Effects of In Vivo β-Adrenoceptor Down-Regulation on Cardiac Responses to Prenalterol and Pirbuterol

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Abstract
Summary The effects of β-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 μg·kg-1·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 β-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 β-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.