CARDIOSTIMULATORY AND ANTIARRHYTHMIC ACTIVITY OF TUBULIN-BINDING AGENTS

Rhythmic, spontaneously pulsating cardiac cells cultured from newborn rats are immediately stimulated to beat faster by addition of a number of tubulin-binding agents but not by their non-tubulin-binding analogues. The tubulin-binding agents tested include vinblastine, vincristine, navel-bine, two analogs of vinblastine (S12362 and S12363), nocodazole, colchicine, and podophyllotoxin. In addition to binding tubulin, all of the above agents also depolymerize microtubules. In contrast, taxol, a tubulin-binding agent that stabilizes microtubules, does not stimulate cardiac cells. Moreover, the immediate and ensuing cardiac stimulation by vinblastine at 0.05-mu-g/ml is completely blocked by pre- and cotreatment with taxol at 1.0-mu-g/ml. The time necessary to reverse the cardio-stimulatory effect of vinblastine is significantly longer than that required for nocodazole, further implicating depolymerization of microtubules in the cardiac activity of these agents. All of the tubulin-binding agents tested (including taxol) also immediately reverse adriamycin-induced arrhythmias. By using a monoclonal antibody to alpha-tubulin, typical filamentous microtubules are visualized in cardiac muscle and cocultured non-muscle cells by immunofluorescence. When cells are treated for 2 hr with vinblastine at 0.05-mu-g/ml, fluorescence is detected in cross-striated patterns in cardiac muscle cells. Overall, these data open the possibility of uncovering an additional relationship between cytoskeletal elements (other than actin and myosin) and the contractility of cardiac muscle. They also suggest an alternative mechanism for affecting cardiac cell function in vitro (namely, by tubulin-binding agents). If these agents are shown to be cardioactive in vivo, they may provide another approach to the treatment and management of cardiac arrhythmias.