title: Imbalances emerge in cardiac autonomic cell signaling after neonatal exposure to terbutaline or chlorpyrifos, alone or in combination.
abstract: During early neonatal development, the future reactivity of the heart to cardiac autonomic stimulation is programmed by the timing and intensity of the arrival of parasympathetic and sympathetic inputs. In neonatal rats, we examined the effects of exposure to terbutaline, a beta-adrenoceptor (betaAR) agonist used to arrest preterm labor, and chlorpyrifos (CPF), a widely used organophosphate pesticide that acts in part through inhibition of cholinesterase, using scenarios mimicking the likely developmental stages corresponding to peak human exposures: postnatal days (PN) 2-5 for terbutaline and PN11-14 for CPF. Terbutaline evoked a progressive deficit in cardiac betaAR binding but did not interfere with the ability of the receptors to stimulate adenylyl cyclase (AC). Terbutaline also reduced expression of m2 muscarinic acetylcholine receptors and suppressed their ability to inhibit AC. Surprisingly, CPF produced similar actions, a decrement in betaAR and m2 muscarinic receptor binding and a loss of the cholinergic AC response, and also augmented the ability of betaARs to stimulate AC. The effects of CPF are thus unlikely to reside in cholinergic hyperstimulation resulting from cholinesterase inhibition but instead involve other actions converging on receptors and cell signaling. Exposure to both agents, terbutaline followed by CPF, produced a summation of the two individual effects. Our findings at the level of cell signaling thus indicate that neonatal exposure to terbutaline or CPF, or sequentially to both agents, results in an imbalance of cardiac autonomic inputs favoring increased excitability, an outcome that may have an impact on cardiovascular responses.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813 DUMC, Durham, NC 27710, USA. t.slotkin@duke.edu
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Slotkin
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Tate
authors.forename: Mandy M
authors.initials: MM
authors.lastname: Cousins
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: Seidler
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002217:Carbachol / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004390:Chlorpyrifos / Q000494:pharmacology*; D018679:Cholinergic Agonists / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D006321:Heart / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000166:cytology; D011247:Pregnancy; D011485:Protein Binding / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2 / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects*; D013726:Terbutaline / Q000494:pharmacology*
chemical_list: D000318:Adrenergic beta-Agonists; D018679:Cholinergic Agonists; D002800:Cholinesterase Inhibitors; D004338:Drug Combinations; D043585:Receptor, Muscarinic M2; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D002217:Carbachol; D000262:Adenylyl Cyclases; D004390:Chlorpyrifos; D007545:Isoproterenol; D013726:Terbutaline