The phosphodiesterase inhibitors dipyridamole and zaprinast have divergent effects on contractile function of rat diaphragm in vitro

Recent studies in our laboratory have demonstrated that nitric oxide (NO) inhibits contractile function of rat diaphragm by elevating cyclic guanosine monophosphate (cGMP) levels (Nature 372:546-548.1994) whereas cyclic adonne moaophosphate (cAMP) is known to increase force. Phospohdiesterase (PDE) inhibitors increase intracellular cGMP. cAMP, or both depending on the PDE isoforms expressed by an individual cell type and so have the potential to alter skeletal muscle function in a complex and unpredictable manner. HYPOTHESIS: PDE inhibitors alter contractile function of diaphragm fiber bundles in vitro METHODS: Diaphragm fiber bundles from male Sprague-Dawhy rats were stimulated directly and force was measured at 37°C. Dose-response studies of dipyridamole (DPM) 1-30 uM and zaprinast (ZAP) 0 1-3.0 nuM (n=6/gronp) identified dosages for formal studies that measured twitch characteristics, the force-frequency relationship (1-200 Hz), and acute fatigue (30 Hz, 350 s TD; 1 tetanus every 2 s for 10 nun) RESULTS: DPM 1 μM depressed submaximal tetanic (40 Hz) force slightly in dose-response trials but had no overall effect on twitch characteristics, the force-frequency curve, or acute fatigue. In contrast. ZAP ImM increased twitch characteristics (twitch-tetanus ratio, time to peak tension, dP/dt. -dP/dt) and produced a small (∼2%) increase in maximal tetanic force (Po) that is unique in this muscle at 37°C; ZAP abo elevated the force-frequency curve and abolished post-tetanic potenliation but did not alter fatigue. ZAP effects reversed with washout. Bom DPM and ZAP accelerated functional deterioration (the rate of decline of Po) at these concentrations CONCLUSIONS: PDE inhibitors have diverse effects on muscle function. DPM effects are small and difficult to resolve. ZAP improves excitation-contraction coupling markedly which suggests that this agent may elevate cAMP levels in muscle.