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.
Department of Pediatrics, UCLA School of Medicine, Torrance 90502.
H M
HM
Stein
K
K
Oyama
R
R
Sapien
B A
BA
Chappell
J F
JF
Padbury
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