Key result
3,4-diaminopyridine increased diaphragm isometric twitch force by 181% in young-adult muscle and by 144% in old muscle (p<0.05), demonstrating substantial inotropic effects despite aging.
p-value: p=<0.05
3,4-diaminopyridine exerts substantial inotropic effects by prolonging action potentials in both young and old rat diaphragms, though the effect is modestly attenuated in older muscle.
May augment aged diaphragm force; hypothesis-generating for DAP in human respiratory muscle weakness, pending clinical trials.
The aminopyridines block several types of potassium (K+) channels and exert a direct inotropic effect on skeletal muscle by prolonging the duration of the action potential. Aging influences skeletal muscle Cl- channels and their regulation, and affects both resting whole-cell K+ conductance and adenosine triphosphate (ATP)-sensitive K+ channels, although in opposite directions. The present study tested the hypothesis that aging affects diaphragm-muscle K+ channels responsible for repolarization of the action potential and force production. Diaphragms of young adult (age 3 to 4 mo) and old (age 20 to 21 mo) male Fischer 344 rats was studied in vitro at 37 degrees C. The K+-channel blocker 3,4-diaminopyridine (DAP, 0.3 mM) did not alter resting membrane potential or action-potential height, overshoot, or rate of depolarization of either young-adult or old muscle. However, DAP slowed the rate of repolarization of the action potential and increased the action-potential area in young-adult and old muscle; the time for the action potential to repolarize by 80% increased from 0.59 +/- 0.02 ms (mean +/- SE) to 3.37 +/- 0.68 ms (p < 0.05) in young-adult muscle and from 0.87 +/- 0.06 ms to 2.52 +/- 0.54 ms (p < 0.05) in old muscle, whereas the action-potential area increased from 56 +/- 3 mVms to 193 +/- 34 mVms (p < 0.05) in young-adult muscle and from 72 +/- 5 mVms to 134 +/- 20 mVms (p < 0. 05) in old muscle. The action-potential area was not different in young-adult and old diaphragm without DAP, but was significantly larger in young-adult than in old diaphragm with DAP (p < 0.05). The functional consequence was that DAP increased diaphragm isometric twitch force by 181 +/- 12% (p < 0.05) in young-adult muscle and by 144 +/- 24% (p < 0.05) in old muscle; the increase was significantly greater in young-adult than in old muscle (p < 0.05). These data suggest an aging-associated reduction in, or reduced DAP sensitivity of, diaphragm K+ conductance during action potentials, which most likely reflects aging-associated alterations in delayed-rectifier K+ conductance. Although the inotropic effect of DAP was greater for young-adult than for old diaphragm muscle, the difference was sufficiently modest to show that DAP has substantial inotropic effects in old muscle.
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Lunteren et al. (1998) studied Aging effects on diaphragm muscle K+ channels. 3,4-diaminopyridine (DAP) vs. Without DAP was evaluated on Isometric twitch force (p=<0.05). 3,4-diaminopyridine increased diaphragm isometric twitch force by 181% in young-adult muscle and by 144% in old muscle (p<0.05), demonstrating substantial inotropic effects despite aging.
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