title: The effect on rat embryonic heart rate of Na+, K+, and Ca2+ channel blockers, and the human teratogen phenytoin, changes with gestational age.
abstract: In this study, we compared the effects of four ion channel blockers on rat embryonic heart function during the organogenic period from gestational day (GD) 10 to 15, to determine the changes in dependence on ion channels during rat cardiac development. Rat embryos in culture were exposed to either the human ether-á-go-go-related gene potassium channel blocker, dofetilide (400 nM); the sodium channel blocker, lidocaine (250 μM); the L-type calcium channel blocker, nifedipine (1.8 μM); or the multichannel blocker, phenytoin (200 μM). Lidocaine slowed the heart rate (HR) with the effect becoming more severe with increasing GD. Dofetilide slowed the embryonic HR and caused arrhythmias with the most severe effect on GD 11 to 13. Nifedipine primarily caused a negative inotropic effect except on GD 10 when it stopped the heart in most embryos. Phenytoin stopped the heart of most GD 10 to 12 embryos while on GD 13 to 15 phenytoin slowed the heart. The results demonstrate that as the rat heart develops during the organogenic period its functional dependence on ion channels changes markedly. These changes are important for understanding drug effects on the embryo during pregnancy and the methodology used provides a simple procedure for assessing drug effects on the developing heart.
authors: Drug Safety and Toxicology, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors: Mats F
authors: MF
authors: Nilsson
authors: Helen
authors: H
authors: Ritchie
authors: William S
authors: WS
authors: Webster
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000633:toxicity*; D005260:Female; D005865:Gestational Age; D006340:Heart Rate, Fetal / Q000187:drug effects*; D008012:Lidocaine / Q000633:toxicity; D009543:Nifedipine / Q000633:toxicity; D010627:Phenethylamines / Q000633:toxicity; D010672:Phenytoin / Q000633:toxicity*; D026902:Potassium Channel Blockers / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000633:toxicity*; D013449:Sulfonamides / Q000633:toxicity
chemical_list: D002121:Calcium Channel Blockers; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D026941:Sodium Channel Blockers; D013449:Sulfonamides; D010672:Phenytoin; D008012:Lidocaine; D009543:Nifedipine; C063533:dofetilide
keywords: embryo/fetal physiology; in vitro screens; pharmaceuticals; teratogenicity