Vagus nerve stimulation protects against ventricular fibrillation independent of muscarinic receptor activation (original) (raw)
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The Journal of Physiology, 2009
Information regarding vagal innervation in the cardiac ventricle is limited and the direct effect of vagal stimulation on ventricular myocardial function is controversial. We have recently provided indirect evidence that the anti-fibrillatory effect of vagus nerve stimulation on the ventricle is mediated by nitric oxide (NO). The aim of this study was to provide direct evidence for the release of nitric oxide in the cardiac ventricle during stimulation of the efferent parasympathetic fibres of the cervical vagus nerve. The isolated innervated rabbit heart was employed with the use of the NO fluorescent indicator 4,5-diaminofluorescein diacetate (DAF-2 DA) during stimulation of the cervical vagus nerves and acetylcholine perfusion in the absence and presence of the non-specific NO synthase inhibitor N G -nito-l-arginine (l-NNA) and the neuronal NO synthase selective inhibitor 1-(2-trifluormethylphenyl)imidazole (TRIM). Using the novel fluorescence method in the beating heart, we have shown that NO-dependent fluorescence is increased by 0.92 ± 0.26, 1.20 ± 0.30 and 1.91 ± 0.27% (during low, medium and high frequency, respectively) in the ventricle in a stimulation frequency-dependent manner during vagus nerve stimulation, with comparable increases seen during separate stimulation of the left and right cervical vagus nerves. Background fluorescence is reduced during perfusion with l-NNA and the increase in fluorescence during high frequency vagal stimulation is inhibited during perfusion with both l-NNA (1.97 ± 0.35% increase before l-NNA, 0.00 ± 0.02% during l-NNA) and TRIM (1.78 ± 0.18% increase before TRIM, −0.11 ± 0.08% during TRIM). Perfusion with 0.1 μm acetylcholine increased NO fluorescence by 0.76 ± 0.09% which was blocked by l-NNA (change of 0.00 ± 0.03%) but not TRIM (increase of 0.82 ± 0.21%). Activation of cardiac parasympathetic efferent nerve fibres by stimulation of the cervical vagus is associated with NO production and release in the ventricle of the rabbit, via the neuronal isoform of nitric oxide synthase.
The Journal of Physiology, 2007
We have previously shown that direct vagus nerve stimulation (VNS) reduces the slope of action potential duration (APD) restitution while simultaneously protecting the heart against induction of ventricular fibrillation (VF) in the absence of any sympathetic activity or tone. In the current study we have examined the role of nitric oxide (NO) in the effect of VNS. Monophasic action potentials were recorded from a left ventricular epicardial site on innervated, isolated rabbit hearts (n = 7). Standard restitution, effective refractory period (ERP) and VF threshold (VFT) were measured at baseline and during VNS in the presence of the NO synthase inhibitor N G -nitro-L-arginine (L-NA, 200 μM) and during reversing NO blockade with L-arginine (L-Arg, 1 mM). Data represent the mean ± S.E.M. The restitution curve was shifted upwards and became less steep with VNS when compared to baseline. L-NA blocked the effect of VNS whereas L-Arg restored the effect of VNS. The maximum slope of restitution was reduced from 1.17 ± 0.14 to 0.60 ± 0.09 (50 ± 5%, P < 0.0001) during control, from 0.98 ± 0.14 to 0.93 ± 0.12 (2 ± 10%, P = NS) in the presence of L-NA and from 1.16 ± 0.17 to 0.50 ± 0.10 (41 ± 9%, P = 0.003) with L-Arg plus L-NA. ERP was increased by VNS in control from 119 ± 6 ms to 130 ± 6 ms (10 ± 5%, P = 0.045) and this increase was not affected by L-NA (120 ± 4 to 133 ± 4 ms, 11 ± 3%, P = 0.0019) or L-Arg with L-NA (114 ± 4 to 123 ± 4 ms, 8 ± 2%, P = 0.006). VFT was increased from 3.0 ± 0.3 to 5.8 ± 0.5 mA (98 ± 12%, P = 0.0017) in control, 3.4 ± 0.4 to 3.8 ± 0.5 mA (13 ± 12%, P = 0.6) during perfusion with L-NA and 2.5 ± 0.4 to 6.0 ± 0.7 mA (175 ± 50%, P = 0.0017) during perfusion with L-Arg plus L-NA. Direct VNS increased VFT and flattened the slope of APD restitution curve in this isolated rabbit heart preparation with intact autonomic nerves. These effects were blocked using L-NA and reversed by replenishing the substrate for NO production with L-Arg. This is the first study to demonstrate that NO plays an important role in the anti-fibrillatory effect of VNS on the rabbit ventricle, possibly via effects on APD restitution.
