Beta-adrenoceptor modulation of transiently overexpressed alpha 2-adrenoceptors in brain and peripheral tissues: cellular mechanisms underlying the developmental toxicity of terbutaline.
Terbutaline, a selective beta(2)-adrenoceptor (beta(2)AR) agonist, is widely used as a tocolytic to arrest preterm labor but recent studies indicate that excessive betaAR stimulation can alter the expression and function of other neurotransmitter receptors that are essential to fetal/neonatal development. In many immature tissues, alpha(2)-adrenergic receptors (alpha(2)ARs) are overexpressed and the receptors are thought to play a role in cell proliferation and architectural assembly. We evaluated whether betaAR agonists perturb the expression of alpha(2)ARs in central and peripheral tissues during various developmental stages in the fetal and neonatal rat. In peripheral tissues (heart, liver, kidney) administration of terbutaline (10mg/kg s.c. for 4 days) elicited decrements in alpha(2)AR expression only during a critical developmental window that differed for each tissue; terbutaline was more effective than isoproterenol, a mixed beta(1)/beta(2) agonist. Neonatal destruction of sympathetic nerves with 6-hydroxydopamine (6-OHDA) had a biphasic effect, initially reducing alpha(2)ARs but subsequently elevating receptor expression. In contrast to the effects in the periphery, terbutaline administration promoted alpha(2)AR expression in neonatal brain regions with effects preferential to males. As the rat is an altricial species, these results during late gestation and the early neonatal period indicate that betaAR input modulates alpha(2)AR expression during developmental stages in which betaAR tocolytics are likely to be used. Disruption of alpha(2)AR expression and function may therefore contribute to adverse effects that have been noted in the offspring of pregnant women treated with terbutaline.
Kreider
Marisa L
ML
Department of Pharmacology & Cancer Biology, Duke University Medical Center, Box 3813 DUMC, Durham, NC 27710, USA.
Seidler
Frederic J
FJ
Slotkin
Theodore A
TA
D058647:Adrenergic alpha-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects* / Q000502:physiology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000096:biosynthesis / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D013726:Terbutaline / Q000633:toxicity*; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
D058647:Adrenergic alpha-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D018341:Receptors, Adrenergic, alpha-2; D011943:Receptors, Adrenergic, beta; D013726:Terbutaline