Intravenous Allopurinol Decreases Myocardial Oxygen Consumption and Increases Mechanical Efficiency in Dogs With Pacing-Induced Heart Failure

• DOI: 10.1161/01.res.85.5.437
• Publication Date: 2012-06-12T00:47:05Z
• Authors: Ulf E. G. Ekelund; Robert W. Harrison; Ori Shokek; Rajiv N. Thakkar; Richard S. Tunin; Hideaki Senzaki; David A. Kass; Eduardo Marbán; Joshua M. Hare
• Keywords: Heart Failure; Male; Cardiotonic Agents; Consciousness; Allopurinol; Myocardium; Cardiac Pacing, Artificial; Drug Evaluation, Preclinical; Muscle Proteins; Myocardial Contraction; 3. Good health; Oxidative Stress; 03 medical and health sciences; Dogs; Oxygen Consumption; 0302 clinical medicine; Diastole; Heart Rate; Injections, Intravenous; Disease Progression; Animals; Enzyme Inhibitors; Energy Metabolism

Abstract—Allopurinol, an inhibitor of xanthine oxidase, increases myofilament calcium responsiveness and blunts calcium cycling in isolated cardiac muscle. We sought to extend these observations to conscious dogs with and without pacing-induced heart failure and tested the prediction that allopurinol would have a positive inotropic effect without increasing energy expenditure, thereby increasing mechanical efficiency. In control dogs (n=10), allopurinol (200 mg IV) caused a small positive inotropic effect; (dP/dt)maxincreased from 3103±162 to 3373±225 mm Hg/s (+8.3±3.2%;P=0.01), but preload-recruitable stroke work and ventricular elastance did not change. In heart failure (n=5), this effect was larger; (dP/dt)maxrose from 1602±190 to 1988±251 mm Hg/s (+24.4±8.7%;P=0.03), preload-recruitable stroke work increased from 55.8±9.1 to 84.9±12.2 mm Hg (+28.1±5.3%;P=0.02), and ventricular elastance rose from 6.0±1.6 to 10.5±2.2 mm Hg/mm (P=0.03). Allopurinol did not affect myocardial lusitropic properties either in control or heart failure dogs. In heart failure dogs, but not controls, allopurinol decreased myocardial oxygen consumption (–49±4.6%;P=0.002) and substantially increased mechanical efficiency (stroke work/myocardial oxygen consumption; +122±42%;P=0.04). Moreover, xanthine oxidase activity was ≈4-fold increased in failing versus control dog hearts (387±125 versus 78±72 pmol/min · mg–1;P=0.04) but was not detectable in plasma. These data indicate that allopurinol possesses unique inotropic properties, increasing myocardial contractility while simultaneously reducing cardiac energy requirements. The resultant boost in myocardial contractile efficiency may prove beneficial in the treatment of congestive heart failure.