부산대학교 도서관

Introduction We have previously shown that vagus nerve stimulation (VNS) flattens electrical restitution (RT) slope and increases ventricular fibrillation threshold (VFT) via a nitric oxide (NO) dependent mechanism [1] that is independent on acetycholine [2]. The aim of this study was to elucidate whether NO release from neuronal nitric oxide synthase (nNOS) mediates this anti-fibrillatory effect. Methods Adult New Zealand White rabbits (n=5, 3.0-3.5Kg) 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.), anaesthetised (propofol, 5mg as required, i.v.) and their hearts isolated with intact autonomic innervation. Animals were humanely killed with an overdose of sodium pentobarbitone (160mg/kg, i.v.). The preparations were perfused in constant flow Langendorff mode and instrumented for the measurement of left ventricular pressure (LVP) and epicardial monophasic action potentials. RT slope and effective refractory period (ERP) was measured using single extrastimulus protocol (300ms cycle length). VFT was the minimum current needed to induce sustained VF with burst pacing (30x30ms). The effects of VNS on baseline (BL) parameters were measured in control conditions, during perfusion of the selective nNOS inhibitor (TRIM,200µM) and following drug washout. Data are mean±SEM. 2-way ANOVA with Bonferroni or paired t-test, *P<0.05 vs. BL, **P<0.01 vs. BL, ***P<0.001 vs. BL. Results VNS flattened the maximum RT slope (Fig 1A), prolonged ERP (Fig 1B) and increased VFT (Fig 1C). Perfusion of TRIM abolished the effects of VNS on RT slope and VFT but had no effect on the VNS increase in ERP (Fig 1). TRIM exerted a negative inotropic effect reducing peak LVP (33±3 [TRIM] vs. 41±3 [Control] mmHg, P<0.05) with no effect on baseline heart rate (135 ±5 [TRIM] vs. 135±5 [Control] bpm) or coronary perfusion pressure (30±2 [TRIM] vs. 30±1 [Control] mmHg). The degree of heart rate reduction during VNS was reduced by TRIM perfusion (change in heart rate, -45±6 [TRIM] vs. -63±5 [Control] bpm, P<0.05). All effects of TRIM were reversed on drug washout. Conclusion NO release from nNOS mediates the direct anti-fibrillatory action of VNS. Further experimental work is required to investigate the mechanism by which NO exerts this protective effects. [ABSTRACT FROM AUTHOR]