The β3-adrenoceptor and its regulation in cardiac tissue

In addition to beta1 and beta2-adrenoceptors, the recently cloned beta3-adrenoceptor is also expressed at the surface of myocardial and vascular cells, albeit with considerable variability among species. In human ventricular muscle, stimulation of this receptor produces a negative inotropic effect that involves, at least in part, activation of the endothelial nitric oxide synthase (eNOS) through G-alpha-i proteins, and intracellular increases in cyclic GMP. In the non-failing heart, this beta3-adrenoceptor pathway may protect the myocardium against the toxic effects of excessive stimulation by catecholamines. In biopsy samples from human failing ventricular myocardium (from ischemic, dilated or septic cardiomyopathies), the abundnace of beta3-adrenoceptor proteins is increased, as that of the coupling G-alpha-i proteins. In the setting of high orthosympathetic input to the heart, catecholamine stimulation of the poorly desentitizable beta3-adrenoceptor, combined with desensitized/downregulated beta1 and beta2-adrenaceptors, may favor a sustained and prevailing beta3-adrenergic negative inotropic effect. The pathophysiological importance of this pathway in the clinical syndrome of heart failure will await the result of trials with antagonists specific for the human cardiac beta3-adrenoceptor.