Beta adrenergic receptor blockade of feline myocardium. Cardiac mechanics, energetics, and beta adrenoceptor regulation

Abstract

Myocardial oxygen consumption is regulated by interrelated mechanical and inotropic conditions; there is a parallel increase in the aerobic metabolism and inotropic state during β- adrenergic stimulation under fixed mechanical conditions. In contrast, there is some evidence that β-blockade may reduce oxygen consumption through effects independent of its influence on mechanical conditions and contractile state, and that prolonged β-blockade may sensitize the myocardium to β-adrenergic stimulation. To clarify these two points, the present study examined the relationship of myocardial energetics to mechanics and inotropism during acute β-blockade and after the withdrawal of long-term β-blockade, whereupon the basis for any effect observed was sought by characterizing the number, affinity, and affinity states of the β-receptors as well as the coupling of activated β-receptors to cyclic AMP generation. Studies of right ventricular papillary muscles from control and chronically β-blocked cats demonstrated contractile and energetic properties as well as dose-response behavior and inotropic specificity suggestive of an increase in myocardial sensitivity to β-adrenoceptor stimulation in the latter group. Assays of cardiac β-adrenoceptors from further groups of control and pretreated cats, both in cardiac tissue and in isolated cardiac muscle cells, failed to define a difference between the two groups either in terms of receptor number and affinity or in terms of the proportion of receptors in the high-affinity state. However, coupling of the activated β-adrenoceptors to cyclic AMP generation was enhanced in cardiac muscle cells from chronically β-blocked cats. These data demonstrate that β-adrenoceptor blockade (a) produces parallel effects on inotropic state and oxygen consumption without an independent effect on either and (b) increases myocardial sensitivity to β-adrenergic stimulation after β-blockade withdrawal, not by 'up-regulation' of the cardiac β-adrenoceptors, but instead by more effective coupling of these receptors when activated to cyclic AMP generation.