Vol. 299, Issue 2, 558-566, November 2001

A Novel Thienylhydrazone, (2-Thienylidene)3,4-methylenedioxybenzoylhydrazine, Increases Inotropism and Decreases Fatigue of Skeletal Muscle

Hugo Gonzalez-Serratos, Ruzhang Chang, Edna F. R. Pereira, Newton G. Castro, Yasco Aracava, Paulo A. Melo, Patrícia C. Lima, Carlos A. M. Fraga, Eliezer J. Barreiro and Edson X. Albuquerque

Departments of Physiology (H.G.-S., R.C.) and Pharmacology and Experimental Therapeutics (E.F.R.P., E.X.A.), University of Maryland School of Medicine, Baltimore, Maryland; and Departamento de Farmacologia Básica e Clínica (E.X.A., N.G.C., Y.A., P.A.M.), Instituto de Ciências Biomédicas, and Departamento de Fármacos (P.C.L., C.A.M.F., E.J.B.), Faculdade de Farmácia, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

This study was designed to investigate the effects on single skeletal muscle fibers of a novel thienylhydrazone, referred to as LASSBio-294, which is a bioisoster of pyridazinone compounds that inhibit the cyclic AMP-specific phosphodiesterase (PDE) 4. Twitch and fatigue were analyzed in single skeletal muscle fibers isolated from either the semitendinous or the tibialis anterior muscles dissected from the frog Rana pipiens. LASSBio-294 (12.5-100 µM) increased twitch tension, accelerated the maximal rate of tension decay during relaxation, and had very little effect in the maximal rate of tension development of muscle fibers directly stimulated at 30 Hz. The positive inotropic effect of LASSBio-294 developed slowly, reaching its maximum at 40 min and was inversely proportional to the frequency of stimulation, becoming negligible at 60 and 90 Hz. The concentration-response relationship for LASSBio-294-induced potentiation of twitch tension was bell-shaped, with maximal effect occurring at 25 µM. In addition, LASSBio-294 reduced development of fatigue induced by tetanic stimulation of the muscle fibers and reduced the time needed for 80% prefatigue tension recovery after fatigue had developed to 50% of the maximal pretetanic force. These effects of LASSBio-294 can be fully explained by stimulation of the sarcoplasmic reticulum Ca²⁺ pump and could be ascribed to an increase in cellular levels of cyclic AMP due to PDE inhibition. The novel thienylhydrazone LASSBio-294 may be useful for treatment of patients suffering from conditions in which muscle fatigue is a debilitating symptom (e.g., chronic heart failure).