Vol. 295, Issue 3, 994-1004, December 2000

Pharmacological Characterization of a New Ca²⁺ Sensitizer¹

Paola Dorigo, Maura Floreani, Giovanni Santostasi, Ildebrando Maragno, Daniela Danieli-Betto, Elena Germinario, Sebastiano Marciani Magno, Gianpaolo Primofiore, Anna Maria Marini and Federico Da Settimo

Departments of Pharmacology and Anesthesiology (P.D., M.F., G.S., I.M.), Human Anatomy and Physiology (D.D.B., E.G.), and Pharmaceutical Sciences (S.M.M.), University of Padova, Padova, Italy; and Department of Pharmaceutical Sciences, University of Pisa, Pisa, Italy (G.P., A.M.M., F.D.S.)

The benzimidazole molecule was modified to synthesize a Ca²⁺ sensitizer devoid of additional effects associated with Ca²⁺ overload. Newly synthesized compounds, termed 1, 2, 3, 4, and 5, were evaluated in spontaneously beating and electrically driven atria from reserpine-treated guinea pigs. Compound 3 resulted as the most effective positive inotropic agent, and experiments were performed to study its mechanism of action. In spontaneously beating atria, the inotropic effect of 3 was concentration-dependent (3.0 µM-0.3 mM). Compound 3 was more potent and more active than the structurally related Ca²⁺ sensitizers sulmazole and caffeine, but unlike them it did not increase the heart rate. In electrically driven atria, the inotropic activity of 3 was well preserved and it was not inhibited by propranolol, prazosin, ranitidine, pyrilamine, carbachol, adenosine deaminase, or ruthenium red. At high concentrations (0.1-1.0 mM) 3 inhibited phosphodiesterase-III, whereas it did not affect Na⁺/K⁺-ATPase, sarcolemmal Ca²⁺-ATPase, Na⁺/Ca²⁺ exchange carrier, or sarcoplasmic reticulum Ca²⁺ pump activities of guinea pig heart. In skinned fibers obtained from guinea pig papillary muscle and skeletal soleus muscle, compound 3 (0.1 mM, 1 mM) shifted the pCa/tension relation curve to the left, with no effect on maximal tension and no signs of toxicity. Compound 3 did not influence the basal or raised tone of guinea pig isolated aorta rings, whose cells do not contain the contractile protein troponin. The present results indicate that the inotropic effect of compound 3 seems to be primarily sustained by sensitization of the contractile proteins to Ca²⁺.