AUTORADIOGRAPHIC IDENTIFICATION OF KIDNEY ANGIOTENSIN-IV BINDING-SITES AND ANGIOTENSIN-IV-INDUCED RENAL CORTICAL BLOOD-FLOW CHANGES IN RATS

The present investigation initially determined that specific binding s ites for the hexapeptide angiotensin TV (AngIV) are present in the rat kidney cortex and outer medulla but not in the inner medulla, using i n vitro autoradiographic techniques. This binding site has been termed AT(4), is distinct from the previously characterized AT, and AT, site s, and does not bind the specific AT(1) receptor antagonist DuP753 or the AT(2) receptor antagonist PD123177. Renal artery infusions of AngI V produced a dose-dependent increase in cortical blood flow without al tering systemic blood pressure. In contrast, the infusion of angiotens in II (AngII) induced a dramatic decrease in cortical blood flow, acco mpanied by a significant elevation in systemic blood pressure. The inf usion of [D-Val(1)]AngIV, an analog that does not bind at the AT(4) re ceptor site, and the C-terminal truncated analogs AngIV (1-4) and AngI V (1-5) that possess lower affinity for this site, produced no change in cortical blood flow. The infusion of [Nle(1)]AngIV and [Lys(1)]AngI V, analogs that bind with high affinity at the AT(4) receptor site, pr oduced increases in cortical blood flow with no influence on blood pre ssure. Pretreatment with a specific AT(4) receptor antagonist, Divalin al-AngIV, completely blocked AngIV-induced elevations in blood flow, b ut failed to influence AngII-induced decreases in blood flow, suggesti ng that these ligands are acting at different receptor sites. Pretreat ment with the nitric oxide synthase inhibitor, N-G-Monomethyl-L-Argini ne, also blocked subsequent AngIV-induced increases in cortical blood flow. These data support the notion that AngIV exerts a unique influen ce upon renal hemodynamics via the AT(4) receptor subtype, and suggest that AngIV-induced elevations in blood flow may be mediated by nitric oxide. (C) 1998 Elsevier Science Inc.