Decreased isoproterenol-induced "down"-regulation of beta-adrenergic receptors in the myocardium of SHR.
The number of cardiac beta-adrenergic receptors and the activity of isoproterenol-stimulated adenylate cyclase are lower in spontaneously hypertensive rats (SHRs) and may account for diminished inotropic responsiveness to beta-agonists. Differences in isoproterenol-induced desensitization of the cardiac adenylate cyclase system between 14- to 16-week-old SHRs and Wistar-Kyoto (WKY) controls were studied using cardiac membranes, isolated cardiac myocytes, and intact animals. In both animal strains, the isoproterenol-induced "loss" of beta-adrenergic receptors in the cardiac membranes required adenosine triphosphate (ATP), magnesium (Mg2+), and guanosine 5'-triphosphate (GTP). The ATP and Mg2+ requirement may reflect a crucial role for a phosphorylation step, since desensitization was prevented by cordycepin, a nonspecific phosphorylation inhibitor. In both isolated myocytes and intact animals, isoproterenol induced a redistribution of the beta-adrenergic receptors (but not of adenylate cyclase) from the cell membrane to the cytosol. Internalization of the receptors was not secondary to the loss of membrane fragments to the cytosol, since the receptors sequestered in a fraction devoid of cell surface markers. In all three preparations, the extent of isoproterenol-induced "loss" of beta-receptors and isoproterenol-stimulated adenylate cyclase was considerably lower in SHRs than WKYs. This difference appeared to be due to a reduced capacity of isoproterenol to induce translocation of beta-receptors from the membranes to the cytosol of SHRs, because of a change in the physical properties of either the beta-receptors themselves or the membranes into which they were embedded.
D000818:Animals; D002462:Cell Membrane / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006352:Heart Ventricles / Q000503:physiopathology; D006973:Hypertension / Q000503:physiopathology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011922:Rats, Mutant Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D016276:Ventricular Function
D011943:Receptors, Adrenergic, beta; D011433:Propranolol; D007545:Isoproterenol; D009638:Norepinephrine; D004837:Epinephrine