The Antifibrillatory Effects of Vagus Nerve Stimulation in the Rabbit Ventricle involves cGMP‐Dependent Mechanisms

Abstract

We have previously shown that vagus nerve stimulation (VNS) increases effective refractory period (ERP) and ventricular fibrillation threshold (VFT) whilst reducing electrical restitution slope, via an acetycholine independent ‐ nitric oxide (NO) dependent mechanism. NO activates soluble guanylyl cyclase [sGC] to produce cyclic guanylyl monophosphate (cGMP) to modulate cardiac function. Our aim was to investigate if the effects of the VNS‐NO pathway on ERP, VFT and restitution slope were mediated via cGMP mechanisms. The innervated rabbit heart was used (n=5, 2.5–3kg) in constant flow Langendorff mode. Ventricular ERP was determined using a single extrastimulus protocol (300ms cycle length) and maximal restitution slope was measured. VFT was the minimum current needed to induce sustained VF with burst pacing (30×30ms). These were measured at baseline [BL] and during VNS [10Hz, 9V] in control (Ctrl) and following sGC inhibition with (1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one [ODQ], 10μM). Data are mean±SEM, Student's T‐Test, P<0.05 * vs BL, ** vs Ctrl. VNS increased ERP and VFT whilst reducing restitution slope. During sGC inhibition, the vagal effect on restitution slope and VFT were reduced, whilst the effect on ERP was preserved. Cyclic GMP is involved in the protective effects of VNS‐NO pathway against VF but concurrent cGMP independent mechanisms could also be at work. KEB is supported by a British Heart Foundation IBSR Fellowship Table ERP (ms) Slope VFT (mA) Ctrl BL 131.0±3.3 1.48±0.2 3.6 ±0.7 Ctrl VNS 158.0±9.3* 0.99±0.21* 7.0±0.6* Change 16.8±5.9 −0.5±0.1 3.4±0.2 ODQ BL 144.2±4.5 1.3±0.1 3.5±0.7 ODQ VNS 159.0±7.6* 1.2±0.1 5.2±0.8* Change 12.0±3.0 −0.1±0.1** 1.7±0.1**