in CBF.
Kramár
E A
EA
Department of Psychology, Washington State University, Pullman 99164-4820, USA.
Harding
J W
JW
Wright
J W
JW
D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D017078:Laser-Doppler Flowmetry; D019808:Losartan; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D011725:Pyridines; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology
C090830:AT4 receptor; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C104765:divalinal-angiotensin IV; D000804:Angiotensin II; C066253:PD 123177; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D019808:Losartan