Heart Failure Reviews, 2013
Classical physiology teaches that vagal postganglionic nerves modulate the heart via acetylcholine acting at muscarinic receptors, whilst it is accepted that vagus nerve stimulation (VNS) slows heart rate, atrioventricular conduction and decreases atrial contraction; there is continued controversy as to whether the vagus has any significant direct effect on ventricular performance. Despite this, there is a significant body of evidence from experimental and clinical studies, demonstrating that the vagus nerve has an anti-arrhythmic action, protecting against induced and spontaneously occurring ventricular arrhythmias. Over 100 years ago Einbrodt first demonstrated that direct cervical VNS significantly increased the threshold for experimentally induced ventricular fibrillation. A large body of evidence has subsequently been collected supporting the existence of an anti-arrhythmic effect of the vagus on the ventricle. The development of prognostic indicators of heart rate variability and baroreceptor reflex sensitivity-measures of parasympathetic tone and reflex activation respectively-and the more recent interest in chronic VNS therapy are a direct consequence of the earlier experimental studies. Despite this, mechanisms underlying the anti-arrhythmic actions of the vagus nerve have not been fully characterised and are not well understood. This review summarises historical and recently published data to highlight the importance of this powerful endogenous protective phenomenon.
Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2014
Intermittent vagal nerve stimulation (VNS) has emerged as a potential therapy to treat cardiovascular diseases by delivering electrical stimulation to the vagus nerves. The purpose of this study was to investigate the electrophysiological changes in the atrium resulting from long-term intermittent VNS therapy in the chronic myocardial infarction (MI) rat model. MI was induced via left anterior descending coronary artery (LAD) ligation in male Sprague-Dawley rats, randomized into two groups: MI (implanted with nonfunctional VNS stimulators) and MI-VNS (implanted with functional VNS stimulators and received chronic intermittent VNS treatment) groups. Further, a sham group was used as control in which MI was not performed and received nonfunctional VNS stimulators. At 12 weeks, optical mapping of right atrium (RA) of sinus rhythm was performed. Our results demonstrated that chronic MI changed the electrical properties of the atrium action potentials and resulted in reduced action poten...
The role of neuronal nitric oxide in the vagal control of cardiac interval of the rat heart in vitro
Autonomic Neuroscience, 2004
The aim of this study was to examine the role of neuronal nitric oxide (NO) on vagal regulation of the rat heart in vitro using the neuronal nitric oxide synthase (nNOS) inhibitor 1-(2-trifluoromethylphenyl) imidazole (TRIM). All experiments were carried out in the presence of the h-adrenoreceptor antagonist atenolol (4 AM). Right thoracic vagus, or its cardiac branch, was stimulated at frequencies of 2, 4, 8, 16 and 32 Hz (pulse duration 1 ms, 20 V, for 20 s) before and after addition of TRIM (0.14 mM) and cardiac interval (ms) assessed. There was a significant positive linear correlation between cardiac interval and vagal frequency giving a slope of 2.76 F 0.8 ms/Hz (slope F S.E. slope; data pooled from eight rats) which was significantly attenuated following TRIM to 0.4 F 0.6 ms/Hz ( P < 0.05 ANOVA; n = 8 rats). Nicotine applied in cumulative concentrations (0.03, 0.1, 0.3, 0.5, 1 mM) caused a linear concentration-dependent increase in cardiac interval, with a slope of 403 F 72 ms/mM (n = 10 rats) which was significantly attenuated after treatment with hexamethonium (28 AM), to 190 F 36 ms/mM (n = 10 rats, P < 0.05 ANOVA), and atropine (3 AM) 100 F 31 ms/mM (n = 9 rats, P < 0.05 ANOVA) but not following TRIM (0.14 mM) 262 F 48 ms/mM (n = 9 rats, P < 0.05 ANOVA). These results suggest that NO facilitates vagal effects on the rat heart in vitro by an action at the pre-ganglionic/post-ganglionic synapse. D
