Effects of a metalloendopeptidase-24.15. Inhibitor on renal hemodynamics and function in rats.
N-[1-(R,S)-carboxyl-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate (cFP-AAF-pAB), an active-site-directed inhibitor of metalloendopeptidase-24.15, has been shown to lower blood pressure, increase cardiac output and renal blood flow, and potentiate the intravenous bradykinin-induced vasodepressor response. Because in vivo cFP-AAF-pAB can be converted to N-[1-(R,S)-carboxyl-3-phenylpropyl]-Ala-Ala (a compound with angiotensin converting enzyme inhibitory activity) by metalloendopeptidase-24.11, it is possible that some of its effects are due to angiotensin converting enzyme 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 an angiotensin converting enzyme inhibitor. cFP-AAF-pAB alone (3 mumol in 300 microL per rat) almost abolished the blood pressure response to angiotensin I, suggesting that in vivo it inhibits angiotensin converting enzyme. In rats pretreated with a high dose of enalaprilat (1 mg/kg), cFP-AAF-pAB had no further effect on blood pressure, renal blood flow, or potentiation of the vasodepressor response to bradykinin but still increased glomerular filtration rate by 44 +/- 9% (P < .01); urine volume increased by 118 +/- 10% (P < .001), urinary sodium excretion by 230 +/- 31% (P < .001), urinary potassium excretion by 68 +/- 14% (P < .01), and urinary cyclic GMP by 55 +/- 18% (P < .01). All of these changes were significant compared with enalaprilat/vehicle-treated rats. Fractional excretion of sodium and potassium did not differ from controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Yang
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Department of Medicine, Henry Ford Hospital, Detroit, MI 48202.
Saitoh
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Scicli
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Mascha
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Orlowski
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Carretero
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OA
D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012039:Regional Blood Flow / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects*; D014554:Urination / Q000187:drug effects
D009842:Oligopeptides; D000804:Angiotensin II; C064939:N-(1-carboxy-3-phenylpropyl)-alanyl-alanyl-phenylalanine-4-aminobenzoate; D000803:Angiotensin I; D008666:Metalloendopeptidases; C022510:thimet oligopeptidase; D001920:Bradykinin