The effect of drugs with ion channel-blocking activity on the early embryonic rat heart.
This study investigated the effects of a range of pharmaceutical drugs with ion channel-blocking activity on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the blockade of the I(Kr)/hERG channel, that is highly important for the normal functioning of the embryonic rat heart, would cause bradycardia and arrhythmia. Concomitant blockade of other channels was expected to modify the effects of hERG blockade. Fourteen drugs with varying degrees of specificity and affinity toward potassium, sodium, and calcium channels were tested over a range of concentrations. The rat embryos were maintained for 2 hr in culture, 1 hr to acclimatize, and 1 hr to test the effect of the drug. All the drugs caused a concentration-dependent bradycardia except nifedipine, which primarily caused a negative inotropic effect eventually stopping the heart. A number of drugs induced arrhythmias and these appeared to be related to either sodium channel blockade, which resulted in a double atrial beat for each ventricular beat, or I(Kr)/hERG blockade, which caused irregular atrial and ventricular beats. However, it is difficult to make a precise prediction of the effect of a drug on the embryonic heart just by looking at the polypharmacological action on ion channels. The results indicate that the use of the tested drugs during pregnancy could potentially damage the embryo by causing periods of hypoxia. In general, the effects on the embryonic heart were only seen at concentrations greater than those likely to occur with normal therapeutic dosing.
Abela
Dominique
D
Department of Anatomy and Histology, Sydney Medical School, University of Sydney, Sydney, Australia.
Ritchie
Helen
H
Ababneh
Deena
D
Gavin
Caroline
C
Nilsson
Mats F
MF
Khan
Muhammad Khalid
MK
Carlsson
Kristin
K
Webster
William S
WS
D000014:Abnormalities, Drug-Induced; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D001919:Bradycardia / Q000139:chemically induced / Q000196:embryology; D046149:Embryo Culture Techniques; D005260:Female; D006321:Heart / Q000187:drug effects / Q000196:embryology* / Q000503:physiopathology*; D000860:Hypoxia / Q000139:chemically induced / Q000196:embryology; D008297:Male; D010672:Phenytoin / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000009:adverse effects*; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects; D011247:Pregnancy; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D010672:Phenytoin