EFFECTS OF A METALLOENDOPEPTIDASE-24.15 INHIBITOR ON RENAL HEMODYNAMICS AND FUNCTION IN RATS

rboxyl-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate (cFP-AAF-pAB), an a ctive-site-directed inhibitor of metalloendopeptidase-24.15, has been shown to lower blood pressure, increase cardiac output and renal blood how, and potentiate the intravenous bradykinin-induced vasodepressor response. Because in vivo cFP-AAF-pAB can be converted to N-[1-(R,S)-c arboxyl-3-phenylpropyl]-Ala-Ala (a compound with angiotensin convertin g enzyme inhibitory activity) by metalloendopeptidase-24.11, it is pos sible that some of its effects are due to angiotensin converting enzym e inhibition. In the present study, we questioned (1) whether cFP-AAF- pAB inhibits angiotensin converting enzyme in vivo and (2) whether cFP -AAF-pAB has renal effects that are independent of its conversion to a n angiotensin converting enzyme inhibitor. cFP-AAF-pAB alone (3 mu mol in 300 mu L per rat) almost abolished the blood pressure response to angiotensin I, suggesting that in vivo it inhibits angiotensin convert ing enzyme. In rats pretreated with a high dose of enalaprilat (1 mg/k g), cFP-AAF-pAB had no further effect on blood pressure, renal blood f low, or potentiation of the vasodepressor response to bradykinin but s till increased glomerular filtration rate by 44+/-9% (P<.01); urine vo lume increased by 118+/-10% (P<.001), urinary sodium excretion by 230/-31% (P<.001), urinary potassium excretion by 68+/-14% (P<.01), and u rinary cyclic GMP by 55+/-18% (P<.01). All of these changes were signi ficant compared with enalaprilat/vehicle-treated rats. Fractional excr etion of sodium and potassium did not differ from controls. These resu lts suggest that effects of cFP-AAF-pAB on blood pressure, renal blood flow, and potentiation of the vasodepressor response to bradykinin co uld be mediated by angiotensin converting enzyme inhibition. However, some of the renal effects may be due to inhibition of metalloendopepti dase-24.15 or peptidases other than angiotensin converting enzyme.