Suppressive Effects of Bay K 8644 on Toxicity of Calcium Channel Blockers in Cultured Rat Embryos

Previous study revealed that calcium channel blockers (CCBs)reduced embryonic heart rates (HRs) and produced morphologicalabnormalities when Gestational Day (GD) 11.5 rat embryos werecultured for 20 hr. The present study was to investigate whethera calcium channel agonist, Bay K 8644 (BAY), prevented CCB-inducedembryotoxicity in vitro. GD 11.5 embryos were exposed to nifedipine(NIF), diltiazem (DIL), and verapamil (VER) either alone orin combination with BAY at 0.1, 1.0, and 10 µg/ml. Thesedoses of BAY alone had no effect on gross morphology. EmbryonicHRs were increased at 10 µg/ml of BAY, but were withincontrol levels at 0.1 and 1.0 µg/ml. The doses of NIF,DIL, and VER were 40, 6.0, and 2.0 µg/ml, respectively,and were the minimum concentrations to produce a 100% effecton morphological abnormalities. Embryonic HRs were reduced to22, 31, and 34% below control levels in the NIF, DIL, and VERgroups, respectively. The negative chronotropic effects of CCBswere inhibited by coadministration with BAY, depending on itsconcentration. When embryos exposed to each CCB were supplementedwith BAY at 1.0 or 10 µg/ml, embryonic HRs were comparableto those of controls. Combined exposures of each CCB and 10µg/mlBAY did not cause any morphological abnormalities. These resultssuggested that mechanisms of CCB embryotoxicity were directlyrelated to pharmacological consequences of calcium channel blockagein developing rats.