Agents that block many types of K⁺ channels (e.g., the aminopyridines) have substantial inotropic effects in skeletal muscle. Specific blockers of ATP-sensitive and Ca²⁺-activated K⁺ channels, on the other hand, do not, or minimally, alter the force of nonfatigued muscle, consistent with a predominant role for voltage-gated K⁺ channels in regulating muscle force. To test this more directly, we examined the effects of peptide toxins, which in other tissues specifically block voltage-gated K⁺ channels, on rat diaphragm in vitro. Twitch force was increased in response to -, -, and -dendrotoxin and tityustoxin K (17 ± 6, 22 ± 5, 42 ± 14, and 13 ± 5%; P < 0.05, < 0.01, < 0.05, < 0.05, respectively) but not in response to -dendrotoxin or BSA (in which toxins were dissolved). Force during 20-Hz stimulation was also increased significantly by -, -, and -dendrotoxin and tityustoxin K. Among agents, increases in twitch force correlated with the degree to which contraction time was prolonged (r = 0.88, P < 0.02). To determine whether inotropic effects could be maintained during repeated contractions, muscle strips underwent intermittent 20-Hz train stimulation for a duration of 2 min in presence or absence of -dendrotoxin. Force was significantly greater with than without -dendrotoxin during repetitive stimulation for the first 60 s of repetitive contractions. Despite the ~55% higher value for initial force in the presence vs. absence of -dendrotoxin, the rate at which fatigue occurred was not accelerated by the toxin, as assessed by the amount of time over which force declined by 25 and 50%. These data suggest that blocking voltage-activated K⁺ channels may be a useful therapeutic strategy for augmenting diaphragm force, provided less toxic blockers of these channels can be found.

skeletal muscle; contraction; fatigue; dendrotoxin; tityustoxin