Beta adrenergic receptor blockade of feline myocardium. Cardiac mechanics, energetics, and beta adrenoceptor regulation.
Myocardial oxygen consumption is regulated by interrelated mechanical and inotropic conditions; there is a parallel increase in the aerobic metabolism and inotropic state during beta-adrenergic stimulation under fixed mechanical conditions. In contrast, there is some evidence that beta-blockade may reduce oxygen consumption through effects independent of its influence on mechanical conditions and contractile state, and that prolonged beta-blockade may sensitize the myocardium to beta-adrenergic stimulation. To clarify these two points, the present study examined the relationship of myocardial energetics to mechanics and inotropism during acute beta-blockade and after the withdrawal of long-term beta-blockade, whereupon the basis for any effect observed was sought by characterizing the number, affinity, and affinity states of the beta-receptors as well as the coupling of activated beta-receptors to cyclic AMP generation. Studies of right ventricular papillary muscles from control and chronically beta-blocked cats demonstrated contractile and energetic properties as well as dose-response behavior and inotropic specificity suggestive of an increase in myocardial sensitivity to beta-adrenoceptor stimulation in the latter group. Assays of cardiac beta-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 beta-adrenoceptors to cyclic AMP generation was enhanced in cardiac muscle cells from chronically beta-blocked cats. These data demonstrate that beta-adrenoceptor blockade (a) produces parallel effects on inotropic state and oxygen consumption without an independent effect on either and (b) increases myocardial sensitivity to beta-adrenergic stimulation after beta-blockade withdrawal, not by "up-regulation" of the cardiac beta-adrenoceptors, but instead by more effective coupling of these receptors when activated to cyclic AMP generation.
Cooper
G
G
Kent
R L
RL
McGonigle
P
P
Watanabe
A M
AM
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002415:Cats; D000242:Cyclic AMP / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011869:Radioligand Assay; D011943:Receptors, Adrenergic, beta / Q000502:physiology*
D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D010656:Phenylephrine; D011433:Propranolol; D000242:Cyclic AMP; D007545:Isoproterenol; D009638:Norepinephrine