The lack of toxicity of potassium channel activators in heart cell cultures

High doses of the potassium channel activators (KCAs) BRL 44269, levcromakalin and pinacidil in a number of laboratory animal species cause a profound reduction in blood pressure which results in reflex tachycardia, ischaemia and myocardial necrosis. Thus, it is considered that the in vivo cardiac pathology seen with KCAs is an indirect effect as a consequence of excessive pharmacological effects rather than direct myocardial toxicity. This hypothesis was tested, in vitro, in the chick embryonic myocardial myocyte reaggregate (MMR) model system. Changes in spontaneous beating activity (SBA), leakage of lactate dehydrogenase (LDH) and cell morphology by light and transmission electron microscopy were used to assess toxicity. The MMRs were cultured for up to 24 hr in a series of different concentrations of the three KCAs in the range 1-10,000 mu M. In addition to an untreated control, allylamine (50 mu M), a known direct acting myocardial cytotoxin, was used as a positive control. Incubation with allylamine caused clear evidence of toxicity and permanent cessation of SBA. In contrast, KCAs caused changes in SBA and significant toxicity was only seen at the highest concentration (10,000 mu M) of BRL 44269. These results are supportive of the view that KCA-induced cardiac pathology in vivo is due to an indirect pharmacological action rather than a direct, cytotoxic mechanism.