ROLE OF ANGIOTENSIN-II GENERATED BY ANGIOTENSIN-CONVERTING ENZYME-INDEPENDENT PATHWAYS IN CANINE KIDNEY

Recent studies have provided evidence of angiotensin converting enzyme (ACE)-independent angiotensin (Ang) II formation in tissue renin-angi otensin systems. We studied the effects of Ang II generated by ACE-ind ependent pathways on renal hemodynamics. We used a synthetic peptide, [Pro(11), D-Ala(12)]-Ang I (S). which yields Ang II by chymase, but no t by ACE. Infusion of Ang I into a renal artery caused a decrease in r enal blood flow, and reciprocally an increase in mean arterial pressur e. Infusion of S (1 nmol/kg) caused a decrease in renal blood flow (-2 0%). but a larger dose was needed to increase mean arterial pressure. Studies with an intravital needle-probe CCD camera revealed that the A ng I infusion induced dose-dependent vasoconstriction of afferent and efferent arterioles (49% and 54%, respectively at 1 nmol/kg). In contr ast, infusion of S elicited only 30% constriction of these vessels at a dose of 1 nmol/kg and induced no further constriction at higher dose s, indicating that different segments of renal vessels responded in di fferent fashions to Ang II formed via ACE-independent pathways. These vasoconstrictions were abolished by an angiotensin II receptor (AT-1) antagonist. Enzymatic assays using reverse-phase HPLC revealed that th e ACE-dependent pathway was predominant in the renal cortex (approxima tely 80%). We also determined Ang II concentrations in renal cortex sp ecimens obtained by needle biopsy. Intrarenal S infusion (10 nmol/kg) increased plasma and renal Ang II concentrations to 160% and 710% of t he respective baseline levels. This study provides in vivo evidence of ACE-independent Ang II formation in renal tissue and suggests that th is locally-formed Ang II influences the renal circulation in a paracri ne fashion.