ROLE OF ENDOTHELIAL KININS IN CONTROL OF CORONARY NITRIC-OXIDE PRODUCTION

The purpose of the present study was to determine whether intervention s that promote kinin production or decrease kinin inactivation affect nitric oxide production in isolated canine coronary microvessels. Acco rdingly, bradykinin (10(-8) to 10(-5) mol/L), ramiprilat (10(-10) to 1 0(-8) mol/L), A23187 (10(-8) to 10(-6) mol/L), kallikrein (1 to 20 U/m L), and kininogen (0.5 to 10 mu g/mL) were used to stimulate endotheli um-dependent nitric oxide production. Receptor antagonists, serine pro tease inhibitors, and a kinin antibody were used to inactivate local k allikrein-kinin activity. Nitrite, the metabolite of nitric oxide in a queous solution, was measured using the Griess reaction. All the agoni sts significantly increased nitrite release. For instance, the highest dose of bradykinin, ramiprilat, A23187, kallikrein, and kininogen mar kedly increased nitrite production, from 60+/-10 to 156+/-12, 153+/-11 , 161+/-15, 176+/-15, and 168+/-16 pmol/mg (all P<.05), respectively. The increased nitrite production caused by these agents was not only b locked by N-omega-nitro-L-arginine methyl ester (L-NAME) and HOE 140 ( which blocks B-2 kinin receptor) but by the kinin antibody also. For i nstance, nitrite production elicited by bradykinin, ramiprilat, A23187 , and kininogen was reduced to 95+/-8, 87+/-8, 94+/-11, and 85+/-11 pm ol/mg (all P<.05), respectively, by the kinin antibody. Carbachol-indu ced nitrite production (from 66+/-8 to 144+/-13) was blocked by L-NAME but not by HOE 140 or the kinin antibody. These results suggest that either increasing kininogen to promote endogenous kinin formation or i nhibiting angiotensin-converting enzyme to decrease kinin breakdown, i ncreases nitric oxide production in isolated coronary microvessels. Th ese data indicate that a microvessel kallikrein-kinin system has an im portant role in the control of nitric oxide production in coronary mic rovessels.