Vagal nerve stimulation therapy: what is being stimulated?

Vagal nerve stimulation in cardiac therapy involves delivering electrical current to the vagal sympathetic complex in patients experiencing heart failure. The therapy has shown promise but the mechanisms by which any benefit accrues is not understood. In this paper we model the response to increased levels of stimulation of individual components of the vagal sympathetic complex as a differential activation of each component in the control of heart rate. The model provides insight beyond what is available in the animal experiment in as much as allowing the simultaneous assessment of neuronal activity throughout the cardiac neural axis. The results indicate that there is sensitivity of the neural network to low level subthreshold stimulation. This leads us to propose that the chronic effects of vagal nerve stimulation therapy lie within the indirect pathways that target intrinsic cardiac local circuit neurons because they have the capacity for plasticity

The binding of botulinum neurotoxins to different peripheral neurons

Botulinum neurotoxins are the most potent toxins known. The double receptor binding modality represents one of the most significant properties of botulinum neurotoxins and largely accounts for their incredible potency and lethality. Despite the high affinity and the very specific binding, botulinum neurotoxins are versatile and multi-tasking toxins. Indeed they are able to act both at the somatic and at the autonomic nervous system. In spite of the preference for cholinergic nerve terminals botulinum neurotoxins have been shown to inhibit to some extent also the noradrenergic postganglionic sympathetic nerve terminals and the afferent nerve terminals of the sensory neurons inhibiting the release of neuropeptides and glutamate, which are responsible of nociception. Therefore, there is increasing evidence that the therapeutic effect in both motor and autonomic disorders is based on a complex mode of botulinum neurotoxin action modulating the activity of efferent as well as afferent nerve fibres

Preganglionic innervation of the pancreas islet cells in the rat

The position and number of preganglionic somata innervating the insulin-secreting β-cells of the endocrine pancreas were investigated in Wistar rats. This question was approached by comparing the innervation of the pancreas of normal rats with the innervation of the pancreas in alloxan-induced diabetic animals. The presumption was made that alloxan treatment destroys the β-cells of the islet of Langerhans and results in a selective degeneration of the β-cells innervation. Cell bodies of preganglionic fibers innervating the pancreas were identified by retrograde transport of horseradish peroxidase following pancreas injections. It was found that 25% of the cells innervating the pancreas in the left dorsal vagal motor nucleus, 50% of the cells in the ambiguus nucleus and 50% of the cells innervating the pancreas, that originate in segments C3-C4 of the spinal cord, fail to become labeled after alloxan treatment. The position and distribution of these cell groups are described in detail and are assumed to be involved in preganglionic β-cell innervation. A second cell population in the ventral horn and intermediolateral column of the segments T3-L2 of the cord also was labeled in normal rats and was not affected by the alloxan treatment. These thoracic cell groups are thus considered as sympathetic preganglionic somata that maintain direct connections to the pancreas. Additional preliminary information is presented dealing with the general aspects of sympathetic and parasympathetic organization of the pancreas innervation.

Photoplethysmography for Quantitative Assessment of Sympathetic Nerve Activity (SNA) During Cold Stress

The differences in the degree of sympathetic nerve activity (SNA) over cutaneous blood vessels, although known to be more prominent in the periphery than the core vasculature, has not been thoroughly investigated quantitatively. Hence, two studies were carried out to investigate the differences in SNA between the periphery and the core during the cold pressor test (CPT) (right-hand immersion in ice water) and cold exposure (whole body exposed to cold air) using photoplethysmography (PPG). Two methods utilizing PPG, namely differential multi-site PTT measurements and low-frequency spectral analysis were explored for quantitative determination of SNA. Each study involved 12 healthy volunteers, and PPG signals were acquired from the right index finger (RIF), left index finger (LIF) (periphery) and the ear canal (core). During CPT, Pulse Transit Time (PTT) was measured to the respective locations and the mean percentage change in PTT during ice immersion at each location was used as an indicator for the extent of SNA. During cold exposure, the low-frequency spectral analysis was performed on the acquired raw PPGs to extract the power of the sympathetic [low-frequency (LF): 0.04–0.15 Hz] and parasympathetic components [high-frequency (HF): 0.15–0.4 Hz]. The ratio of LF/HF components was then used to quantify the differences in the influence of SNA on the peripheral and core circulation. PTT measured from the EC, and the LIF has dropped by 5 and 7%, respectively during ice immersion. The RIF PTT, on the other hand, has dropped significantly (P < 0.05) by 12%. During the cold exposure, the LF/HF power ratio at the finger has increased to 86.4 during the cold exposure from 19.2 at the baseline (statistically significant P = 0.002). While the ear canal LF/HF ratio has decreased to 1.38 during the cold exposure from 1.62 at baseline (P = 0.781). From these observations, it is evident that differential PTT measurements or low-frequency analysis can be used to quantify SNA. The results also demonstrate the effectiveness of the central auto-regulation during both short and long-term stress stimulus as compared to the periphery

Neural regulation of cardiovascular response to exercise: role of central command and peripheral afferents

During dynamic exercise, mechanisms controlling the cardiovascular apparatus operate to provide adequate oxygen to fulfill metabolic demand of exercising muscles and to guarantee metabolic end-products washout. Moreover, arterial blood pressure is regulated to maintain adequate perfusion of the vital organs without excessive pressure variations. The autonomic nervous system adjustments are characterized by a parasympathetic withdrawal and a sympathetic activation. In this review, we briefly summarize neural reflexes operating during dynamic exercise. The main focus of the present review will be on the central command, the arterial baroreflex and chemoreflex, and the exercise pressure reflex. The regulation and integration of these reflexes operating during dynamic exercise and their possible role in the pathophysiology of some cardiovascular diseases are also discusse

