The effects of tubulin-binding agents on stretch-induced ventricular arrhythmias

Stretch-activated ion channels have been identified as transducers of mecha noelectric coupling in the heart, where they may play a role in arrhythmoge nesis. The role of the cytoskeleton in ion channel control has been a topic of recent study and the transmission of mechanical stresses to stretch-act ivated channels by cytoskeletal attachment has been hypothesized. We studie d the arrhythmogenic effects of stretch in 16 Langendorff-perfused rabbit h earts in which we pharmacologically manipulated the microtubular network of the cardiac myocytes, Group 1 (n = 5) was treated with colchicine, which d epolymerizes microtubules, and Group 2 (n = 6) was treated with taxol, whic h polymerizes microtubules. Stretch-induced arrhythmias were produced by tr ansiently increasing the volume of a fluid-filled left ventricular balloon with a volume pump driven by a computer-controlled stepper motor. Electrica l events were recorded by a contact electrode which provided high-fidelity recordings of monophasic action potentials and stretch-induced depolarizati ons. The probability of eliciting a stretch-induced arrhythmia increased (0 .22 +/- 0.11 to 0.62 +/- 0.19, p = 0.001) in hearts treated with taxol (5 m uM), whereas hearts treated with colchicine (100 muM) showed no statistical ly significant change. We conclude that proliferation of microtubules incre ased the arrhythmogenic effect of transient left ventricle diastolic stretc h. This result indicates a possible mode of arrhythmogenesis in chemotherap eutic patients and patients exhibiting uncompensated ventricular hypertroph y. The data would indicate that the cytoskeleton represents a possible targ et for antiarrhythmic therapies. (C) 2001 Elsevier Science B.V. All rights reserved.