Peptide toxin blockers of voltage-sensitive K+ channels: inotropic effectson diaphragm

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 mi nimally, alter the force of nonfatigued muscle, consistent with a predomina nt role for voltage-gated K+ channels in regulating muscle force. To test t his more directly, we examined the effects of peptide toxins, which in othe r tissues specifically block voltage-gated K+ channels, on rat diaphragm in vitro. Twitch force was increased in response to alpha-, beta-, and gamma- dendrotoxin and tityustoxin K alpha (17 +/- 6, 22 +/- 5, 42 +/- 14, and 13 +/- 5%; P < 0.05, < 0.01, < 0.05, < 0.05, respectively) but not in response to delta-dendrotoxin or BSA (in which toxins were dissolved). Force during 20-Hz stimulation was also increased significantly by alpha-, beta-, and g amma-dendrotoxin and tityustoxin K alpha. 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 mainta ined during repeated contractions, muscle strips underwent intermittent 20- Hz train stimulation for a duration of 2 min in presence or absence of gamm a-dendrotoxin. Force was significantly greater with than without gamma-dend rotoxin during repetitive stimulation for the first 60 s of repetitive cont ractions. Despite the similar to 55% higher value for initial force in the presence vs. absence of gamma-dendrotoxin, the rate at which fatigue occurr ed 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 volta ge-activated K+ channels may be a useful therapeutic strategy for augmentin g diaphragm force, provided less toxic blockers of these channels can be fo und.