Identification of atropine-and P2X1 receptor antagonist-reistant, neurogenic contractions of the urinary bladder

Acetylcholine and ATP are excitatory cotransmitters in parasympathetic nerves. We used P2X1 receptor antagonists to further characterize the purinergic component of neurotransmission in isolated detrusor muscle of guinea pig urinary bladder. In the presence of atropine (1 μm) and prazosin (100 nm), pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS) (0.1–100 μm) and suramin (1–300 μm) inhibited contractions evoked by 4 Hz nerve stimulation in a concentration-dependent manner (IC50 of 6.9 and 13.4 μm, respectively). Maximum inhibition was 50–60%, which was unaffected by coadministration of the ectonucleotidase inhibitor ARL67156 (6-N,N-diethyl-d-β,γ-dibromomethyleneATP) (100 μm). The remaining responses were abolished by tetrodotoxin (1 μm). PPADS and suramin also reduced contractions to exogenous ATP (300 μm) by 40–50%, but abolished those to the P2X1 agonist α,β-methyleneATP (α,β-meATP) (1 μm). The P2X1 antagonists reactive blue 2, NF279 (8,8′-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)] bis-1,3,5-naphthalenetrisulfonic acid), MRS2159 (pyridoxal-α5-phosphate-6-phenylazo-4′-carboxylic acid) (100 μm), and NF449 [4,4′,4,4-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis-benzene-1,3-disulfonic acid] (3 μm) abolished contractions to α,β-meATP (1 μm; n = 4–5), but only reduced contractions evoked by 4 Hz nerve stimulation by ∼40–60% (n = 4–6) and ATP by 30–60% (n = 4–7). However, prolonged exposure to α,β-meATP (50 μm) abolished contractions evoked by all three stimuli (n = 5–12). PPADS (100 μm) and suramin (300 μm) reduced the peak neurogenic contraction of the mouse urinary bladder to 30–40% of control. At the same concentrations, the P2X1 antagonists abolished the nonadrenergic, purinergic component of neurogenic contractions in the guinea pig vas deferens (n = 4–5). Thus, P2X1 receptor antagonists inhibit, but do not abolish, the noncholinergic component of neurogenic contractions of guinea pig and mouse urinary bladder, indicating a second mode of action of neuronally released ATP. This has important implications for treatment of dysfunctional urinary bladder, for which this atropine- and P2X1 antagonist-resistant site represents a novel therapeutic target

Autonomic regulation therapy to enhance myocardial function in heart failure patients: the ANTHEM-HFpEF study.

BackgroundApproximately half of the patients presenting with new-onset heart failure (HF) have HF with preserved left ventricular ejection fraction (HFpEF) and HF with mid-range left ventricular ejection fraction (HFmrEF). These patients have neurohormonal activation like that of HF with reduced ejection fraction; however, beta-blockers and angiotensin-converting enzyme inhibitors have not been shown to improve their outcomes, and current treatment for these patients is symptom based and empiric. Sympathoinhibition using parasympathetic stimulation has been shown to improve central and peripheral aspects of the cardiac nervous system, reflex control, induce myocyte cardioprotection, and can lead to regression of left ventricular hypertrophy. Beneficial effects of autonomic regulation therapy (ART) using vagus nerve stimulation (VNS) have also been observed in several animal models of HFpEF, suggesting a potential role for ART in patients with this disease.MethodsThe Autonomic Neural Regulation Therapy to Enhance Myocardial Function in Patients with Heart Failure and Preserved Ejection Fraction (ANTHEM-HFpEF) study is designed to evaluate the feasibility, tolerability, and safety of ART using right cervical VNS in patients with chronic, stable HFpEF and HFmrEF. Patients with symptomatic HF and HFpEF or HFmrEF fulfilling the enrolment criteria will receive chronic ART with a subcutaneous VNS system attached to the right cervical vagus nerve. Safety parameters will be continuously monitored, and cardiac function and HF symptoms will be assessed every 3 months during a post-titration follow-up period of at least 12 months.ConclusionsThe ANTHEM-HFpEF study is likely to provide valuable information intended to expand our understanding of the potential role of ART in patients with chronic symptomatic HFpEF and HFmrEF

Effect of obesity on autonomic nervous system

The present study was carried out on 100 volunteers of which 50 subjects with BMI > 30kg/m2 were included in study group and 50 subjects with BMI < 30kg/m2 (non obese) were included in control group. The functioning of Autonomic nervous system was evaluated by six non-invasive tests- four of which were based mainly on parasympathetic control (30:15 ratio, standing to lying ratio (S/L ratio), expiration/inspiration ratio (E/I ratio) and valsalva maneuver) and two on sympathetic control (Blood pressure response to standing and cold pressor test). The results of the present study showed significantly low (p=0.001) S/L ratio in study group (1.04 ± 0.12) when compared to controls (1.12 ± 0.11) indicating impaired parasympathetic function. The mean change in sytolic blood pressure before and after cold pressor test (CPT) was less in study group (7.12 ± 5.28) as compared to control group (10.38 ± 6.35) and this was statistically significant (p=0.006) indicating impaired sympatheitc function. Thus ,in obese both division of ANS are affected which may be the cause of various cardiovascular complications