Effects of calcium channel blockers on the development of early rat postimplantation embryos in culture

Abstract

Rat embryos (9.5-day-old) were cultured for 48 h in the presence of nifedipine (NIF), nimodipine (NIM), nitrendipine (NIT), gallopamil HCl (GAL), verapamil HCl (VER) and diltiazem HCl (DIL). The effects on growth and morphogenetic differentiation in vitro were monitored. Dose-response relationships were evaluated, including an assessment of the "no-observed-effect-level" (NOEL) or the "lowest-observed-effect-level" (LOEL), and the lowest concentration tested inducing abnormalities in 100% of the embryos ("100% EL"). The morphological alterations observed at the highest concentrations were very similar for all six drugs. The abnormalities concerned yolk sac circulation and morphology, as well as heartbeat, the morphology of the heart, head, neural tube, or forelimbs, and the shape of the embryo. The abnormal embryos were also growth retarded (decrease in protein content and crown-rump length). Interference with calcium channel functions seems to represent an interesting model for studying a special kind of abnormal prenatal development, especially the differentiation of certain mesenchymal structures. The concentration ranges between NOELs and 100% ELs were found to be: NIM = 0.1-1 microgram/ml; NIT and VER = 1-10 micrograms/ml; DIL = 1-30 micrograms/ml, and LOELs-100% ELs were: GAL = 1-10 micrograms/ml; NIF = 10-30 micrograms/ml.

Calcium Channel Blockade in Embryonic Cardiac Progenitor Cells Disrupts Normal Cardiac Cell Differentiation

“…Cultured mouse embryos exposed to L-type channel blockade at later stages than we addressed here, embryonic day 7.5 and older, displayed abnormal cardiac looping, gene expression, and organ development that may relate to effects also on later differentiation, possibly of the second heart field, as well as heart function [23,24]. Similarly, Ca channel blockers also were shown in cultured postimplantation rat embryos to induce morphological anomalies of the heart, head, neural tube, and forelimb [25].…”

A Calcium Agonist, Bay k 8644, Suppresses the Embryotoxic Effects Induced by Dihydropyridines Calcium Channel Blockers in Cultured Rat Embryos.

“…The dysmorphogenic features predominantly consisted of alteration in the yolk sac and embryonic circulation, enlargement of the cardiac tube or pericardium, craniofacial abnormalities and irregular neural tube. Stein et al [23] examined embryotoxicities of six calcium channel blockers, including NIF and NIT, and suggested that breakdown of yolk sac circulation may drastically affect embryonic development.…”

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

“…Our results indicated that calcium channels were instrumental in controlling preinnervation heartbeats and were functioning at this stage of development (GD 11 to 12) in rat. Stein et al (1990) reported that CCBs affected the yolk sac circulation and embryonic development when rat embryos were cultured with the compounds from GD 9.5 for 48 hr. Our findings were in good agreement with those of Stein's study, although the embryonic ages tested were different.…”

“…They also suggested that the digital defects were attributable to maternal and fetal vascular disruptions, which result in a decreased oxygen supply to embryonic/fetal tissue (Danielsson ex al, 1992). Stein et al (1990) found effects of CCBs on embryonic development, particularly on the yolk sac circulation, when rat embryos were cultured with the compounds from Gestation Day (GD) 9.5 for 48 hr. They speculated that the malfunction of the yolk sac circulation might affect embryonic development and that these effects were probably due to the calcium channel blocking properties.…”