Mechanism of Action of Adrenergic Agents in Acute Congestive Heart Failure

Abstract

β ₁ - and β ₂ -Adrenoceptor Activation : The subclassification of catecholamine-mediated cardiovascular responses into α and β was originally proposed by Ahlquist [1] who was first to demonstrate that the in vivo actions of adrenaline, noradrenaline and isoprenaline could be explained most simply by the presence of two adrenoceptor subtypes; the first, α, which mediates vasoconstriction, uterine and ureter smooth muscle excitation, nictitating membrane contraction and inhibition of intestinal motility. The second adrenoceptor subtype, β mediates vasodilation, uterine relaxation and myocardial activation. Later work by Lands et al. [2, 3] further subdivided the β-adrenoceptor-mediated cardiovascular responses into β₁, characterized by increases in myocardial rate and force of contraction and lipolysis, and β₂ which mediates vascular and pulmonary smooth muscle relaxation. While this work was seminal in our understanding of the actions and functions of the sympathetic nervous system, it also resulted in the identification of a specific therapeutic target, the β-adrenoceptor, for pharmacologic intervention in states of myocardial insufficiency. β₁-Adrenoceptor activation has long been known to mediate increases in chronotropic and inotropic state. More recent studies have demonstrated the presence of β₂-adrenoceptors in cardiac tissue which also mediate positive chronotropic and inotropic responses [4, 5], such that stimulation of both β-adrenoceptor subtypes has the capacity to increase the rate and force of cardiac contraction, thereby improving cardiac output and tissue perfusion. The increases in cardiac rate and force of contraction evoked by activation of myocardial β₁- and β₂-adrenoceptors result from the activation of adenylate cyclase and the subsequent accumulation of cyclic AMP.