Pharmacological characterization of a new Ca2+ sensitizer

The benzimidazole molecule was modified to synthesize a Ca2+ sensitizer dev oid of additional effects associated with Ca2+ overload. Newly synthesized compounds, termed 1, 2, 3, 4, and 5, were evaluated in spontaneously beatin g and electrically driven atria from reserpine-treated guinea pigs. Compoun d 3 resulted as the most effective positive inotropic agent, and experiment s were performed to study its mechanism of action. In spontaneously beating atria, the inotropic effect of 3 was concentration-dependent (3.0 muM-0.3 mM). Compound 3 was more potent and more active than the structurally relat ed Ca2+ sensitizers sulmazole and caffeine, but unlike them it did not incr ease the heart rate. In electrically driven atria, the inotropic activity o f 3 was well preserved and it was not inhibited by propranolol, prazosin, r anitidine, pyrilamine, carbachol, adenosine deaminase, or ruthenium red. At high concentrations (0.1-1.0 mM) 3 inhibited phosphodiesterase-III, wherea s it did not affect Na+/K+-ATPase, sarcolemmal Ca2+-ATPase, Na+/Ca2+ exchan ge carrier, or sarcoplasmic reticulum Ca2+ pump activities of guinea pig he art. In skinned fibers obtained from guinea pig papillary muscle and skelet al soleus muscle, compound 3 (0.1 mM, 1 mM) shifted the pCa/tension relatio n curve to the left, with no effect on maximal tension and no signs of toxi city. Compound 3 did not influence the basal or raised tone of guinea pig i solated aorta rings, whose cells do not contain the contractile protein tro ponin. The present results indicate that the inotropic effect of compound 3 seems to be primarily sustained by sensitization of the contractile protei ns to Ca2+.