Effects of hexamethonium on transmitter release from the rat phrenic nerve

The Journal of Physiology

Fiekers

Henderson³

et al. 1998

1. We have studied the effects of the nicotinic acetylcholine (ACh) receptor agonist dimethylphenylpiperazinium (DMPP) on the evoked release of ACh from motor terminals in the rat isolated hemidiaphragm using an electrophysiological approach. 2. DMPP (1-4 ìÒ) had no effect on the rate of spontaneous quantal ACh release but increased the number of quanta of ACh released per impulse during 50 Hz stimulation. The DMPPinduced increase in evoked ACh release was dependent on the frequency of stimulation, being absent when it was reduced to 0·5 Hz, but was not Ca¥ dependent, being unaffected at 50 Hz by a 4-fold decrease in the extracellular Ca¥ concentration. 3. The facilitation of evoked ACh release at 50 Hz by 2 ìÒ DMPP was abolished by 10 ìÒ of the calmodulin antagonist W7 (N-(6-aminohexyl)-5-chloro-1-naphthalenesulphonamide hydrochloride) and, in the presence of W7, 2 ìÒ DMPP depressed evoked ACh release at 0·5 Hz. The ability of the nicotinic ACh receptor antagonist vecuronium (1 ìÒ) to depress evoked ACh release at 50 Hz was also abolished by 10 ìÒ W7. 4. The present findings demonstrate, using an electrophysiological technique, that DMPP can produce changes in the evoked ACh release from rat motor nerve terminals that are consistent with the existence of facilitatory nicotinic ACh receptors on the motor nerve endings. Further, they indicate a role for calmodulin-dependent systems in this facilitatory effect of the compound.

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Prejunctional effects of the nicotinic ACh receptor agonist dimethylphenylpiperazinium at the rat neuromuscular junction

The Journal of Physiology

Fiekers

Henderson³

et al. 1998

“…tubocurarine is an antagonist of both muscle-and neuronal-type nicotinic ACh receptors. In contrast, neither vecuronium (Durant, Marshall, Savage, Nelson, Sleigh & Carlyle, 1979) nor metocurine (Durant, Bowman & Marshall, 1977) (Wilson & Thomsen, 1992). Structurally, the neuronal-type nicotinic ACh receptor subunit composition is different from that of muscle-type nicotinic ACh receptors (Deneris, Connolly, Rogers & Duvoison, 1991).…”

Section: Discussionmentioning

confidence: 99%

Nicotinic antagonist‐produced frequency‐dependent changes in acetylcholine release from rat motor nerve terminals.

Tian

The Journal of Physiology

Dempster

et al. 1994

1. The frequency (0-5-150 Hz) and calcium dependence (0-5-2-0 mM) of the effects of the nicotinic antagonist tubocurarine (0f2 /uM) on acetylcholine (ACh) liberation from motor nerve terminals has been examined using binomial analysis of quantal transmitter release. 5. Binomial analysis revealed that all the changes in EPC quantal content associated with both nicotinic antagonists were due to changes in the size of the pool of quanta in the nerve terminal available for immediate release with no effect on the probability of release of an individual quantum. Stertz, Peper, Chau & Wilson, 1973;Glavinovic, 1979c; Magleby, Pallotta & Zhang, 1990). This is manifest in twitch tension Terrar, 1981;Gibb & Marshall, 1984 L. Tian, C. Prior, J. Dempster and I. C. Marshall colleagues (for reviews see Bowman, Gibb, Harvey & Marshall, 1986;Bowman, Marshall, Gibb & Harborne, 1988;Bowman, Prior & Marshall, 1990) have contended that tetanic fade and EPP or EPC amplitude run-down are consequences of tubocurarine inhibiting a nicotinic ACh autoreceptor located on the motor nerve terminal. It is proposed that these putative receptors form part of a positive-feedback system, activation of which by ACh enhances the mobilization and release of ACh during highfrequency motor nerve stimulation. This conclusion is based largely on the ability to detect electrophysiologically a decrease in the quantal release of ACh from motor nerve terminals towards the latter part of high-frequency bursts of motor nerve stimulation . On the other hand, it has been reported that tubocurarine can increase, rather than decrease, ACh release from rat (Wilson, 1982;Wilson & Thomsen, 1991), cat (Blaber, 1970;, frog (Matzner, Parnas & Parnas, 1988) and mouse (Ferry & Kelly, 1988) (Wilson, 1982;Wilson & Thomsen, 1991 have attributed the tubocurarine-induced increase of quantal content, and subsequent increased run-down of EPPs, to a frequency-dependent action of tubocurarine on a negativefeedback motor nerve terminal nicotinic ACh autoreceptor. Blaber (1973) also reported that tubocurarine increased the fractional release of ACh during high-frequency nerve stimulation, although in this study the initial quantal content was not measured. Blaber (1973) proposed that the phenolic moieties of tubocurarine were responsible for its ability to increase fractional release, as trimethyltubocurarine did not increase release. He suggested that these phenolic groups, absent in trimethyltubocurarine, were responsible for the enhancement of the fractional release of ACh, either by increasing the stimulus-evoked influx of calcium ions into the nerve terminal or by increasing the activity of intracellular calcium ions.In an attempt to shed more light on the prejunctional effects of tubocurarine at the neuromuscular junction, we have studied the frequency-and calcium-dependent effects of tubocurarine on the quantal release of ACh from motor nerve terminals. Quantal ACh release at a range of motor nerve stimulation frequencies (0-5-150 Hz) has been determined from the amplitud...

“…More recent observations, one using a wide range of stimulation frequencies (Tian et al , 1994) and others using drugs other than tubocurarine (Wilson & Thomsen, 1991, 1992; Tian et al , 1994), have opened up the possibility of the co‐existence of both positive and negative feedback mechanisms at the neuromuscular junction, with differing frequency‐dependence and drug sensitivities. The present study was designed to study the putative negative feedback mechanism and to confirm the type of nicotinic ACh receptor (AChR) that might be involved in its operation.…”

Section: Introductionmentioning

confidence: 99%

Hexamethonium‐ and methyllycaconitine‐induced changes in acetylcholine release from rat motor nerve terminals

Tian

Dempster

et al. 1997

British J Pharmacology

1 The neuronal nicotinic receptor antagonists hexamethonium and methyllycaconitine (MLA) have been used to study the putative prejunctional nicotinic ACh receptors (AChRs) mediating a negativefeedback control of ACh release from motor nerve terminals in voltage-clamped rat phrenic nerve/ hemidiaphragm preparations. 2 Hexamethonium (200 mM), but not MLA (0.4 ± 2.0 mM), decreased the time constant of decay of both endplate currents (e.p.cs) and miniature endplate currents (m.e.p.cs), indicating endplate ion channel block with hexamethonium. However, driving function analysis and reconvolution of e.p.cs and m.e.p.cs indicated that this ion channel block did not compromise the analysis of e.p.c. quantal content. 3 At low frequencies of stimulation (0.5 ± 2 Hz), hexamethonium (200 mM) and MLA (2.0 mM) increased e.p.c. quantal content by 30 ± 40%. At high frequencies (50 ± 150 Hz) neither compound a ected e.p.c. quantal content. All e ects on quantal content were paralleled by changes in the size of the pool of quanta available for release. 4 The low frequency augmentation of e.p.c. quantal content by hexamethonium was absent when extracellular [Ca 2+ ] was lowered from 2.0 to 0.5 mM. 5 At the concentrations studied, MLA and hexamethonium produced a small (10 ± 20%) decrease in the peak amplitude of m.e.p.cs. 6 Neither apamin (100 nM) nor charybdotoxin (80 nM) had e ects on spontaneous or nerve evoked current amplitudes at any frequency of stimulation. Thus the ability of nicotinic antagonists to augment e.p.c. quantal content is not due to inhibition of Ca 2+ -activated K + -channels. 7 We suggest that hexamethonium and MLA increase evoked ACh release by blocking prejunctional nicotinic AChRs. These receptors exert a negative feedback control over evoked ACh release and are probably of the a-bungarotoxin-insensitive neuronal type.