Differential Inotropic Effects of 4-Aminopyridine and Tetraethyl- ammonium on Rat Diaphragm and Limb Muscles

K channels regulate action potential duration and thereby force of skeletal muscles. Diaphragm differs from limb muscles in the dependence of contraction on extracellular Ca. We hypothesized that diaphragm also differs from limb muscles in the regulation of contraction by membranous K conductances. This was tested in vitro by assessing changes in isometric twitch force and kinetics in response to K channel blockers, and comparing responses of rat diaphragm with that of two limb muscles, the extensor digitorum longus (which contains mainly fast-twitch fibers) and the soleus (which contains mainly slowtwitch fibers). 4-Aminopyridine (0.3 mM) increased twitch force of diaphragm by 71 ± 7%, which was significantly more than that of the extensor digitorum longus (28 ± 11%, P < 0.005) and the soleus (22 ± 3%, P < 0.005). In contrast, tetraethylammonium (10 mM) increased twitch force of the diaphragm by 9 ± 1%, which furthermore was smaller than that of the extensor digitorum longus (41 ± 2%, P < 0.001) and soleus (53 ± 3%, P < 0.001) muscles. There was also a differential pattern among muscles in percent prolongation of isometric contraction time, which paralleled that of twitch force augmentation. Charybdotoxin (10 nM), apamin (100 nM) and glibenclamide (100 μM) did not alter muscle isometric twitch force or kinetics of any muscle. Thus the pattern of diaphragm muscle responses to the K channel blockers 4-aminopyridine and tetraethylammonium differs from that of limb muscles. This can not be attributed to differential blockade among muscles of ATPsensitive or Ca-activated K channels, but could be explained if diaphragm contains different delayed rectifier K channel subtypes from those found in limb muscle.