Physiology and pharmacology of cardiovascular catecholamine receptors: Implications for treatment of chronic heart failure

Abstract

In the sympathetic nervous system the physiologic effects of the endogenous catecholamines noradrenaline (NA) and adrenaline (A) are mediated by α- and β-adrenoreceptors (ARs). Both AR-types can be subdivided into two major subtypes: α-ARs into α-1 (predominant effect: vasoconstriction) and α-2 (presynaptic: inhibition of NA-release; postsynaptic: vasoconstriction), β-ARs into β-1 (cardiac effects, renal renin release, and lipolysis) and β-2 (presynaptic: facilitation of NA-release; postsynaptic: vascular, bronchial, and uterine smooth muscle relaxation, glycogenolysis and possibly part of the A-mediated cardiac effects). During the last 30 years growing evidence has accumulated that dopamine (DA), the third endogenous catecholamine and the immediate precursor of NA, may also cause peripheral effects through stimulation of specific DA-receptors, in addition to its known action at α- and β-ARs. It is now well accepted that at least two different DA-receptors are present in many peripheral tissues (DA 1 and DA 2), including those of the cardiovascular and autonomic nervous system. They seem to be involved in dilation of certain vascular beds, inhibition of NA-release during nerve stimulation, natriuresis, and aldosterone release. In chronic heart failure cardiac β-AR function decreases (presumably due to endogenous “down-regulation” by the elevated catecholamines), and this decrease is related to the severity of heart failure (judged clinically by New York Heart Association functional class). The human heart contains both functional β-1 and β-2 ARs; cardiac β-1 and β-2 ARs seem to be differentially affected by different kinds of heart failure; in end-stage dilated cardiomyopathy β-1 ARs are selectively reduced, whereas β-2 ARs are nearly normal. Under these (pathologic) conditions β-2 ARs may substitute for the loss in β-1 AR function, thereby maintaining contractility, at least partially. In mitral valve disease and end-stage ischemic cardiomyopathy, on the other hand, the decrease in cardiac β-AR function is due to a concomitant decrease in β-1 and β-2 ARs. However, very little is known about changes in α-ARs and DA-receptors in chronic heart failure. Epinine (N-metyl-DA), the active metabolite of ibopamine, is a full agonist at DA 1 and DA 2 receptors with an affinity equal to or even slightly higher than DA. Similarly, its affinity to α-1 and α-2 as well as to β-1 ARs is comparable with DA, whereas at β-2 ARs the affinity of epinine is about 10 times higher than that of DA. In addition, epinine induces in isolated electrically driven human right atria its positive inotropic effect via stimulation of β-1 and β-2 ARs (being a full agonist), whereas DA is a partial agonist acting solely at β-1 ARs. Thus long-term application of ibopamine (i.e. epinine) should lead to the following cardiovascular and endocrine effects: it should cause positive inotropic effects through stimulation of cardiac β-1 and β-2 ARs, direct vasodilation through stimulation of β-2 ARs and DA 1 receptors, indirect vasodilation through stimulation of presynaptic DA 2 receptors and α-2 ARs (which leads to inhibition of NA-release), diuresis and natriuresis through stimulation of (renal) DA 1 receptors. Blood pressure may increase slightly (but only at higher doses) via stimulation of postsynaptic α-1 and α-2 ARs. Thus the properties of epinine may be a suitable combination of effects to treat patients with chronic heart failure, provided that downregulation of receptor function can be prevented.