The effect of nitric oxide and endothelin on skeletal muscle contractility changes when stimulation is altered.

To investigate the effect of endothelial-derived products on the force of contraction of blood-perfused skeletal muscle, we infused S-nitroso-N-acetylpenicillamine (SNAP, 10(-4) M) (a nitric oxide (NO) donor), endothelin-1 (ET-1, 10(-8) M), N-acetylpenicillamine (NAP, 10(-4) M), or saline at a constant vascular concentration into the vascular bed of pump-perfused dog gastrocnemius-plantaris muscles in situ (n = 17). Muscles performed isometric twitch contractions at 0.5, 1.5, and 4 Hz and isometric tetanic contractions (150 ms, 50 Hz) at 12 and 40 contractions/min. We perfused the muscle at a constant pressure at rest and for the first 3 min of the 6-min contraction period, and then switched to constant flow perfusion and infused the substance over the remaining 3 min. Neither NAP nor saline had a significant effect on force of contraction or perfusion pressure. SNAP significantly attenuated developed force as compared with NAP at 40 contractions/min and at 1.5 and 4 Hz. The effect of SNAP on developed force was greater during twitch than tetanic contractions. ET-1 had no significant effect on twitch or tetanic developed force. To test for these results on another mammalian skeletal muscle preparation, we stimulated curarized trimmed mouse soleus in vitro for 500 ms at 50 Hz at either 2 or 4 contractions/min in the presence of SNAP (10(-4) M) or ET-1 (10(-9) M). SNAP, which increased force at 1 contraction/90 s, had no significant effect at the higher contraction frequencies. The inhibition by ET-1 at 2 contractions/min disappeared at 4 contractions/min. Therefore the effect of both NO and ET-1 on mammalian skeletal muscle appears to be dependent upon contraction pattern and frequency.