The Lack of Toxicity of Potassium ChannelActivators in Heart Cell Cultures

Area of Science:

• Pharmacology
• Cardiovascular Toxicology
• Cell Biology

Background:

• Potassium channel activators (KCAs) like BRL 44269, levcromakalin, and pinacidil can induce significant hypotension and subsequent cardiac pathology in animal models.
• The prevailing hypothesis suggests that KCA-induced in vivo cardiac issues stem from excessive pharmacological effects (e.g., reflex tachycardia, ischemia) rather than direct myocardial toxicity.

Purpose of the Study:

• To investigate the in vitro cardiotoxicity of KCAs using a chick embryonic myocardial myocyte reaggregate (MMR) model.
• To differentiate between direct cytotoxic effects and indirect pharmacological mechanisms contributing to KCA-induced cardiac pathology.

Main Methods:

• Chick embryonic MMRs were exposed to varying concentrations of BRL 44269, levcromakalin, and pinacidil for up to 24 hours.
• Assays included monitoring spontaneous beating activity (SBA), lactate dehydrogenase (LDH) leakage, and cell morphology via light and transmission electron microscopy.
• Allylamine, a known myocardial cytotoxin, served as a positive control.

Main Results:

• Allylamine exposure resulted in significant toxicity and irreversible cessation of SBA, validating the model.
• KCAs induced alterations in SBA, with significant toxicity observed only at a very high concentration (10,000 μM) of BRL 44269.
• No substantial direct cytotoxic effects were evident for KCAs at relevant concentrations.

Conclusions:

• The in vitro findings support the hypothesis that KCA-induced cardiac pathology in vivo is primarily an indirect consequence of their potent pharmacological actions.
• KCAs do not appear to possess direct myocardial cytotoxic properties, suggesting that observed cardiac damage in animal studies is secondary to hemodynamic changes.