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Nitric oxide-cGMP pathway facilitates acetylcholine release and bradycardia during vagal nerve stimulation in the guinea-pig in vitro

Neil Herring and David J. Paterson

1. We tested the hypothesis that nitric oxide (NO) augments vagal neurotransmission and bradycardia via phosphorylation of presynaptic calcium channels to increase vesicular release of acetylcholine.
2. The effects of enzyme inhibitors and calcium channel blockers on the actions of the NO donor sodium nitroprusside (SNP) were evaluated in isolated guinea-pig atrial-right vagal nerve preparations.
3. SNP (10 µM) augmented the heart rate response to vagal nerve stimulation but not to the acetylcholine analogue carbamylcholine (100 nM). SNP also increased the release of [³H]acetylcholine in response to field stimulation. No effect of SNP was observed on either the release of [³H] acetylcholine or the HR response to vagal nerve stimulation in the presence of the guanylyl cyclase inhibitor 1H-(1,2,4)-oxadiazolo-(4,3-a)-quinoxalin-1-one (ODQ, 10 µM).
4. The phosphodiesterase 3 (PDE 3) inhibitor milrinone (1 µM) increased the release of [³H] acetylcholine and the vagal bradycardia and prevented any further increase by SNP. SNP was still able to augment the vagal bradycardia in the presence of the protein kinase G inhibitor KT5823 (1 µM) but not after protein kinase A (PKA) inhibition with H-89 (0.5 µM) or KT5720 (1 µM) had reduced the HR response to vagal nerve stimulation. Neither milrinone nor H-89 changed the HR response to carbamylcholine.
5. SNP had no effect on the magnitude of the vagal bradycardia after inhibition of N-type calcium channels with -conotoxin GVIA (100 nM).
6. These results suggests that NO acts presynaptically to facilitate vagal neurotransmission via a cGMP-PDE 3-dependent pathway leading to an increase in cAMP-PKA-dependent phosphorylation of presynaptic N-type calcium channels. This pathway may augment the HR response to vagal nerve stimulation by increasing presynaptic calcium influx and vesicular release of acetylcholine.

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