Effects of DAP on diaphragm force and fatigue, including fatigue due to neurotransmission failure

Abstract

Among the aminopyridines, 3,4-diaminopyridine (DAP) is a more effective K+ channel blocker than is 4-aminopyridine (4-AP), and, furthermore, DAP enhances neuromuscular transmission. Because 4-AP improves muscle contractility, we hypothesized that DAP would also increase force and, in addition, ameliorate fatigue and improve the neurotransmission failure component of fatigue. Rat diaphragm strips were studied in vitro (37 degrees C). In field-stimulated muscle, 0.3 mM DAP significantly increased diaphragm twitch force, prolonged contraction time, and shifted the force-frequency relationship to the left without-altering peak tetanic force, resulting in increased force at stimulation frequencies < or = 50 Hz. During 20-Hz intermittent stimulation, DAP increased diaphragm peak force compared with control during a 150-s fatigue run and, furthermore, significantly improved maintenance of intratrain force. The relative contribution of neurotransmission failure to fatigue was estimated by comparing the force generated by phrenic nerve-stimulated muscles with that generated by curare-treated field-stimulated muscles. DAP significantly increased force in nerve-stimulated muscles and, in addition, reduced the neurotransmission failure contribution to diaphragm fatigue. Thus DAP increases muscle force at low-to-intermediate stimulation frequencies, improves overall force and intratrain fatigue during 20-Hz intermittent stimulation, and reduces neurotransmission failure.

Sternohyoid Muscle Fatigue Properties of dy/dy Dystrophic Mice, an Animal Model of Merosin-Deficient Congenital Muscular Dystrophy

“…STERNOHYOID MUSCLE OF DYSTROPHIC MICE (13,16,23,24) and sternohyoid muscles (16), as was also the case in the present study for sternohyoid muscle from normal animals. A third issue is whether a stimulation frequency of 25 Hz is physiologically appropriate based on motor unit firing rates during breathing.…”

“…duty cycle of one third). This paradigm is based on the classic work of Burke and colleagues (19,20) and has been used extensively by others (21,22) and in our previous studies (13,16,17,23,24). This type of a protocol is reasonable for a muscle that is phasically active mainly during the inspiratory portion of the respiratory cycle, as inspiration is shorter than expiration in most species.…”

“…Blocking these channels pharmacologically with the aminopyridines (in particular DAP and 552 van LUNTEREN AND MOYER 4-aminopyridine) prolongs action potential duration, increases intracellular calcium levels, and augments muscle force (13,23,24,31). In normal rat diaphragm, the aminopyridines increase force at low to intermediate stimulation frequencies by up to approximately 150%, and the force increases can be maintained during the course of repetitive 20-Hz stimulation (24). We recently tested the effects of DAP on dy/dy dystrophic mouse diaphragm (13).…”

Adverse effects of myasthenia gravis on rat phrenic diaphragm contractile performance

“…During fatigue testing, to factor out the effects of interstrip variability in size as well as myasthenia-induced baseline force reductions, all force values were normalized to the initial 50-Hz tetanic force measurement immediately preceding the fatigue test. Intratrain fatigue was assessed by measuring the force at the end of the 330-ms-long train and expressing this as a percentage of the maximum force within the same tetanus (F330) (31).…”

“…Despite the protective safety factor, neurotransmission failure does occur under experimental conditions, especially during prolonged activation at higher frequencies. In rat phrenic nerve and diaphragm, estimates of the maximal contribution of neurotransmission failure to diaphragm fatigue range from 15 to Ͼ75% (1,14,16,31), with greater values generally being noted during higher stimulation frequencies (16).…”