REGULATION OF NITRIC-OXIDE PRODUCTION IN HUMAN CORONARY MICROVESSELS AND THE CONTRIBUTION OF LOCAL KININ FORMATION

Background The goal of this study was to define the regulation of nitr ic oxide release by coronary microvessels from the failing and nonfail ing human heart and to determine the role of local kinin production in the elaboration of nitric oxide by human coronary microvascular endot helium. Methods and Results Ten hearts from humans with endstage heart failure and two hearts from patients without heart failure were harve sted at the time of orthotopic cardiac transplantation. Microvessels w ere sieved and the production of nitrite was determined by the Griess reaction. Microvessels were incubated in the presence of agonists for nitric oxide production (acetylcholine and bradykinin), which caused d ose-dependent increases in nitrite, a response that was blocked by N-G -nitro-L-arginine methyl ester and receptor-specific antagonists (atro pine and HOE 140, respectively). In addition, the production of nitrit e by microvessels from the failing heart appeared to be less than that produced by microvessels from the nonfailing heart. Incubation with n orepinephrine or the alpha(2)-adrenergic agonist BHT 920 also caused d ose-dependent increases in nitrite production, which were blocked by t he B-2-receptor antagonist HOE 140. This implicated local kinin synthe sis as an intermediate step in the production of nitric oxide in respo nse to alpha(2)-adrenoceptor stimulation. The production of nitric oxi de was also prevented by the addition of serine protease inhibitors, w hich blocked the action of local kallikrein, again suggesting a role f or local kinin synthesis. Conclusions Our results indicate that nitric oxide is produced by human coronary microvessels, that nitric oxide p roduction may be reduced but certainly not increased in microvessels f rom the failing human heart, and that there is active local kinin gene ration in these blood vessels.