Positive inotropic effects of the calcium sensitizer CGP 48506 in guinea pig myocardium.

In isolated papillary muscles from reserpinized guinea pigs, CGP 48506 increased force of contraction in a concentration-dependent and reversible manner, starting at 10 mumol/l and reaching 364.14 +/- 46.10% of predrug values at 100 mumol/l. The positive inotropic effect of CGP 48506 was not sensitive to 10 mumol/l carbachol. The positive inotropic effect of CGP 48506 was accompanied by increases in time to peak tension and in time of relaxation amounting to 223.37 +/- 6.87% and 247.10 +/- 9.34% of control, respectively, at 100 mumol/l (n = 10). CGP 48506 sensitized trabeculae from guinea pig hearts to calcium with an EC50 value of 22 mumol/l. However, CGP 48506 (up to 300 mumol/l) did not affect the activity of cardiac PDE isoenzymes I to IV. Likewise, CGP 48506 (up to 100 mumol/l) did not increase phosphorylation of select cardiac regulatory proteins or cyclic AMP content in guinea pig ventricular cardiomyocytes and did not affect cardiac phosphorylase phosphatase activity. CGP 48506 is the first pharmacological agent with noteworthy calcium-sensitizing properties that has been found to be devoid of inhibitory activity on cardiac PDE.