Heart rate changes mediate the embryotoxic effect of antiarrhythmic drugs in the chick embryo

0396918 - FGÚ 2014 RIV US eng J - Journal Article
Kočková, Radka - Svatůňková, Jarmila - Novotný, J. - Hejnová, L. - Ošťádal, Bohuslav - Sedmera, David
Heart rate changes mediate the embryotoxic effect of antiarrhythmic drugs in the chick embryo.
American Journal of Physiology-Heart and Circulatory Physiology. Roč. 304, č. 6 (2013), H895-H902. ISSN 0363-6135. E-ISSN 1522-1539
R&D Projects: GA ČR(CZ) GAP302/11/1308; GA ČR(CZ) GA304/08/0615
Institutional research plan: CEZ:AV0Z50110509
Institutional support: RVO:67985823
Keywords : beta-blocking agents * embryonic heart * embryotoxicity * pregnancy * bradycardia
Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery
Impact factor: 4.012, year: 2013

A significant increase in cardiovascular medication use during pregnancy occurred in recent years. Only limited evidence on safety profiles is available, and little is known about the mechanisms of adverse effect on the fetus. We hypothesized that drug-induced bradycardia is the leading mechanism of developmental toxicity. Embryotoxicity was tested in ovo after administration of various doses of metoprolol, carvedilol, or ivabradine. Embryonic day (ED) 4 and 8 chick embryos were studied by video microscopy and ultrasound biomicroscopy ex ovo after intraamniotic injection of the drug for a period of 30 min. Stroke volume was calculated by the Simpson method and prolate ellipsoid formula. Significant dose-dependent mortality was achieved in embryos injected with carvedilol and ivabradine. In ED4 embryos, metoprolol, carvedilol, and ivabradine reduced the heart rate by 33%, 27%, and 55%, respectively, compared with controls (6%). In ED8 embryos this effect was more pronounced with a heart rate reduction by 71%, 54%, and 53%, respectively (controls, 36%). Cardiac output decreased in all tested groups but only proved significant in the metoprolol group in ED8 embryos. The number of beta-adrenergic receptors showed a downward tendency during embryonic development. A negative chronotropic effect of metoprolol, carvedilol, and ivabradine was increasingly pronounced with embryonic maturity despite a downward trend in the number of beta-adrenergic receptors. This effect was associated with reduced cardiac output in chick embryos, probably leading to premature death. Although standard doses of these drugs appear relatively safe, high doses have a potentially adverse effect on the fetus through reduced heart rate
Permanent Link: http://hdl.handle.net/11104/0224628