Experimental Physiology, 2010
The effects of direct autonomic nerve stimulation on the heart may be quite different to those of perfusion with pharmacological neuromodulating agents. This study was designed to investigate the effect of autonomic nerve stimulation on intracellular calcium fluorescence using fura-2 AM in the isolated Langendorff-perfused rabbit heart preparation with intact dual autonomic innervation. The effects of autonomic nerve stimulation on cardiac force and calcium transients were more obvious during intrinsic sinus rhythm. High-frequency (15 Hz, n = 5) right vagus nerve stimulation (VS) decreased heart rate from 142.7 ± 2.6 to 75.5 ± 10.2 beats min -1 and left ventricular pressure from 36.4 ± 3.2 to 25.9 ± 1.9 mmHg, whilst simultaneously decreasing the diastolic and systolic level of the calcium transient. Direct sympathetic nerve stimulation (7 Hz, n = 8) increased heart rate (from 144.7 ± 10.5 to 213.2 ± 4.9 beats min -1 ) and left ventricular pressure (from 37.5 ± 3.6 to 43.7 ± 2.8 mmHg), whilst simultaneously increasing the diastolic and systolic level of the calcium transient. During constant ventricular pacing, the highfrequency right vagus nerve stimulation did not have any direct effect on ventricular force or the calcium transient (n = 8), but was effective in reducing the effect of direct sympathetic nerve stimulation.
Exp Physiol, 2010
The effects of direct autonomic nerve stimulation on the heart may be quite different to those of perfusion with pharmacological neuromodulating agents. This study was designed to investigate the effect of autonomic nerve stimulation on intracellular calcium fluorescence using fura-2 AM in the isolated Langendorff-perfused rabbit heart preparation with intact dual autonomic innervation. The effects of autonomic nerve stimulation on cardiac force and calcium transients were more obvious during intrinsic sinus rhythm. High-frequency (15 Hz, n = 5) right vagus nerve stimulation (VS) decreased heart rate from 142.7 ± 2.6 to 75.5 ± 10.2 beats min -1 and left ventricular pressure from 36.4 ± 3.2 to 25.9 ± 1.9 mmHg, whilst simultaneously decreasing the diastolic and systolic level of the calcium transient. Direct sympathetic nerve stimulation (7 Hz, n = 8) increased heart rate (from 144.7 ± 10.5 to 213.2 ± 4.9 beats min -1 ) and left ventricular pressure (from 37.5 ± 3.6 to 43.7 ± 2.8 mmHg), whilst simultaneously increasing the diastolic and systolic level of the calcium transient. During constant ventricular pacing, the highfrequency right vagus nerve stimulation did not have any direct effect on ventricular force or the calcium transient (n = 8), but was effective in reducing the effect of direct sympathetic nerve stimulation.
Vagal Nerve Stimulation Evoked Heart Rate Changes and Protection from Cardiac Remodeling
Journal of Cardiovascular Translational Research, 2016
This study investigated whether vagal nerve stimulation (VNS) leads to improvements in ischemic heart failure via heart rate modulation. At 7 ± 1 days post left anterior descending artery (LAD) ligation, 63 rats with myocardial infarctions (MI) were implanted with ECG transmitters and VNS devices (MI + VNS, N = 44) or just ECG transmitters (MI, N = 17). VNS stimulation was active from 14 ± 1 days to 8 ± 1 weeks post MI. The average left ventricular (LV) end diastolic volumes at 8 ± 1 weeks were MI = 672.40 μl and MI + VNS = 519.35 μl, p = 0.03. The average heart weights, normalized to body weight (±std) at 14 ± 1 weeks were MI = 3.2 ± 0.6 g*kg(-1) and MI + VNS = 2.9 ± 0.3 g*kg(-1), p = 0.03. The degree of cardiac remodeling was correlated with the magnitude of acute VNS-evoked heart rate (HR) changes. Further research is required to determine if the acute heart rate response to VNS activation is useful as a heart failure biomarker or as a tool for VNS therapy characterization.