Nitric oxide inhibits the positive inotropic response to beta-adrenergic stimulation in humans with left ventricular dysfunction

Abstract

Background: Nitric oxide (NO) attenuates the contractile response to beta-adrenergic stimulation in cultured cardiac myocytes in vitro and in myocardium in vivo. We tested the hypothesis that NO synthesized in the heart inhibits the positive inotropic response to beta-adrenergic stimulation in humans with left ventricular (LV) dysfunction.

Methods and results: Patients with various degrees of LV dysfunction and free from epicardial coronary artery disease were instrumented with an infusion catheter in the left main coronary artery and a high-fidelity micromanometer-tipped catheter in the LV. Measurements included LV pressure, aortic pressure, heart rate, and LV peak +dP/dt. In eight subjects, dobutamine was infused via the left main coronary artery (25 or 50 micrograms/min) before and concurrent with intracoronary infusion of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 20 mumol/min for 10 minutes). In six other subjects, dobutamine was infused (6, 10, or 15 micrograms.kg-1.min-1) via a peripheral vein. Intracoronary (n = 8) dobutamine infusions increased LV peak +dP/dt by an average of 33 +/- 3%. The intracoronary infusion of L-NMMA had no effect on baseline LV peak +dP/dt, LV systolic or end-diastolic pressures, aortic pressure, or heart rate. The intracoronary infusion of L-NMMA, concurrent with a second infusion of dobutamine, potentiated the +dP/dt response to dobutamine by 30 +/- 10% (P < .04 versus dobutamine alone). The intracoronary infusion of L-NMMA likewise potentiated the +dP/dt response to the peripheral infusion of dobutamine by 37 +/- 18%.

Conclusions: Nitric oxide produced in the heart attenuates the positive inotropic response to beta-adrenergic stimulation in humans with LV dysfunction. NO may contribute to beta-adrenergic hyporesponsiveness in patients with LV dysfunction.