ON THE CARDIAC CONTRACTILE, BIOCHEMICAL AND ELECTROPHYSIOLOGICAL EFFECTS OF CANTHARIDIN, A PHOSPHATASE INHIBITOR

Cantharidin concentration dependently increased the force of contracti on in isolated guinea pig papillary muscles (1-100 mu M). The positive inotropic effect is accompanied by a reduction in time to peak tensio n and relaxation time. Cantharidin did not exert a positive chronotrop ic effect in spontaneously beating right atria, L-type calcium channel currents of guinea pig cardiomyocytes were moderately increased by ca ntharidin (by about 20%), both at the whole-cell level (2 mM Ca2+) and at the single channel level (70 mM Ba2+). There was a correspondingly small increment of single channel availability, Additionally, a large r proportion of single-channel sweeps displayed high open probability- gating (so-called mode 2-gating). Cantharidin inhibited both type 1 an d type 2A phosphatase activity in phosphatases purified from guinea pi g ventricles [IC50 2.70 (2.06-3.53) and 0.13 (0.05-0.34) mu M, n = 5-6 , With 95% confidence intervals, respectively]. In isolated [P-32]-lab eled guinea pig ventricular cardiomyocytes, cantharidin (10 mu M) incr eased the phosphorylation state of phospholamban (to 210% of control), the inhibitory subunit of troponin (to 155% of control), C-protein (t o 156% control) and various additional proteins. It is concluded that the effects of cantharidin are likely mediated by increasing the phosp horylation state of several regulatory proteins. Furthermore, canthari din might be an economical tool to investigate the function of phospha tases in model organ systems.