The effects of tubulin-binding agents on stretch-induced ventricular arrhythmias.
Stretch-activated ion channels have been identified as transducers of mechanoelectric coupling in the heart, where they may play a role in arrhythmogenesis. The role of the cytoskeleton in ion channel control has been a topic of recent study and the transmission of mechanical stresses to stretch-activated channels by cytoskeletal attachment has been hypothesized. We studied the arrhythmogenic effects of stretch in 16 Langendorff-perfused rabbit hearts in which we pharmacologically manipulated the microtubular network of the cardiac myocytes. Group 1 (n=5) was treated with colchicine, which depolymerizes microtubules, and Group 2 (n=6) was treated with taxol, which polymerizes microtubules. Stretch-induced arrhythmias were produced by transiently increasing the volume of a fluid-filled left ventricular balloon with a volume pump driven by a computer-controlled stepper motor. Electrical events were recorded by a contact electrode which provided high-fidelity recordings of monophasic action potentials and stretch-induced depolarizations. 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 microM), whereas hearts treated with colchicine (100 microM) showed no statistically significant change. We conclude that proliferation of microtubules increased the arrhythmogenic effect of transient left ventricle diastolic stretch. This result indicates a possible mode of arrhythmogenesis in chemotherapeutic patients and patients exhibiting uncompensated ventricular hypertrophy. The data would indicate that the cytoskeleton represents a possible target for antiarrhythmic therapies.
Parker
K K
KK
Living State Physics Group, Department of Physics and Astronomy, Vanderbilt University, Box 1807 Station B, Nashville, TN 37235, USA.
Taylor
L K
LK
Atkinson
J B
JB
Hansen
D E
DE
Wikswo
J P
JP
Atkinson
B
B
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology*; D003078:Colchicine / Q000378:metabolism / Q000494:pharmacology*; D006352:Heart Ventricles / Q000503:physiopathology; D006439:Hemodynamics / Q000502:physiology; D066298:In Vitro Techniques; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011817:Rabbits; D013314:Stress, Mechanical; D014404:Tubulin / Q000378:metabolism*; D018754:Ventricular Dysfunction / Q000209:etiology / Q000503:physiopathology*
D014404:Tubulin; D017239:Paclitaxel; D003078:Colchicine