Effects of in vivo beta-adrenoceptor down-regulation on cardiac responses to prenalterol and pirbuterol.
The effects of beta-adrenoceptor down-regulation on rat left atrial responses to the full agonist isoproterenol and the partial agonists prenalterol and pirbuterol were studied. Atria from rats implanted with a mini-osmotic-pump subcutaneously delivering isoproterenol at 400 micrograms X kg-1 X h-1 for 4 days were 12-16 times less sensitive to isoproterenol than normal atria. Scatchard analyses indicated that the implantation of these mini-osmotic-pumps produced a 50% decrease in the number of beta-adrenoceptors in the ventricles with no alteration in the binding constant of [3H]dihydroalprenolol. Receptor down-regulation produced a parallel shift to the right of concentration-response curves to isoproterenol, and a complete suppression of responses to both partial agonists. The affinities of the partial agonists for the receptors were not altered; in desensitized atria the partial agonists were functional beta-antagonists blocking the responses to isoproterenol. The data are modeled by equations from classical receptor theory which predict the depression of responses to partial agonists with receptor down-regulation. These results are discussed with respect to the utility of prenalterol and pirbuterol in congestive heart failure since possible tachyphylaxis to these drugs with chronic usage could limit their value.
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D007545:Isoproterenol / Q000037:antagonists & inhibitors; D007700:Kinetics; D008297:Male; D011217:Practolol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011294:Prenalterol; D051381:Rats; D011941:Receptors, Adrenergic / Q000187:drug effects*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*
D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D011941:Receptors, Adrenergic; D011943:Receptors, Adrenergic, beta; D007545:Isoproterenol; D011294:Prenalterol; C009118:pirbuterol; D011217:Practolol