Electrophysiologic and inotropic effects of K+-channel blockade in aged diaphragm.
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.
van LUNTEREN
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Departments of Medicine (Pulmonary) and Neurosciences, Cleveland Veterans Administration Medical Center and Case Western Reserve University, Cleveland, Ohio, USA. exv4@po.cwru.edu
Moyer
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D015761:4-Aminopyridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects*; D000255:Adenosine Triphosphate / Q000502:physiology; D000375:Aging / Q000502:physiology*; D000077770:Amifampridine; D000704:Analysis of Variance; D000818:Animals; D018118:Chloride Channels / Q000037:antagonists & inhibitors; D003964:Diaphragm / Q000187:drug effects* / Q000502:physiology; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects; D026902:Potassium Channel Blockers; D051381:Rats; D011916:Rats, Inbred F344; D011930:Reaction Time / Q000187:drug effects
D018118:Chloride Channels; D026902:Potassium Channel Blockers; D000255:Adenosine Triphosphate; D015761:4-Aminopyridine; D000077770:Amifampridine