The role of cardiac beta1- and beta2-adrenoceptor stimulation in heart failure.

Substantial evidence has accumulated that in the human heart both beta1- and beta2-adrenoceptors coexist. As a rule, the amount of beta2-adrenoceptors is higher in the atria (about 30% of the total beta-adrenoceptor population) than in the ventricular myocardium (about 20%). Both beta1- and beta2-adrenoceptors couple to adenylate cyclase and mediate positive inotropic effects of isoproterenol and epinephrine on isolated, electrically driven cardiac preparations. In the atria, stimulation of both beta1- and beta2-adrenoceptors causes maximal increases in contractile force; in the ventricular myocardium, however, only beta1-adrenoceptor stimulation maximally increases contractile force, whereas beta2-adrenoceptor stimulation evokes only submaximal increases. On the other hand, norepinephrine induces its positive inotropic effect on atrial and ventricular preparations solely via beta1-adrenoceptor stimulation. Because norepinephrine is the main transmitter of the human sympathetic nervous system, this indicates that under normal physiological conditions, the heart rate and contractility are under the control of cardiac beta1-adrenoceptors, whereas cardiac beta2-adrenoceptors play only a minor role, if at all. However, in situations of stress, when large amounts of epinephrine (acting at both beta1- and beta2-adrenoceptors with the same affinity) are released from the adrenal medulla, activation of cardiac beta2-adrenoceptors may contribute to an additional increase in heart rate and/or contractility. In chronic heart failure, cardiac beta-adrenoceptor function decreases (presumably due to endogenous "downregulation" by the elevated catecholamines), and this decrease is related to the severity of the disease (judged clinically by NYHA functional class). However, cardiac beta1- and beta2-adrenoceptors seem to be differentially affected in different kinds of heart failure: in end-stage dilated cardiomyopathy, beta1-adrenoceptors selectively decrease, whereas beta2-adrenoceptors are nearly normal. Under these (pathological) conditions, beta2-adrenoceptors may substitute for the loss in beta1-adrenoceptors, thereby maintaining contractility, at least partially. On the other hand, in end-stage ischemic cardiomyopathy, tetralogy of Fallot, and mitral valve disease, both beta1- and beta2-adrenoceptors concomitantly decrease. The reason for this differential regulation of cardiac beta1- and beta2-adrenoceptors in different forms of heart failure remains to be elucidated.