Inhibition of endopeptidase-24.15 decreases blood pressure in normotensive rats.
The potent vasodilatory peptide bradykinin is cleaved at the Phe5-Ser6 bond in vitro by the metalloenzyme endopeptidase-24.15 (E.C.3.4.24.15). We now report that intravenous infusion of N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate, a specific active site-directed inhibitor of endopeptidase-24.15, produces an immediate drop in mean arterial pressure of as much as 50 mm Hg in pentobarbital-anesthetized, normotensive rats. Arterial pressure recovers within 5 minutes. The B2 bradykinin antagonist [Arg0,Hyp3,Thi5,8,D-Phe7]-bradykinin attenuates the decrease in mean arterial pressure resulting from treatment with the inhibitor. The endopeptidase-24.15 inhibitor potentiates the hypotensive effect of intravenous bradykinin infusion, increasing the maximal effect of the peptide by 47% and increasing the potency by almost 10-fold, while the response to intra-arterial bradykinin is less affected by the inhibitor. These results support a role for endopeptidase-24.15 in the inactivation of endogenous and exogenous bradykinin and suggest a direct involvement of the enzyme in the control of blood pressure.
Genden
E M
EM
Department of Pharmacology, Mount Sinai School of Medicine, CUNY, NY 10029.
Molineaux
C J
CJ
D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D001920:Bradykinin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values
D009842:Oligopeptides; C053748:B 4162; C064939:N-(1-carboxy-3-phenylpropyl)-alanyl-alanyl-phenylalanine-4-aminobenzoate; D008666:Metalloendopeptidases; C022510:thimet oligopeptidase; D001920:Bradykinin