Alpha-adrenergic mechanisms in the pathophysiology of left ventricular heart failure —an analysis of their role in systolic and diastolic dysfunction

Abstract

Alpha-adrenoceptor (alpha-AR) mechanisms may contribute to systolic and diastolic dysfunction of the left ventricle. Centrally acting alpha₂-AR agonist drugs, including methyldopa, clonidine, and guanabenz, activate brainstem alpha₂-AR and this activation results in a decrease in overall sympathetic tone and an increase in parasympathetic tone. Peripherally acting alpha₁-AR antagonists, such as prazosin, inhibit the actions of catecholamines at post-synaptic receptor sites. Heart failure is characterized by hyperactivity of sympathetic pathways and parasympathetic withdrawal. In this situation, alpha₂-agonists reduce sympathetic activity and improve hemodynamic parameters of cardiac function; both acute and chronic administration of alpha₂-AR have been demonstrated to reduce serum catecholamine levels, heart rate, and arterial blood pressure, and to improve exercise performance. Diastolic dysfunction of the left ventricle is characterized by a marked decrease in ventricular complicance, often a result of hypertension and left ventricular hypertrophy; the end result is an increase in left ventricular filling pressure and pulmonary venous pressure. Treatment with alpha₂-AR, by decreasing sympathetic tone and blood pressure, and alpha₁-AR antagonists, by reducing blood pressure and by directly inhibiting the actions of catecholamines at alpha₁-AR, may produce a reduction in the degree of ventricular hypertrophy and improve diastolic performance of the left ventricle. Thus, therapeutic intervention in heart failure with either alpha₂-AR agonists or alpha₁-AR antagonists may favorably modulate these alterations in sympathetic tone and improve ventricular function.