CGP 41251, a new potential anticancer drug, improves contractility of rat isolated cardiac muscle subjected to hypoxia

The aim of the present work was to examine the effects of 4'-N-benzoyl stau rosporine (CGP 41251), a protein kinase C inhibitor with broad antiprolifer ative activity in many cell lines, on the rat isolated heart contractility under normoxic and hypoxic conditions. Additionally, we examined the effect s of CGP 41251, WB-4101 (alpha (1a)-adrenoceptor antagonist), chloroethylcl onidine (CEC) (alpha (1b)-adrenoceptor antagonist) and selective damage of endocardial endothelium by Triton X-100 on the protection against hypoxia i nduced by preconditioning of rat heart tissue. Experiments were performed o n rat isolated left ventricular papillary muscle, The following parameters were measured: force of contraction (Fc), velocity of contraction (+dF/dt) and velocity of relaxation (-dF/dt). The temperature of the bath solution w as 37 degreesC +/- 0.5 degreesC, and rate of electrical stimulation was 0.5 Hz. At concentrations less than 1 muM CGP 41251 did not cause any changes in contractility of rat heart. At 1 and 3 muM, significant positive inotrop ic action was observed. Treatment of rat papillary muscle by CGP 41251 at 3 muM reduced decreasing of contractility by simulated hypoxia and reperfusi on. Moreover, protective effects of preconditioning was not affected by add ition of CGP 41251 neither at 1 nor at 3 muM. Pretreatment with CEC at 3 mu M, and selective damage of endocardial endothelium induced by fast (1-s) im mersion of papillary muscle in 0.5% Triton X-100, but not pretreatment with WB-4101, abolished the protective effects of preconditioning, The results imply that CGP 41251 improves contractility of heart muscle under normoxic and hypoxic conditions, and does not alter hypoxic preconditioning in rat i solated cardiac tissue. Moreover, it was shown that alpha (1b)-adrenoceptor s and endocardial endothelium are involved in triggering of preconditioning in rat isolated heart muscle.