title: Comparative effects of sodium channel blockers in short term rat whole embryo culture.
abstract: This study was undertaken to examine the effect on the rat embryonic heart of two experimental drugs (AZA and AZB) which are known to block the sodium channel Nav1.5, the hERG potassium channel and the l-type calcium channel. The sodium channel blockers bupivacaine, lidocaine, and the l-type calcium channel blocker nifedipine were used as reference substances. The experimental model was the gestational day (GD) 13 rat embryo cultured in vitro. In this model the embryonic heart activity can be directly observed, recorded and analyzed using computer assisted image analysis as it responds to the addition of test drugs. The effect on the heart was studied for a range of concentrations and for a duration up to 3h. The results showed that AZA and AZB caused a concentration-dependent bradycardia of the embryonic heart and at high concentrations heart block. These effects were reversible on washout. In terms of potency to cause bradycardia the compounds were ranked AZB>bupivacaine>AZA>lidocaine>nifedipine. Comparison with results from previous studies with more specific ion channel blockers suggests that the primary effect of AZA and AZB was sodium channel blockage. The study shows that the short-term rat whole embryo culture (WEC) is a suitable system to detect substances hazardous to the embryonic heart.
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Sweden. Electronic address: Mats.Nilsson@farmbio.uu.se.
authors.forename: Mats F
authors.initials: MF
authors.lastname: Nilsson
authors.forename: Anna-Carin
authors.initials: AC
authors.lastname: Sköld
authors.forename: Ann-Christin
authors.initials: AC
authors.lastname: Ericson
authors.forename: Anita
authors.initials: A
authors.lastname: Annas
authors.forename: Rodrigo Palma
authors.initials: RP
authors.lastname: Villar
authors.forename: Gvido
authors.initials: G
authors.lastname: Cebers
authors.forename: Heike
authors.initials: H
authors.lastname: Hellmold
authors.forename: Anne-Lee
authors.initials: AL
authors.lastname: Gustafson
authors.forename: William S
authors.initials: WS
authors.lastname: Webster
mesh_terms: D000818:Animals; D001919:Bradycardia / Q000139:chemically induced* / Q000196:embryology; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000633:toxicity*; D006321:Heart / Q000187:drug effects* / Q000196:embryology*; D006327:Heart Block / Q000139:chemically induced* / Q000196:embryology; D006339:Heart Rate / Q000187:drug effects; D007091:Image Processing, Computer-Assisted; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors
chemical_list: D002121:Calcium Channel Blockers; D015507:Drugs, Investigational; D062554:NAV1.5 Voltage-Gated Sodium Channel; D026941:Sodium Channel Blockers
keywords: Cardiac function; Drugs during pregnancy; Embryonic physiology; Hazard identification; Sodium channel blocker