Introduction We have previously shown that vagus nerve stimulation (VNS) increases effective refractory period (ERP) and ventricular fibrillation threshold (VFT) [1], via a nitric oxide (NO) dependent mechanism [2] that is independent on acetycholine [3]. NO can activate soluble guanylyl cyclase [sGC] to produce cyclic guanylyl monophosphate (cGMP) and modulate cardiac function. The aim of this study was to investigate if the effects of VNS-NO pathway on ERP and VFT were mediated via cGMP mechanisms. Methods Adult New Zealand White rabbits (n=7, 2.5-4kg) were pre-sedated with an i.m mixture of ketamine (10mg/kg), medetomidine hydrochloride (0.2mg/kg) and butorphanol (0.05mg/kg). Following sedation, animals were heparinised (1000IU, i.v.) and humanely killed with an overdose of sodium pentobarbitone (160mg/kg, i.v.). Hearts were removed and perfused in constant flow Langendorff mode with ventricular electrophysiology measured using contact electrodes. ERP were measured using single extrastimulus protocol (300ms cycle length). VFT was the minimum current needed to induce sustained VF with burst pacing (30x30ms). These were measured at baseline [BL] and with: 1) NO donor (Sodium Nitroprusside [SNP], 100μM), 2) sGC inhibition (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one [ODQ], 10μM), 3) vagus nerve stimulation [VNS, 10H9V] and (4) VNS or SNP in the presence of ODQ. Data are mean±SEM, Students T-Test, P<0.05 compared with BL. Results (see Table): SNP and VNS both increased ERP and VFT. The effects of SNP were preserved during sGC inhibition, whilst the effects from VNS were inhibited. Conclusion Cyclic GMP is involved in the protective effects of VNS-NO pathway against VF but concurrent cGMP independent mechanisms could also be at work.