© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Potential role of eNOS in the therapeutic control of myocardial oxygen consumption by ACE inhibitors and amlodipine
aDepartment of Physiology, New York Medical College, Valhalla, NY and Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, MI, USA
bDepartment of Physiology, Basic Science Building, Room 636, New York Medical College, Valhalla, NY 10595, USA
* Corresponding author. Tel.: +1-914-594-3633; fax: +1-914-594-4018 thomas_hintze{at}nymc.edu
Objectives: Our aim was to investigate the potential therapeutic role of endothelial nitric oxide synthase (eNOS) in the modulation of cardiac O2 consumption induced by the angiotensin converting enzyme (ACE) inhibitor ramiprilat and amlodipine. Methods: Three different groups of mice were used; wild type, wild type in the presence of N-nitro-L-arginine methyl ester (L-NAME, 10–4 mol/l) or genetically altered mice lacking the eNOS gene (eNOS –/–). Myocardial O2 consumption was measured using a Clark-type O2 electrode in an air-tight stirred bath. Concentration–response curves to ramiprilat (RAM), amlodipine (AMLO), diltiazem (DIL), carbachol (CCL), substance P (SP) and S-nitroso-N-acetyl-penicillamine (SNAP) were performed. The rate of decrease in O2 concentration was expressed as a percentage of the baseline. Results: Baseline O2 consumption was not different between the three groups of mice. In tissues from wild type mice, RAM (10–5 mol/l), AMLO (10–5 mol/l), DIL (10–4 mol/l), CCL (10–4 mol/l), SP (10–7 mol/l) and SNAP (10–4 mol/l) reduced myocardial O2 consumption by –32±4, –27±10, –20±6, –25±2, –22±4 and –42±4%, respectively. The responses to RAM, AMLO, CCL and SP were absent in tissues taken from eNOS –/– mice (–7.1±4.3, –5.0±6.0, –5.2±5.1 and –0.4±0.2%, respectively). In addition, L-NAME significantly (P<0.05) inhibited the reduction in O2 consumption induced by RAM (–9.8±4.4%), AMLO (–1.0±6.0%), CCL (–8.8±3.7%) and SP (–6.6±4.9%) in cardiac tissues from wild type mice. In contrast, NO-independent responses to the calcium channel antagonist, DIL, and responses to the NO donor, SNAP, were not affected in cardiac tissues taken from eNOS –/– (DIL: –20±4%; SNAP: –46±6%) or L-NAME-treated (DIL: –17±2%; SNAP: –33±5%) mice. Conclusions: These results suggest that endogenous endothelial NO synthase derived NO serves an important role in the regulation of myocardial O2 consumption. This action may contribute to the therapeutic action of ACE inhibitors and amlodipine.
KEYWORDS ACE inhibitors; Nitric oxide; Oxygen consumption