A novel thienylhydrazone, (2-thienylidene)3,4-methylenedioxybenzoylhydrazine, increases inotropism and decreases fatigue of skeletal muscle

This study was designed to investigate the effects on single skeletal muscl e 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 skel etal muscle fibers isolated from either the semitendinous or the tibialis a nterior muscles dissected from the frog Rana pipiens. LASSBio-294 (12.5-100 muM) increased twitch tension, accelerated the maximal rate of tension dec ay during relaxation, and had very little effect in the maximal rate of ten sion development of muscle fibers directly stimulated at less than or equal to 30 Hz. The positive inotropic effect of LASSBio-294 developed slowly, r eaching its maximum at 40 min and was inversely proportional to the frequen cy of stimulation, becoming negligible at 60 and 90 Hz. The concentration-r esponse relationship for LASSBio-294-induced potentiation of twitch tension was bell-shaped, with maximal effect occurring at 25 muM. In addition, LAS SBio-294 reduced development of fatigue induced by tetanic stimulation of t he muscle fibers and reduced the time needed for 80% prefatigue tension rec overy after fatigue had developed to 50% of the maximal pretetanic force. T hese effects of LASSBio-294 can be fully explained by stimulation of the sa rcoplasmic reticulum Ca2+ pump and could be ascribed to an increase in cell ular levels of cyclic AMP due to PDE inhibition. The novel thienylhydrazone LASSBio-294 may be useful for treatment of patients suffering from conditi ons in which muscle fatigue is a debilitating symptom (e.g., chronic heart failure).