Lung peptidases, including carboxypeptidase, modulate airway reactivity to intravenous bradykinin.
We investigated the effect of inhibition of carboxypeptidase, neutral endopeptidase, or angiotensin converting enzyme on airway reactivity to intravenous bradykinin in guinea pigs. Bradykinin reactivity in intact, unanesthetized, spontaneously breathing animals was determined by measuring specific airway resistance in response to increasing doses of intravenous bradykinin or acetylcholine. We found that phosphoramidon and/or captopril (specific antagonists of neutral endopeptidase and angiotensin converting enzyme, respectively) increased airway reactivity to bradykinin, but the combination had no effect on muscarinic reactivity. Although 2-mercaptomethyl-3-guanidinoethylthiopropanoic acid (MGTA, a carboxypeptidase inhibitor) alone did not alter bradykinin reactivity, MGTA in the presence of both phosphoramidon and captopril significantly potentiated bradykinin-induced airway reactivity. In comparison, this did not affect reactivity to acetylcholine. Having found that carboxypeptidase inhibition could augment kinin-induced airway reactivity, we subsequently assayed for and identified carboxypeptidase M activity in guinea pig lung. We found considerable carboxypeptidase M activity in guinea pig lung subcellular fractions, the 100,000 x g membrane pellet having the highest specific activity. Our data indicate that airway reactivity to intravenous bradykinin is modulated by the activity of endogenous neutral endopeptidase, angiotensin converting enzyme, and carboxypeptidase, all of which are present in lung cell membranes. This study also suggests that the influence of carboxypeptidase per se may be substantially enhanced if endogenous pulmonary neutral endopeptidase and angiotensin converting enzyme activities are reduced.
Chodimella
V
V
Department of Medicine, Rush University, Chicago, Illinois.
Skidgel
R A
RA
Krowiak
E J
EJ
Murlas
C G
CG
D000109:Acetylcholine / Q000494:pharmacology; D000403:Airway Resistance / Q000187:drug effects* / Q000502:physiology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000008:administration & dosage / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D058851:GPI-Linked Proteins; D006168:Guinea Pigs; D007275:Injections, Intravenous; D008168:Lung / Q000201:enzymology*; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D015260:Neprilysin / Q000037:antagonists & inhibitors
D000806:Angiotensin-Converting Enzyme Inhibitors; D058851:GPI-Linked Proteins; C058479:carboxypeptidase M; D008666:Metalloendopeptidases; D015260:Neprilysin; D000109:Acetylcholine; D001920:Bradykinin