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- Title
Protection against ventricular fibrillation via cholinergic receptor stimulation and the generation of nitric oxide.
- Authors
Kalla, Manish; Chotalia, Minesh; Coughlan, Charles; Hao, Guoliang; Crabtree, Mark J.; Tomek, Jakub; Bub, Gil; Paterson, David J.; Herring, Neil
- Abstract
Implantable cardiac vagal nerve stimulators are a promising treatment for ventricular arrhythmia in patients with heart failure. Animal studies suggest the anti-fibrillatory effect may be nitric oxide (NO) dependent, although the exact site of action is controversial. We investigated whether a stable analogue of acetylcholine could raise ventricular fibrillation threshold (VFT), and whether this was dependent onNOgeneration and/ormuscarinic/nicotinic receptor stimulation. VFT was determined in Langendorff perfused rat hearts by burst pacing until sustained VF was induced. Carbamylcholine (CCh, 200 nmol l-1, n = 9) significantly (P < 0.05) reduced heart rate from 292 ± 8 to 224 ± 6 b.p.m. Independent of this heart rate change, CCh caused a significant increase in VFT (control 1.5 ± 0.3 mA, CCh 2.4 ± 0.4 mA, wash 1.1 ± 0.2 mA) and flattened the restitution curve (n = 6) derived from optically mapped action potentials. The effect of CCh on VFT was abolished by a muscarinic (atropine, 0.1 μmol l-1, n = 6) or a nicotinic receptor antagonist (mecamylamine, 10 μmol l-1, n = 6). CCh significantly increased NOx content in coronary effluent (n = 8), but not in the presence of mecamylamine (n = 8). The neuronal nitric oxide synthase inhibitor AAAN (N-(4S)-4-amino-5-[aminoethyl]aminopentyl-N'-nitroguanidine; 10 μmol l-1, n=6) or soluble guanylate cyclase (sGC) inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; 10 μmol l-1, n = 6) prevented the rise in VFT with CCh. The NO donor sodium nitrprusside (10 μmol l-1, n = 8) mimicked the action of CCh on VFT, an effect that was also blocked by atropine (n = 10). These data demonstrate a protective effect of CCh on VFT that depends upon both muscarinic and nicotinic receptor stimulation, where the generation of NO is likely to be via a neuronal nNOS/sGC-dependent pathway.
- Subjects
VENTRICULAR fibrillation treatment; HEART failure patients; CHOLINERGIC receptors; NITRIC-oxide synthase inhibitors; ACETYLCHOLINE; LABORATORY rats
- Publication
Journal of Physiology, 2016, Vol 594, Issue 14, p3981
- ISSN
0022-3751
- Publication type
Article
- DOI
10.1113/JP271588