Prolonged beta-agonist infusion does not induce desensitization or down-regulation of beta-adrenergic receptors in newborn sheep.
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.
Stein
H M
HM
Department of Pediatrics, UCLA School of Medicine, Torrance 90502.
Oyama
K
K
Sapien
R
R
Chappell
B A
BA
Padbury
J F
JF
D000318:Adrenergic beta-Agonists / Q000008:administration & dosage*; D000818:Animals; D000831:Animals, Newborn; D015536:Down-Regulation; D004837:Epinephrine / Q000008:administration & dosage; D006439:Hemodynamics / Q000187:drug effects; D007262:Infusions, Intravenous; D007545:Isoproterenol / Q000008:administration & dosage; D009206:Myocardium / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D012756:Sheep
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D007545:Isoproterenol; D004837:Epinephrine