Protection against ventricular fibrillation via cholinergic receptor stimulation and the generation of nitric oxide

摘要

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 on NO generation and/or muscarinicicotinic 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 mu mol l(-1), n = 6) or a nicotinic receptor antagonist (mecamylamine, 10 mu mol 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 mu mol l(-1), n=6) or soluble guanylate cyclase (sGC) inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; 10 mu mol l(-1), n = 6) prevented the rise in VFT with CCh. The NO donor sodium nitrprusside (10 mu mol 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.