Allopurinol enhances the contractile response to dobutamine and exercise in dogs with pacing-induced heart failure

Abstract

Background - Superoxide (O2-) generated by enhanced xanthine oxidase (XO) activity may contribute to the increased myocardial oxidative stress in heart failure (CHF). Because blocking XO with allopurinol augments myofilament Ca2+ sensitivity in reperfusion injury and CHF, we hypothesized that it may improve adrenergic inotropic responsiveness in CHF. Methods and Results - We studied the effect of allopurinol on the contractile response to dobutamine and exercise in 7 chronically instrumented conscious dogs before and after producing CHF by rapid pacing. Left ventricular (LV) contractile performance was measured by the slopes of the LV end-systolic pressure-volume relation (EES) and stroke work-end-diastolic volume relation (MSW). Before CHF, allopurinol produced no change in LV contractile performance and did not alter the response to dobutamine or exercise. After CHF, allopurinol produced significant (P<0.05) increases in EES (5.0±0.6 versus 3.3±0.6 mm Hg/mL) and MSW. Dobutamine and allopurinol produced greater increases in EES (5.4±0.6 versus 7.4±0.6 mm Hg/mL) and MSW (60.1±7.4 versus 73.7±4.4 mm Hg) than did dobutamine alone. After allopurinol, dP/dtmax, stroke volume, and MSW were higher during CHF exercise. LV diastolic pressures were lower during CHF exercise after allopurinol. Conclusions - Allopurinol has no discernable effects on LV contractile function or adrenergic responsiveness in normal, conscious animals. In pacing-induced CHF, however, allopurinol improves LV systolic function at rest and during adrenergic stimulation and exercise.