CORONARY KININ GENERATION MEDIATES NITRIC-OXIDE RELEASE AFTER ANGIOTENSIN RECEPTOR STIMULATION

Our goal was to determine whether angiotensin II (Ang II) and its meta bolic fragments release nitric oxide and the mechanisms by which this occurs in blood vessels from the canine heart. We incubated 20 mg of m icrovessels or large coronary arteries in phosphate-buffered saline fo r 20 minutes and measured nitrite release. Nitrite release increased f rom 27+/-2 up to 103+/-5, 145+/-17, 84+/-4, 107+/-16, and 54+/-4 pmol/ mg (P<.05) in response to 10(-5) mol/L of Ang I, II, III, IV, and Ang- (1-7), respectively. The effects of all angiotensins were blocked by N -omega-nitro-L-arginine methyl ester (100 mu mol/L), indicating that n itrite was a product of nitric oxide metabolism, and by Hoe 140 (10 mu mol/L), a specific bradykinin B-2? receptor antagonist, indicating a potential role for local kinin formation. The protease inhibitors apro tinin (10 mu mol/L) and soybean trypsin inhibitor, which block local k inin formation, inhibited nitrite release by all of the angiotensins. Angiotensin nonselective (saralasin), type 1-specific (losartan), and type 2-specific (PD 123319) receptor antagonists abolished the nitrite released in response to all the fragments. Angiotensin type 1 and typ e 2 and receptors mediate nitrite release after Ang I, II, III, and An g-(1-7), whereas only type 2 receptors mediate nitrite release after A ng IV. Similar results were obtained in large coronary arteries. In su mmary, formation of nitrite from coronary microvessels and large arter ies in the normal dog heart in response to angiotensin peptides is due to the activation of local kinin production in the coronary vessel wa ll.