The Role of Cardiac β1- and β2-Adrenoceptor Stimulation in Heart Failure

Substantial evidence has accumulated that in the human heart both β1- and β2-adrenoceptors coexist. As a rule. the amount of β2-adrenoceptors is higher in the atria (about 30% of the total β-adrenoceptor population) than in the ventricular myocardium (about 20%). Both β1- and β2-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 β1- and β2-adrenoceptors causes maximal increases in contractile force: in the ventricular myocardium. however. only β1-adrenoceptor stimulation maximally increases contractile force. whereas β2-adrenoceptor stimulation evokes only submaximal increases. On the other hand. norepinephrine induces its positive inotropic effect on atrial and ventricular preparations solely via β1-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 β1-adrenoceptors. whereas cardiac β2-adrenoceptors play only a minor role. if at all. However, in situations of stress, when large amounts of epinephrine (acting at both β1- and β2-adrenoceptors with the same affinity) are released from the adrenal medulla. activation of cardiac β2-adrenoceptors may contribute to an additional increase in heart rate and/or contractility. In chronic heart failure. cardiac β-adrenoceptor function decreases (presumably due to endogenous “downregulation” by the elevated catechol-amines). and this decrease is related to the severity of the disease (judged clinically by NYHA functional class). However, cardiac β1- and β2-adrenoceptors seem to be differentially affected in different kinds of heart failure: in end-stage dilated cardiomyopathy. β1-adrenoceptors selectively decrease. whereas β2-adrenoceptors are nearly normal. Under these (pathological) conditions. β2-adrenoceptors may substitute for the loss in β1-adrenoceptors. thereby maintaining contractility. at least partially. On the other hand, in endstage ischemic cardiomyopathy. tetralogy of Fallot, and mitral valve disease. both β1- and β2-adrenoceptors concomitantly decrease. The reason for this differential regulation of cardiac β1- and β2-adrenoceptors in different forms of heart failure remains to be elucidated.