(Circulation. 1996;94:44-51.)
© 1996 American Heart Association, Inc.
Articles |
Regulation of Nitric Oxide Production in Human Coronary Microvessels and the Contribution of Local Kinin Formation
Presented in abstract form at FASEB 1994, Anaheim, Calif, and at the 67th Scientific Sessions of the American Heart Association, Dallas, Tex, November 14-17, 1994, and published in abstract form (Circulation. 1994;90:I-295).
From Columbia University, College of Physicians and Surgeons, New York, NY (M.R.K., R.E.M., L.J.A.); New York Medical College, Valhalla (N.S., X.Z., G.K., A.N., T.H.H.); and University of Southern California, Los Angeles (C.C.M.).
Correspondence to Thomas H. Hintze, PhD, Professor, Department of Physiology, New York Medical College, Valhalla, NY 10595.
Background The goal of this study was to define the regulation of nitric oxide release by coronary microvessels from the failing and nonfailing human heart and to determine the role of local kinin production in the elaboration of nitric oxide by human coronary microvascular endothelium.
Methods and Results Ten hearts from humans with
end-stage heart failure and two hearts from patients without heart
failure were harvested at the time of orthotopic cardiac
transplantation. Microvessels were 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
dose-dependent increases in nitrite, a response that was blocked by
NG-nitro-L-arginine methyl
ester and receptor-specific antagonists (atropine and
HOE 140, respectively). In addition, the production of nitrite
by microvessels from the failing heart appeared to be less than that
produced by microvessels from the nonfailing heart. Incubation with
norepinephrine or the 
2-adrenergic agonist
BHT 920 also caused dose-dependent increases in nitrite
production, which were blocked by the B2-receptor
antagonist HOE 140. This implicated local kinin synthesis
as an intermediate step in the production of nitric oxide in
response to 2-adrenoceptor stimulation. The
production of nitric oxide was also prevented by the addition
of serine protease inhibitors, which blocked the action of
local kallikrein, again suggesting a role for local kinin synthesis.
Conclusions Our results indicate that nitric oxide is produced by human coronary microvessels, that nitric oxide production may be reduced but certainly not increased in microvessels from the failing human heart, and that there is active local kinin generation in these blood vessels.
Key Words: endothelium-derived factors • bradykinin • enzymes • norepinephrine • receptors
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