Effects of cantharidin on force of contraction and phosphatase activity in nonfailing and failing human hearts

Abstract

1 The effect of the phosphatase inhibitor, cantharidin (3-300 jgM) on force of contraction was studied in isolated electrically driven right ventricular trabeculae carneae from human myocardium. 2 The positive inotropic effect of cantharidin started at a concentration of 100 jgM with a positive inotropic effect to 199% and to 276% of the predrug value in nonfailing and failing human hearts, respectively. 3 Under basal conditions the contraction time parameters were prolonged in human heart failure vs. nonfailing preparations. However, the positive inotropic effect of cantharidin did not affect contraction time parameters. Thus, time to peak tension, time of relaxation and total contraction time were not shortened by cantharidin in nonfailing and failing preparations. 4 The phosphatase activity was unchanged in preparations from failing hearts compared to nonfailing hearts.5 Cantharidin inhibited phosphatase activity in a concentration-dependent manner. The IC5o value of cantharidin was about 3 jgM in both nonfailing and failing human myocardium. 6 The positive inotropic effect of cantharidin was similar in nonfailing and failing human hearts, accompanied by a similar inhibitory effect of cantharidin on the phosphatase activity. The positive inotropic effect of cantharidin in failing hearts was as strong as the effect of isoprenaline in nonfailing hearts. 7 It is concluded that the treatment with a phosphatase inhibitor may offer a new positive inotropic modality for the treatment of human heart failure.

On the contractile function of protein phosphatases in isolated human coronary arteries

“…It is noteworthy that PP inhibition occurs at lower concentrations of cantharidin than the physiological response. Nevertheless, the difference between IC 50 values for phosphatase activity and the EC 50 values in respect of functional studies is a wellknown behavior for PP inhibitors and probably due to permeability problems, compartmentalization of PP and/or the absence of kinase activity in the PP assay counteracting PP inhibition as assumed before (myocardium: Linck et al 1996;vasculature: Knapp et al 1997vasculature: Knapp et al , 1999.…”

Molecular Mechanisms Underlying Cardiac Protein Phosphatase 2A Regulation in Heart

“…For years, the literature has utilized "broad-stroke" functional kinase and phosphatase assays to assess the phosphor-substrate of a tissue or cell. For example, the use of the phosphatase inhibitors such as okadaic acid, cantharidin, and calyculin A exposed the physiological importance of protein phosphatases and led to the discovery of key regulatory phosphoproteins (57,(61)(62)(63)(64). However, the use of these inhibitors as inotropic therapies has been prevented due to their global and non-compartmentalized inhibitory effects.…”

Cantharidin Revisited

“…Cantharidin has been demonstrated to act as a vasoconstrictor and positive inotrope in guinea pig 46 and human cardiac 47 tissue in vitro. These effects are mediated in part by cantharidin's action as a protein phosphatase inhibitor.…”