title: Angiotensin-converting enzyme inhibitors promote nitric oxide production in coronary microvessels from failing explanted human hearts.
abstract: We have previously shown that nitric oxide (NO) release by the coronary circulation in the failing and nonfailing human heart is, in part, regulated by local kinin production in coronary microvessels. Angiotensin-converting enzyme (ACE) also known as kininase II, inactivates kinins. ACE inhibitors prevent kinin breakdown by ACE, thereby increasing the concentration of bradykinin (BK) and related kinins. The goal of this study was to determine if kinins contribute to the therapeutic action of ACE inhibitors. Six hearts from end-stage heart failure patients were harvested at the time of orthotopic cardiac transplantation. Microvessels were prepared as previously described, and nitrite production, a metabolic product of NO in vitro, was determined by the Griess reaction. Microvessels were incubated in the presence of kininogen and bradykinin, and with the ACE inhibitors ramiprilat, enalaprilat, or captopril. All caused dose-dependent increases in nitrite. For instance, ramiprilat increased nitrite from 76 +/- 5.6 to 155 +/- 15 pmol/min per mg wet weight. Nitrite production in response to ACE inhibition was blocked by N-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, and icatibant (HOE 140), a B2-kinin receptor-specific antagonist. Furthermore, NO production was prevented by 3 different serine protease inhibitors, which block kallikrein, the enzyme responsible for conversion of kininogen to kinins. Our results indicate that ACE/kininase inhibitors increase NO production by the coronary microvasculature in the failing human heart, through increased available active kinins. The therapeutic action of ACE inhibition in the failing human heart may result in part from increased NO production by coronary microvessels.
authors.affiliation: Department of Pediatrics, Columbia University, College of Physicians and Surgeons, New York, New York, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Kichuk
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Oz
authors.forename: R
authors.initials: R
authors.lastname: Michler
authors.forename: G
authors.initials: G
authors.lastname: Kaley
authors.forename: A
authors.initials: A
authors.lastname: Nasjletti
authors.forename: T H
authors.initials: TH
authors.lastname: Hintze
mesh_terms: D000293:Adolescent; D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D003331:Coronary Vessels / Q000378:metabolism*; D005260:Female; D006333:Heart Failure / Q000378:metabolism*; D016027:Heart Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D009569:Nitric Oxide / Q000096:biosynthesis*; D009573:Nitrites / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D009573:Nitrites; D009569:Nitric Oxide