Abstract
The benzimidazole molecule was modified to synthesize a Ca2+ sensitizer devoid of additional effects associated with Ca2+ overload. Newly synthesized compounds, termed1, 2, 3, 4, and5, were evaluated in spontaneously beating and electrically driven atria from reserpine-treated guinea pigs. Compound 3resulted 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 compound3 seems to be primarily sustained by sensitization of the contractile proteins to Ca2+.
Footnotes
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Send reprint requests to: Prof. Paola Dorigo, Department of Pharmacology and Anesthesiology, University of Padova, Largo Meneghetti 2, 35131 Padova, Italy. E-mail:dorigo{at}ux1.unipd.it
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↵1 This study was supported by a grant from Ministero dell'Università e della Ricerca Scientifica e Tecnologica, Italy (MURST 40%), and by a grant from Ministero dell'Università e della Ricerca Scientifica e Tecnologica, Italy (cofinanziamento 9806197882-002 to P.D.).
- Abbreviations:
- PDE
- phosphodiesterase
- DMSO
- dimethyl sulfoxide
- PAGE
- polyacrylamide gel electrophoresis
- IR
- infrared
- MS
- mass spectrometry
- RYR
- ryanodine receptor
- Received April 3, 2000.
- Accepted September 12, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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