Abstract
Concentration-Dependent Effects of Tetrodotoxin in Function of Adult Rat and Rabbit Heart
Highlights
Voltage-gated sodium channels (Navs) govern many aspects of cardiac excitability, including the depolarization of atrial and ventricular myocytes and the propagation of excitation from sinoatrial node (SAN)
In rat we find a major role for TTX-R channels in heart rate (HR) and left ventricular contractility (LVC)
ECG was recorded from unpaced, spontaneously beating hearts for a total of 20 minutes from each concentration, and parameters including HR, PR interval, QRS duration, and QT interval were measured continuously. From these parameters QTc interval (QT interval corrected for heart rate), JT interval (QT - QRS, the duration of ventricular repolarization), and JTc (JT corrected for heart rate) were calculated
Summary
Voltage-gated sodium channels (Navs) govern many aspects of cardiac excitability, including the depolarization of atrial and ventricular myocytes and the propagation of excitation from sinoatrial node (SAN). There are nine isoforms of sodium channel alpha subunits, Nav1.1 through Nav1.9, and these show differences in tissue distribution, biophysical properties, physiological roles, and pharmacology [1,2]. Several sodium channels are expressed in the heart and show differential patterns of expression, and recent work suggests isoform-specific physiological roles. Roles for Nav1.5 at the whole-heart level have not been tested pharmacologically, likely due to the experimental requirement for large amounts of TTX. Immunofluorescence, transcript localization, and some functional measurements at the cellular and whole-heart level suggest a role for TTX-S sodium channels in cardiac function. Mechanistic understanding of the roles of different sodium channels among species is important from the drug discovery point of view, to define cardiac selectivity hurdles and appropriate preclinical species for safety testing.
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