Prolonged beta-agonist infusion does not induce desensitization or down-regulation of beta-adrenergic receptors in...

In adult animals, prolonged beta-agonist exposure leads to down-regulation of beta-adrenergic receptors and desensitization. Prior evidence from our lab suggests that this may not occur in developing animals. To study this, we measured the response to graded epinephrine infusion [2.7, 5.5, 13.6, 27.3 mumol/(kg.min), (0.5, 1.0, 2.5, 5.0 micrograms/(kg.min)], myocardial beta-agonist receptor density, and components of the receptor-cyclase system in newborn lambs before (n = 6) and after (n = 5) 3 d of continuous isoproterenol administration (2 micrograms/kg/min). beta-Adrenergic receptors were measured by radioligand binding. Epinephrine dose-response curves were analyzed for the threshold and slope for changes in mean blood pressure, systolic blood pressure, and heart rate versus plasma epinephrine levels. Despite 3 d of continuous isoproterenol infusion, we observed no desensitization of the hemodynamic response to epinephrine. There was a reduction in receptor density when expressed per membrane protein [155.3 +/- 19.5 (controls) versus 73.2 +/- 3.8 fmol/mg protein (agonist exposed), p less than 0.05], but no alteration in receptor density when expressed per g cardiac wet weight [258.8 +/- 39.9 (controls) versus 406.8 +/- 74.0 fmol/g wet weight (agonist exposed)]. There was no alteration in agonist affinity or in adenylyl cyclase activity after adjustment for membrane protein recovery. Prolonged beta-agonist infusion in newborn lambs does not desensitize hemodynamic responses to infused epinephrine. We propose that receptor regulation in developing animals is fundamentally different than in adult animals.