Impaired Nitric Oxide Modulation of Myocardial Oxygen Consumption in Genetically Cardiomyopathic Hamsters

We investigated the role of kinin and nitric oxide (NO) in the modulation of cardiac O2consumption in Syrian hamsters with overt heart failure (HF) and age-matched normal hamsters. Using echocardiography, the hamsters with heart failure had reduced ejection fraction [31(±8) v 76(±5)%] and LV dilation [4.9(±0.2) v 5.7(±0.3) mm, both P<0.05 from normal]. O2consumption in the left ventricular free wall was measured using a Clark-type O2electrode in an air-tight chamber, containing Krebs solution buffered with Hepes (37°C, pH 7.4). Concentration response curves to bradykinin (BK), ramiprilat (RAM), amlodipine (AMLO) and the NO donor, S -nitroso- N -acetyl-penicillamine (SNAP) were performed. Basal myocardial O2consumption was lower in the HF group compared to normal [316(±21) v 404(±36) nmol O2/min/g, respectively, P<0.05]. In the hearts from normal hamsters BK (10−4mol/l), RAM (10−4mol/l), and AMLO (10−5mol/l) all significantly reduced myocardial O2consumption by 42(±6)%, 29(±7)% and 27(±5)% respectively. This reduction was attenuated in the presence of N -nitro- -arginine methyl ester ( -NAME) [BK: 3.3(±1.5)%, RAM: 3.3(±1.2)%, AMLO: 2.3(±1.2)%, P<0.05]. Interestingly in the hearts from HF group, BK, RAM and AMLO caused a significantly smaller reduction in myocardial O2consumption [10(±2)%, 2.5(±1.3)%, 6.3(±2.3)%, P<0.05]. In contrast, the NO donor SNAP reduced myocardial O2consumption in both groups and all those responses were not affected by -NAME. These data indicate that endogenous NO production thrugh the kinin-dependent mechanism is impaired at end-stage heart failure. The loss of kinin and NO control of mitochondrial respiration may contribute to the pathogenesis of heart failure.