Beta-adrenoceptor-mediated cell signaling in the neonatal heart and liver: responses to terbutaline.
Terbutaline, a beta(2)-adrenoceptor (beta(2)-AR) agonist, is a widely used tocolytic that also crosses the placenta to stimulate fetal beta-ARs. The current study examines the effects of terbutaline administered to neonatal rats. Terbutaline (10 mg/kg sc) given on postnatal day (PN) 2-5 or PN 11-14 elicited significant downregulation of both cardiac and hepatic beta-ARs, with a much greater effect in the liver. Despite the reduction in cardiac beta-ARs, receptor desensitization was absent as evidenced by the maintained ability of isoproterenol to stimulate adenylyl cyclase (AC) in membrane preparations. The underlying mechanism was dissected by using stimulants that operate at different points in the AC signaling pathway, NaF, forskolin, and Mn(2+). When administered in the early neonatal period, terbutaline failed to evoke any changes in cardiac AC activity; however, treatment on PN 11-14 evoked heterologous sensitization downstream from the receptor, evidenced by increases in the response to NaF and forskolin. In the liver, neonatal terbutaline administration elicited a small (approximately equal to 10%) decrease in the AC response to isoproterenol, an effect much smaller than the downregulation of beta-ARs (>40%). In this tissue, desensitization was again offset by heterologous sensitization of AC signaling. These results indicate that, in the developing organism, beta-AR-mediated cell signaling responses are maintained in the face of receptor downregulation through heterologous induction of downstream signaling elements. These unique responses serve to sustain beta-AR signaling in the perinatal period.
Auman
J T
JT
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Seidler
F J
FJ
Tate
C A
CA
Slotkin
T A
TA
D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D012969:Sodium Fluoride / Q000494:pharmacology; D013726:Terbutaline / Q000494:pharmacology*
D008565:Membrane Proteins; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D012969:Sodium Fluoride; D019204:GTP-Binding Proteins; D007545:Isoproterenol; D003000:Clonidine; D013726:Terbutaline