Peptide toxin blockers of voltage-sensitive K+ channels: inotropic effects on diaphragm.

Abstract

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 alpha-, beta-, and gamma-dendrotoxin and tityustoxin Kalpha (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 gamma-dendrotoxin and tityustoxin Kalpha. 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 gamma-dendrotoxin. Force was significantly greater with than without gamma-dendrotoxin during repetitive stimulation for the first 60 s of repetitive contractions. Despite the approximately 55% higher value for initial force in the presence vs. absence of gamma-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.

• Authors: E van Lunteren, M Moyer
• Journal: Journal of applied physiology (Bethesda, Md. : 1985) (J Appl Physiol (1985)) Vol. 86 Issue 3 Pg. 1009-16 (Mar 1999) ISSN: 8750-7587 [Print] United States
• PMID: 10066717 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Elapid Venoms
• Neurotoxins
• Potassium Channel Blockers
• Scorpion Venoms
• tityustoxin
• dendrotoxin

Topics

• Animals
• Diaphragm (drug effects)
• Elapid Venoms (pharmacology)
• In Vitro Techniques
• Ion Channel Gating (drug effects)
• Isometric Contraction (drug effects)
• Kinetics
• Male
• Muscle Contraction (drug effects)
• Muscle Relaxation (drug effects)
• Muscle, Skeletal (drug effects)
• Neurotoxins (pharmacology)
• Potassium Channel Blockers
• Rats
• Rats, Sprague-Dawley
• Scorpion Venoms (pharmacology)
• Time Factors