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Stage-specific skeletal and visceral defects of the I(Kr)-blocker almokalant: further evidence for teratogenicity via a hypoxia-related mechanism.
Teratology. 2001 Dec; 64(6):292-300.T

Abstract

BACKGROUND

As a class effect, potent I(Kr)-blockers have been shown to induce stage-specific external malformations. The aim of this study was to investigate whether I(Kr)-blockers also induce stage-specific visceral and skeletal defects and to further elucidate a proposed arrhythmia-hypoxia hypothesis.

METHODS

Single oral doses of the selective I(Kr)-blocker almokalant (ALM) 25-150 micromol/kg, 7-14 dams/group, were given to Sprague-Dawley rats on gestation days (GD) 10-14, and the fetuses were examined for malformations on GD 21. One group was pretreated with the spin-trapping agent, alpha-phenyl-N-t-butylnitrone (PBN), given intraperitoneally 1 hr before ALM on GD 11.

RESULTS

Cardiac ventricular septum defects and vascular malformations were observed after dosing on GD 10-11 and, to a lesser degree, on GD 12-13. Urogenital defects, absence/malposition of the postcaval lung lobe, and attenuated diaphragm were observed mainly on GD 10-11. Skeletal examination showed a high incidence of vertebral abnormalities on thoracic level on GD 10, on lower thoracic to caudal level on GD 11, and sternebral defects were observed all days. On GD 13 brachy-, oligo-, and syndactyly of the forepaw were induced, and of the hindpaw on GD 14. PBN reduced the incidence of both visceral and skeletal defects.

CONCLUSIONS

The stage specificity of observed visceral and skeletal defects correlates well with what has been reported in the literature after temporary interruption of oxygen supply during the same stages of development. The protective effect by PBN present further evidence that the teratogenicity of potent I(Kr)-blockers is related to induction of hypoxia- reoxygenation injury due to embryonic cardiac arrhythmia.

Authors+Show Affiliations

Department of Pharmaceutical Biosciences, Division of Toxicology, Uppsala University, Box 594, 5751 24 Uppsala, Sweden. anna-carin.skold@astrazeneca.comNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11754171

Citation

Sköld, A C., et al. "Stage-specific Skeletal and Visceral Defects of the I(Kr)-blocker Almokalant: Further Evidence for Teratogenicity Via a Hypoxia-related Mechanism." Teratology, vol. 64, no. 6, 2001, pp. 292-300.
Sköld AC, Wellfelt K, Danielsson BR. Stage-specific skeletal and visceral defects of the I(Kr)-blocker almokalant: further evidence for teratogenicity via a hypoxia-related mechanism. Teratology. 2001;64(6):292-300.
Sköld, A. C., Wellfelt, K., & Danielsson, B. R. (2001). Stage-specific skeletal and visceral defects of the I(Kr)-blocker almokalant: further evidence for teratogenicity via a hypoxia-related mechanism. Teratology, 64(6), 292-300.
Sköld AC, Wellfelt K, Danielsson BR. Stage-specific Skeletal and Visceral Defects of the I(Kr)-blocker Almokalant: Further Evidence for Teratogenicity Via a Hypoxia-related Mechanism. Teratology. 2001;64(6):292-300. PubMed PMID: 11754171.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Stage-specific skeletal and visceral defects of the I(Kr)-blocker almokalant: further evidence for teratogenicity via a hypoxia-related mechanism. AU - Sköld,A C, AU - Wellfelt,K, AU - Danielsson,B R, PY - 2001/12/26/pubmed PY - 2002/2/28/medline PY - 2001/12/26/entrez SP - 292 EP - 300 JF - Teratology JO - Teratology VL - 64 IS - 6 N2 - BACKGROUND: As a class effect, potent I(Kr)-blockers have been shown to induce stage-specific external malformations. The aim of this study was to investigate whether I(Kr)-blockers also induce stage-specific visceral and skeletal defects and to further elucidate a proposed arrhythmia-hypoxia hypothesis. METHODS: Single oral doses of the selective I(Kr)-blocker almokalant (ALM) 25-150 micromol/kg, 7-14 dams/group, were given to Sprague-Dawley rats on gestation days (GD) 10-14, and the fetuses were examined for malformations on GD 21. One group was pretreated with the spin-trapping agent, alpha-phenyl-N-t-butylnitrone (PBN), given intraperitoneally 1 hr before ALM on GD 11. RESULTS: Cardiac ventricular septum defects and vascular malformations were observed after dosing on GD 10-11 and, to a lesser degree, on GD 12-13. Urogenital defects, absence/malposition of the postcaval lung lobe, and attenuated diaphragm were observed mainly on GD 10-11. Skeletal examination showed a high incidence of vertebral abnormalities on thoracic level on GD 10, on lower thoracic to caudal level on GD 11, and sternebral defects were observed all days. On GD 13 brachy-, oligo-, and syndactyly of the forepaw were induced, and of the hindpaw on GD 14. PBN reduced the incidence of both visceral and skeletal defects. CONCLUSIONS: The stage specificity of observed visceral and skeletal defects correlates well with what has been reported in the literature after temporary interruption of oxygen supply during the same stages of development. The protective effect by PBN present further evidence that the teratogenicity of potent I(Kr)-blockers is related to induction of hypoxia- reoxygenation injury due to embryonic cardiac arrhythmia. SN - 0040-3709 UR - https://www.unboundmedicine.com/medline/citation/11754171/Stage_specific_skeletal_and_visceral_defects_of_the_I_Kr__blocker_almokalant:_further_evidence_for_teratogenicity_via_a_hypoxia_related_mechanism_ L2 - https://doi.org/10.1002/tera.1084 DB - PRIME DP - Unbound Medicine ER -