Neutral endopeptidase and angiotensin converting enzyme inhibitors potentiate kinin-induced contraction of ferret trachea.
Neutral endopeptidase (NEP) (enkephalinase, EC 3.4.24.11) and angiotensin converting enzyme (ACE) are two peptidases that can cleave the C-terminal dipeptide bradykinin(8-9) from bradykinin. To determine whether these peptidases play roles in modulating kinin-induced contractions in the airways, we studied the effects of captopril, an ACE inhibitor, and of leucine-thiorphan and phosphoramidon, two NEP inhibitors, on the contractile responses to bradykinin and lysyl-bradykinin in isolated segments of ferret trachea. Bradykinin and lysyl-bradykinin-induced contractions in a concentration-dependent fashion (P less than .001), with a threshold of 10(-7) M and 5 x 10(-7) M, respectively. In contrast, the bradykinin(8-9) and the N-terminal heptapeptide bradykinin(1-7), the major fragments of hydrolysis of bradykinin by NEP and ACE, had a very weak or no effect on tracheal contraction in concentrations as great as 10(-5) M. Captopril, leucine-thiorphan and phosphoramidon (each inhibitor at 10(-5) M, 15 min) shifted the concentration-response curves to lower concentrations by approximately 1 to 1.5 log U (P less than .05). Both NEP inhibitors and the ACE inhibitor potentiated the response to bradykinin in a concentration-dependent fashion (P = .0001), and the combination of phosphoramidon and captopril resulted in an additive potentiation of bradykinin-induced contraction (P less than .02). [D-Pro2-D-Trp7,9]-substance P, a substance P antagonist, did not modify the potentiation of bradykinin-induced contraction by NEP inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)
Dusser
D J
DJ
Cardiovascular Research Institute, University of California, San Francisco.
Nadel
J A
JA
Sekizawa
K
K
Graf
P D
PD
Borson
D B
DB
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002216:Captopril / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005289:Ferrets; D006020:Glycopeptides / Q000494:pharmacology; D007705:Kinins / Q000494:pharmacology*; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D009119:Muscle Contraction / Q000187:drug effects*; D015260:Neprilysin; D015244:Thiorphan / Q000031:analogs & derivatives*; D008625:Tiopronin / Q000031:analogs & derivatives / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects*
D000806:Angiotensin-Converting Enzyme Inhibitors; D006020:Glycopeptides; D007705:Kinins; C054498:leucine thiorphan; D002216:Captopril; D015244:Thiorphan; D008625:Tiopronin; D008666:Metalloendopeptidases; D015260:Neprilysin; C008890:phosphoramidon