Functional Significance of Presynaptic α-Adrenergic Receptors in Failing and Nonfailing Human Left Ventricle

Abstract

There are alpha-adrenergic receptors on human myocardium that exert positive inotropic effects. The effect of alpha-adrenergic receptor blockade on human left ventricular (LV) performance has not been fully explored. Although alpha-adrenergic receptor blockade might have effects on LV function that are mediated via blockade of postsynaptic myocardial alpha-adrenergic receptors, it is also possible that blockade of presynaptic alpha 2-adrenergic receptors and subsequent increased release of norepinephrine would have effects on LV performance. In the present study, we explored the effects of nonselective alpha-adrenergic receptor blockade on LV performance and transcardiac norepinephrine concentrations in a group of patients with normal LV function and in a group of patients with congestive heart failure secondary to dilated cardiomyopathy. Using an intracoronary drug infusion technique, we administered the nonselective alpha-adrenergic antagonist phentolamine to 13 patients with normal LV function and 19 patients with congestive heart failure secondary to dilated cardiomyopathy. With a high-fidelity LV catheter, the systolic (+dP/dt) and diastolic (-dP/dt and Tau) LV function responses to intracoronary infusion of phentolamine (0.2 mg/min x 5 minutes) were assessed. In 8 patients with normal ventricular function and 10 patients with congestive heart failure, arterial and coronary sinus blood samples were drawn to determine the effects of phentolamine on catecholamine concentrations. Phentolamine had no measurable effect on LV performance or catecholamine concentrations in the normal ventricular function group. In patients with congestive heart failure, intracoronary phentolamine caused a significant increase in +dP/dt and the rate of isovolumic LV relaxation (-dP/dt and Tau). These hemodynamic effects were accompanied by a significant increase in coronary sinus norepinephrine concentration but no change in arterial norepinephrine concentration. Myocardial alpha-adrenergic receptor blockade causes significant inotropic and lusitropic effects in the failing but not the nonfailing human LV. These effects appear to be mediated by increased release of norepinephrine from cardiac nerves secondary to blockade of presynaptic alpha 2-adrenergic receptors. Differences in the responses of the failing and nonfailing human LV appear to reflect the higher level of sympathetic activation that is seen in the group with congestive heart failure. This suggests that the presynaptic alpha 2-adrenergic receptor exerts a tonic inhibitory effect on the release of norepinephrine from cardiac nerves in patients with congestive heart failure.