MODULATION OF HUMAN CARDIAC-FUNCTION THROUGH 4 BETA-ADRENOCEPTOR POPULATIONS

In human heart there is now evidence for the involvement of four beta- adrenoceptor populations, three identical to the recombinant beta(1)-, beta(2)- and beta(3)-adrenoceptors, and a fourth as yet uncloned puta tive beta-adrenoceptor population, which we designate provisionally as the cardiac putative beta(4)-adrenoceptor. This review described nove l features of beta-adrenoceptors as modulators of cardiac systolic and diastolic function. We also discuss evidence for modulation by unoccu pied beta(1)- and beta(2)-adrenoceptors. Human cardiac and recombinant beta(1)- and beta(2)-adrenoceptors are both mainly coupled to adenyly l cyclase through Gs protein, the latter more tightly than the former. Activation of both human beta(1)- and beta(2)-adrenoceptors not only increases cardiac force during systole but also hastens relaxation thr ough cyclic AMP-dependent phosphorylation of phospholamban and troponi n I, thereby facilitating diastolic function. Furthermore, both beta(1 ) and beta(2)-adrenoceptors can mediate experimental arrhythmias in hu man cardiac preparations elicited by noradrenaline and adrenaline. Hum an ventricular beta(3)-adrenoceptors appear to be coupled to a pertuss is toxin-sensitive protein (Gi?). beta(3)-Adrenoceptor-selective agoni sts shorten the action potential and cause cardiodepression, suggestin g direct coupling of a Gi protein to a K+ channel. In a variety of spe cies, including man, cardiac putative beta(4)-adrenoceptors mediate ca rdiostimulant effects of non-conventional partial agonists, i.e. high affinity beta(1)- and beta(2)-adrenoceptor blockers that cause agonist effects at concentrations considerably higher than those that block t hese receptors. Putative beta(4)-adrenoceptors appear to be coupled po sitively to a cyclic AMP-dependent cascade and can undergo some desens itisation.