beta-Adrenergic modulation of muscarinic cholinergic receptor expression and function in developing heart.
Imbalances of beta-adrenoceptor (beta-AR) and muscarinic ACh receptor (mAChR) input are thought to underlie perinatal cardiovascular abnormalities in conditions such as sudden infant death syndrome. Administration of isoproterenol, a beta(1)/beta(2)-AR agonist, to neonatal rats on postnatal days (PN) 2-5 caused downregulation of cardiac m(2)AChRs and a corresponding decrement in their control of adenylyl cyclase activity. Terbutaline, a beta(2)-selective agonist that crosses the placenta and the blood-brain barrier, was also effective when given either on PN 2-5 or during gestational days 17-20. Terbutaline failed to downregulate brain m(2)AChRs, even though it downregulated beta-ARs; beta-ARs and m(2)AChRs are located on different cell populations in the brain, but they are on the same cells in the heart. Destruction of catecholaminergic neurons with neonatal 6-hydroxydopamine upregulated cardiac but not brain m(2)AChRs. These results suggest that perinatal beta-AR stimulation shifts cardiac receptor production away from the generation of m(2)AChRs so that the development of sympathetic innervation acts as a negative modulator of cholinergic function. Accordingly, tocolytic therapy with beta-AR agonists may compromise the perinatal balance of adrenergic and cholinergic inputs.
Garofolo
M C
MC
Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Seidler
F J
FJ
Auman
J T
JT
Slotkin
T A
TA
D000262:Adenylyl Cyclases / Q000378:metabolism; D018663:Adrenergic Agents / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000187:drug effects / Q000378:metabolism; D006321:Heart / Q000196:embryology; D007545:Isoproterenol / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D016627:Oxidopamine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk; D043585:Receptor, Muscarinic M2; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D013726:Terbutaline / Q000494:pharmacology
D018663:Adrenergic Agents; D000318:Adrenergic beta-Agonists; D043585:Receptor, Muscarinic M2; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D016627:Oxidopamine; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D013726:Terbutaline