Role of cyclic AMP in cardiac beta-adrenoceptor desensitization: studies using prenalterol and inhibitors of phosphodiesterase.
We examined the effects of prolonged exposure of cardiac cells in primary culture to the partial beta-adrenoceptor agonist prenalterol and inhibitors of phosphodiesterase on their subsequent ability to increase intracellular cyclic AMP during a 5-min exposure to 50 microM isoprenaline (receptor responsiveness). Although prenalterol possesses only 7% of the agonist activity of isoprenaline on adenylate cyclase, it induces extensive beta-adrenoceptor desensitization. Three hours after exposing the cells to 1 microM prenalterol, beta-adrenoceptor responsiveness was reduced by 40% (p less than 0.05), whereas after 12 h the reduction averaged 55%. Prolonging the incubation time to 48 h had no further effect on the magnitude of receptor desensitization. The magnitude of the desensitization was concentration dependent. On exposure of cells to 10(-8) M prenalterol for 16 h, receptor responsiveness was reduced by 19%, and at concentrations of 1 microM and higher responsiveness was reduced by 60% (p less than 0.01). Receptor desensitization appeared to be due to an inability of receptors to activate adenylate cyclase as well as to receptor loss. To investigate if beta-adrenoceptor desensitization as well as receptor loss could be mediated by cyclic AMP, the cells were exposed for 16 h to inhibitors of phosphodiesterase. Exposure of cells to the phosphodiesterase inhibitor isobutylmethylxanthine (0.1 mM) (which increased intracellular cyclic AMP by between 50 and 150%) also induced receptor desensitization. The reduction in receptor responsiveness averaged 62% (p less than 0.01). The loss in responsiveness could be accounted for by an inability of receptors to activate adenylate cyclase as well as by receptor loss.(ABSTRACT TRUNCATED AT 250 WORDS)
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000032:analysis; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002642:Chick Embryo; D000242:Cyclic AMP / Q000502:physiology*; D006321:Heart / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011217:Practolol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011294:Prenalterol; D011743:Pyrimidines / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000032:analysis / Q000187:drug effects*
D000318:Adrenergic beta-Agonists; D010726:Phosphodiesterase Inhibitors; D011743:Pyrimidines; D011943:Receptors, Adrenergic, beta; C006313:ICI 63197; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D011294:Prenalterol; D011217:Practolol; D015056:1-Methyl-3-isobutylxanthine