Bradykinin metabolism pathway in the rat pulmonary circulation.
OBJECTIVE
The contribution made by different enzymes to the degradation of bradykinin in physiological conditions was estimated by examining bradykinin metabolism in rat serum, in the in situ perfused lung and in vivo.


METHODS
Dose-response curves for the hypotensive effect of intra-arterially and intravenously injected bradykinin were obtained in unanaesthetized rats. High-performance liquid chromatography was used to analyse the products of bradykinin breakdown after incubation with rat serum and perfusion through in situ lung preparations.


RESULTS
In rat serum, kininase I degraded 34% and kininase II 11% of bradykinin, no evidence for other activities being detected. In the awake rat, D,L-2-mercaptomethyl-3-guanidino-ethylthiopropionic acid, an inhibitor of kininase I, did not reduce the percentage of bradykinin inactivation in the pulmonary circulation. In the in situ perfused lung 65% of bradykinin was metabolized and the main products were BK1-7, BK1-5 and BK4-9. Enalaprilat (an inhibitor of kininase II) blocked the formation of BK1-7 and BK1-5 and increased the recovery of BK4-9. beta-Mercapto-ethanol, which inhibits aminopeptidase P, and diprotin A, a specific inhibitor of dipeptidylaminopeptidase IV, both reduced the formation of BK4-9. Diprotin A also allowed the recovery of BK2-9. Bradykinin degradation and BK4-9 recovery were not affected by endopeptidase inhibitors.


CONCLUSIONS
Our results show that the main degradation pathway of bradykinin in the lung is through the action of kininase II at the carboxyl terminus, and sequential cleavage by aminopeptidase P followed by dipeptidylaminopeptidase IV at the amino terminus. The amino-terminal degradation of bradykinin represents about 38% of the total lung kininase activity.
Pesquero
J B
JB
Department of Biophysics, Escola Paulista de Medicina, São Paulo, Brazil.
Jubilut
G N
GN
Lindsey
C J
CJ
Paiva
A C
AC
D000626:Aminopeptidases / Q000378:metabolism; D000803:Angiotensin I / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001920:Bradykinin / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D018819:Dipeptidyl Peptidase 4; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008168:Lung / Q000201:enzymology / Q000378:metabolism*; D001121:Lysine Carboxypeptidase / Q000378:metabolism; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011652:Pulmonary Circulation / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D000803:Angiotensin I; D000626:Aminopeptidases; C022750:X-Pro aminopeptidase; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D018819:Dipeptidyl Peptidase 4; D007703:Peptidyl-Dipeptidase A; D001121:Lysine Carboxypeptidase; D001920:Bradykinin