title: Role of nitric oxide in the control of cardiac oxygen consumption in B(2)-kinin receptor knockout mice.
abstract: The aim of this study was to determine whether bradykinin, the angiotensin-converting enzyme inhibitor ramiprilat, and the calcium-channel antagonist amlodipine reduce myocardial oxygen consumption (MV(O2)) via a B(2)-kinin receptor/nitric oxide-dependent mechanism. Left ventricular free wall and septum were isolated from normal and B(2)-kinin receptor knockout (B(2) -/-) mice. Myocardial tissue oxygen consumption was measured in an airtight chamber with a Clark-type oxygen electrode. Baseline MV(O2) was not significantly different between normal (239+/-13 nmol of O(2). min(-1). g(-1)) and B(2) -/- (263+/-24 nmol of O(2). min(-1). g(-1)) mice. S-nitroso-N-acetyl-penicillamine (10(-7) to 10(-4) mol/L) reduced oxygen consumption in a concentration-dependent manner in both normal (maximum, 36+/-3%) and B(2) -/- mice (28+/-3%). This was also true for the endothelium-dependent vasodilator substance P (10(-10) to 10(-7) mol/L; 22+/-7% in normal mice and 20+/-4% in B(2) -/- mice). Bradykinin (10(-7) to 10(-4) mol/L), ramiprilat (10(-7) to 10(-4) mol/L), and amlodipine (10(-7) to 10(-5) mol/L) all caused concentration-dependent decreases in MV(O2)in normal mice. At the highest concentration, tissue O(2) consumption was decreased by 18+/-3%, 20+/-5%, and 28+/-3%, respectively. The reduction in MV(O2) to all 3 drugs was attenuated in the presence of N(G)-nitro-L-arginine-methyl ester. However, in the B(2) -/- mice, bradykinin, ramiprilat, and amlodipine had virtually no effect on MV(O2). Therefore, nitric oxide, through a bradykinin-receptor-dependent mechanism, regulates cardiac oxygen consumption. This physiological mechanism is absent in B(2) -/- mice and may be evidence of an important therapeutic mechanism of action of angiotensin-converting enzyme inhibitors and amlodipine.
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Loke
authors.forename: C M
authors.initials: CM
authors.lastname: Curran
authors.forename: E J
authors.initials: EJ
authors.lastname: Messina
authors.forename: S K
authors.initials: SK
authors.lastname: Laycock
authors.forename: E G
authors.initials: EG
authors.lastname: Shesely
authors.forename: O A
authors.initials: OA
authors.lastname: Carretero
authors.forename: T H
authors.initials: TH
authors.lastname: Hintze
mesh_terms: D017311:Amlodipine / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006321:Heart / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D010101:Oxygen Consumption / Q000187:drug effects* / Q000502:physiology; D017257:Ramipril / Q000031:analogs & derivatives* / Q000494:pharmacology; D018002:Receptors, Bradykinin / Q000187:drug effects; D013373:Substance P / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D018002:Receptors, Bradykinin; D017311:Amlodipine; D009569:Nitric Oxide; D013373:Substance P; C052549:ramiprilat; D017257:Ramipril; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester