Effect of nitric oxide and NO synthase inhibition on nonquantal acetylcholine release in the rat diaphragm

Abstract

After anticholinesterase treatment, the postsynaptic muscle membrane is depolarized by about 5 mV due to nonquantal release of acetylcholine (ACh) from the motor nerve terminal. This can be demonstrated by the hyperpolarization produced by the addition of curare (H-effect). The magnitude of the H-effect was decreased significantly to 3 mV when the nitric oxide (NO) donors, sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) were applied to the muscle, or when NO production was elevated by adding L-arginine, but not D-arginine, as a substrate. The H-effect was increased to 8-9 mV by inhibition of NO synthase by L-nitroarginine methylester (L-NAME), or by guanylyl cyclase inhibition by methylene blue and 1H-[1,2,4]oxidiazolo[4,3-a]quinoxalin-1-one (ODQ). ODQ increased the H-effect to 7.3 +/- 0.2 mV and diminished the SNP-induced decrease of the H-effect when applied together with SNP. The effects of NO donors and L-arginine were eliminated by adding reduced haemoglobin, an extracellular NO scavenger. The present results, together with earlier evidence for the presence of NO synthase in muscle fibres, indicate that nonquantal release of ACh is modulated by NO production in the postsynaptic cell.

Effects of modulation of nitric oxide on rat diaphragm isotonic contractility during hypoxia

“…Thus it was used as further evidence that the observed responses were NO mediated. Because hemoglobin does not enter cells and it scavenges NO extracellularly (37), it may scavenge NO generated intracellularly by creating a diffusion gradient of NO out of the cell "sink" (27).…”

Non-Cholinergic Signaling Pathways at Vertebrate Neuromuscular Junctions

“…The mechanism of neuropeptide action is realized through its extracellular hydrolysis by the GCP II with the formation of glutamate molecules, which, as was shown earlier [89], activate glutamate postsynaptic NMDA receptors and thereby trigger the NO-mediated mechanism of reducing the intensity of the non-quantal ACh release [104].…”

“…The inhibitory action of nitric oxide on spontaneous and induced synaptic currents was shown also in the developing neuromuscular contacts Xenopus laevis [154]. In contrast with endplate of amphibian, NO has no effect on spontaneous and evoked forms of quantal ACh release, but significantly reduces the intensity of non-quantal release of ACh in mammalian NMJ [104]. However, as was shown later, NO can modulate the quantal release in mammals, enhancing transmitter release from motor nerve via a cGMP pathway, but it occurs only when adenosine A1 receptors were blocked [155].…”

“…However, as was shown later, NO can modulate the quantal release in mammals, enhancing transmitter release from motor nerve via a cGMP pathway, but it occurs only when adenosine A1 receptors were blocked [155]. It is also necessary to note the fact that in the synapse of amphibians and mammals, the fact endogenous tonic effect of NO on ACh release processes was confirmed repeatedly [86,89,104,153].…”

The Effect of Nitric Oxide on the Rat Diaphragm at Different Frequencies of Indirect Electrical Stimulation

“…In addition, skeletal muscle nNOS was reported to play a role in the regulation of a number of cellular processes such as contractile activity, glucose uptake, and blood flow distribution, but the importance of sarcolemmal targeting of nNOS for these regulatory functions is largely unknown 22 More importantly, authors found that diaphragmatic NOS activity during postnatal development was strongly controlled at multiple levels, including gene transcription. An endogenous inhibitor, the newly discovered PIN (protein inhibitor of nNOS) is known to be widely expressedin various skeletal muscles including the diaphragm, and to inhibit nNOS activity by preventing its dimerization.…”