Review
Embryonic cardiac arrhythmia and generation of reactive oxygen species: Common teratogenic mechanism for IKr blocking drugs

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Abstract

In the adult organism, it is well established that hypoxia followed by reperfusion may be fatal and result in generation of reactive oxygen species (ROS) and subsequent tissue damage. There is also considerable evidence that temporary decrease or interruption in oxygen supply to the embryo and ROS generation during reperfusion result in tissue damage in embryonic tissues. A wide spectrum of different malformations by transient embryonic hypoxia could be produced, depending on the duration, extent, and timing of the hypoxic event. It is the contention of this paper that drugs that block the potassium channel IKr, either as an intended pharmacologic effect or as an unwanted side-effect, are potentially teratogenic by a common ROS related mechanism. Drugs blocking the IKr channel, such as almokalant, dofetilide, phenytoin, cisapride and astemizole, do all produce a similar pattern of hypoxia-related malformations. Mechanistic studies show that the malformations are preceded by embryonic cardiac arrhythmia and periods of hypoxia/reoxygenation in embryonic tissues. Pretreatment or simultaneous treatment with radical scavengers with capacity to capture ROS, markedly decrease the teratogenicity of different IKr blocking drugs. A second aim of this review is to demonstrate that the conventional design of teratology studies is not optimal to detect malformations caused by IKr blocking drugs. Repeated high doses result in high incidences of embryonic death due embryonic cardiac arrhythmia, thus masking their teratogenic potential. Instead, single dosing on specific days is proposed to be a better way to characterize the teratogenic potential of Ikr blocking drugs.

Introduction

It is well established that hypoxia followed by reperfusion may be fatal and result in generation of reactive oxygen species (ROS) and subsequent tissue damage in the adult organism. Well-known conditions include temporary interruption of oxygen supply to different organs due to myocardial infarction, circulatory collapse and stroke [1]. In the same way, there is considerable evidence that temporary decrease or interruption in oxygen supply to the embryo and ROS generation during reperfusion result in tissue damage in embryonic tissues. A wide spectrum of different malformations by transient embryonic hypoxia could be produced, depending on the duration, extent and timing of the hypoxic event. The main aim of this review is to present data showing that drugs blocking the rapid component of the delayed rectifying potassium current (IKr) of the heart, cause malformations in animal models by a common hypoxia/reoxygenation mechanism, which involve ROS generation. The IKr channel, expressed by the human ether-a-go-gene (hERG), is the primary ion channel involved in cardiac repolarisation and is of major importance for heart rhythm regulation across species in embryonic life. Drugs blocking the IKr channel cause in a dose dependent manner irregular embryonic rhythm and periods of hypoxia/reoxygenation in embryonic tissues. There are also several studies showing that pre-treatment or simultaneous treatment with radical scavengers, with capacity to capture ROS, markedly decrease the teratogenicity of different IKr blocking drugs. A second aim of this review is to demonstrate that the conventional design of teratology studies is not optimal to detect malformations caused by IKr blocking drugs. Repeated high doses of the drug during organogenesis result in high incidences of embryonic death due to embryonic cardiac arrhythmia, thus, masking the teratogenic potential of the drug. Instead, single dosing on a day of susceptibility to stage specific malformations is proposed to be a better way to characterize the teratogenic potential of drugs with IKr blocking properties.

Section snippets

Hypoxia, ROS generation, embryonic tissue damage and teratogenicity

Hypoxia (lack of oxygen in tissues) followed by reoxygenation (reintroduction of oxygen in hypoxic tissues) was one of the first teratogenic stimuli to be identified and studied, and numerous experimental studies in mice, rats and rabbits have been conducted (for review see [2]). Examples of how to obtain temporary embryonic hypoxia is (1) by reducing the oxygen tension in the air for a period or by (2) mechanically clamp the uterine blood vessels leading to impaired uteroplacental blood flow

Pharmacological effects of class III antiarrhythmics on the adult and embryonic heart

Class III antiarrhythmic drugs as a desired effect prolong the duration of the action potential in adult cardiac myocytes by inhibiting the rapid component of the delayed rectifying potassium channel, IKr [21]. The result is a lengthening of the effective refractory period with associated antiarrhythmic activity. The effects of these drugs on myocardial cells manifest themselves as a prolongation of the QT interval (corrected QT interval) on the surface ECG. The QT prolongation can result in

Phenytoin: Pharmacological action and effects on the adult and embryonic heart

The antiepileptic drug phenytoin (PHT) is pharmacologically active by stabilizing membranes of excitable cells, like neurons and cardiac cells. This occurs via interference with especially voltage dependent sodium (Na+) currents, but also calcium (Ca2+) and potassium (K+) ion channels are involved in action potential propagation or burst generation [49]. Recently it has been shown that phenytoin also inhibit IKr specifically at clinically relevant concentrations [50].

PHT has arrhythmogenic

Evidence for a common teratogenic mechanism for IKr blocking drugs

Altogether, conducted animal studies give evidence for a common teratogenic mechanism of a variety of different IKr channel blocking drugs (class III antiarrythmics, phenytoin, dimethadione, cisapride and astemizole). The results indicate that the teratogenic effect is mediated via IKr related embryonic cardiac rhythm disturbances, periods of embryonic hypoxia followed by reoxygenation and ROS generation. In summary, this conclusion is based on:

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    the very similar pattern of stage specific of

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