J. Neumann et al., ON THE CARDIAC CONTRACTILE, BIOCHEMICAL AND ELECTROPHYSIOLOGICAL EFFECTS OF CANTHARIDIN, A PHOSPHATASE INHIBITOR, The Journal of pharmacology and experimental therapeutics, 274(1), 1995, pp. 530-539
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.