Effect of K+ channel blockade on fatigue in rat diaphragm muscle

K+ channel blockers increase skeletal muscle force during twitch contractions; the present study determined whether K+ channel blockade also modulates force during longer term and higher frequency stimulation. 4-Aminopyridine (4-AP; 0.3 mM) increased rat diaphragm force during twitch, 5-Hz and 20-Hz but not 100-Hz stimulation, and prolonged isometric contraction but not half-relaxation time. In response to continuous 5-Hz stimulation, the rate of force decline was accelerated by 4-AP so that over time force dropped below that of control muscle strips. In response to intermittent 20-Hz stimulation, 4-AP produced an early force potentiation; the 4-AP-induced force increase was maintained throughout repetitive stimulation despite an accelerated rate of force decline. In response to continuous 100-Hz stimulation, 4-AP did not affect rate of force decline. During 5- and 20-Hz stimulation, there was an interaction between 4-AP and duration of stimulation in prolonging contraction and especially half-relaxation time. Tetraethylammonium (10 mM) augmented diaphragm force less than did 4-AP, did not affect rate of force decline during 5-Hz stimulation, and did not interact with fatigue to prolong isometric twitch kinetics. These data indicate that K+ channel blockade with 4-AP increases diaphragm force at low to intermediate stimulation frequencies, may increase early force potentiation during repetitive contraction, and depending on stimulation pattern either accelerates or has no effect on rate of fatigue.