© 1996 Oxford University Press
research-article |
Suppressive Effects of Bay K 8644 on Toxicity of Calcium Channel Blockers in Cultured Rat Embryos
*Development Research Laboratories, Banyu Pharmaceutical Co., Ltd. 810 Nishijo, Menuma-machi, Osato-gun, Saitama 360-02, Japan
Department of Veterinary Anatomy, Yamaguchi University 1677-1 Yoshida, Yamaguchi-shi, Yamaguchi 753, Japan
Received March 21, 1996; accepted August 14, 1996
Previous study revealed that calcium channel blockers (CCBs) reduced embryonic heart rates (HRs) and produced morphological abnormalities when Gestational Day (GD) 11.5 rat embryos were cultured for 20 hr. The present study was to investigate whether a calcium channel agonist, Bay K 8644 (BAY), prevented CCB-induced embryotoxicity in vitro. GD 11.5 embryos were exposed to nifedipine (NIF), diltiazem (DIL), and verapamil (VER) either alone or in combination with BAY at 0.1, 1.0, and 10 µg/ml. These doses of BAY alone had no effect on gross morphology. Embryonic HRs were increased at 10 µg/ml of BAY, but were within control 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% effect on morphological abnormalities. Embryonic HRs were reduced to 22, 31, and 34% below control levels in the NIF, DIL, and VER groups, respectively. The negative chronotropic effects of CCBs were inhibited by coadministration with BAY, depending on its concentration. When embryos exposed to each CCB were supplemented with BAY at 1.0 or 10 µg/ml, embryonic HRs were comparable to those of controls. Combined exposures of each CCB and 10µg/ml BAY did not cause any morphological abnormalities. These results suggested that mechanisms of CCB embryotoxicity were directly related to pharmacological consequences of calcium channel blockage in developing rats.