Teratogenicity as a consequence of drug-induced embryonic cardiac arrhythmia : Common mechanism for almokalant, sotalol, cisapride, and phenytoin via inhibition of IKr

• During the last years, drugs that prolong the repolarisation phase of the myocardial action potential, due to inhibition of the rapid component of the delayed-rectifying potassium channel (IKr) have been in focus. In addition to arrhythmogenic potential, selective Ikr-blockers have also been shown to be embryotoxic and teratogenic in animal studies. The aim of this thesis was to investigate a theory that these developmental toxic results from pharmacologically induced episodes of embryonic cardiac arrhythmias leading to hypoxia related damage in the embryo. Almokalant (ALM) was used as a model compound for selective Ikr-blockers. ALM induced embryonic cardiac arrhythmia, and in similarity with results obtained by maternal hypoxia, ALM induced embryonic death and growth retardation in both rats, and mice. The theory of a hypoxia-related mechanism was strengthened by the results that ALM induce phase specific external and visceral defects (e.g. cleft lip/palate, distal digital, cardiovascular, and urogenital defects), and that the skeletal defects (not shown before) showed a clear trend; the later the treatment the more caudal was the site of the defect, which is in accordance with results from maternal hypoxia induced by e.g. lowering of the O2 content in the air. The spin trapping agent PBN decreased almokalant induced malformations, suggesting that the defects mainly are caused by reoxygenation damage after episodes of severe embryonic dysrhythmia, rather than "pure hypoxia".Sotalol was tested in a third species, the rabbit who expresses functional IKr channels both in the embryo and in the adult, where it induced developmental toxicity, and indicating that the embryo is more sensitive than the adult towards arrhythmia caused by IKr-blockers.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)

Nyckelord

Pharmaceutical biosciences

IKr

delayed rectifying K+ channel

embryonic cardiac arrhythmia

teratogenicity

Farmaceutisk biovetenskap

Biopharmacy

Biofarmaci

Toxicology

toxikologi

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