Impaired tissue clearance of verapamil in rat cardiac hypertrophy results in transcriptional repression of ion channels

Abstract

Heart hypertrophy is a common cardiac complication of sustained arterial hypertension and is accompanied by an increased incidence of supraventricular tachyarrhythmia, such as atrial fibrillation and atrial flutter. Verapamil, a phenyalkylamine, belongs to the group of calcium channel antagonists (class IV antiarrhythmic drugs) and is frequently used for the management of supraventricular tachycardia and for ventricular rate control in atrial fibrillation and atrial flutter. Verapamil heart tissue and plasma levels after intraperitoneal dosing of spontaneously hypertensive and normotensive rats were investigated. Transcript expression of various ion channels, ion transporters, calcium handling, and cytoskeletal proteins by reverse transcriptase-polymerase chain reaction (RT-PCR) were further investigated. There was no difference in plasma pharmacokinetics when hypertensive and normotensive animals were compared. Strikingly, the tissue clearance of verapamil was highly significantly impaired in heart tissue of hypertensive animals. Gene expression analysis showed the repression of many cardiac-specific genes in spontaneously hypertensive but not in normotensive rats, therefore providing evidence for different modes of action in healthy and hypertrophic hearts. Verapamil heart tissue levels differed dramatically between normotensive and hypertensive rats and resulted in repression of many cardiac ion channels, ion transporters, and calcium handling proteins. A disturbed ion homeostasis induced by critical tissue levels of verapamil is therefore proposed as a molecular rational for its pro-arrhythmogenic activity. The observed changes can be a significant determinant of spatial electrophysiological heterogeneity, thereby contributing to increased conductance disturbance as observed with some patients.