Blood Pressure Regulation by the Carotid Sinus Nerve: Clinical Implications for Carotid Body Neuromodulation

Chronic carotid sinus nerve (CSN) electrical modulation through kilohertz frequency alternating current improves metabolic control in rat models of type 2 diabetes, underpinning the potential of bioelectronic modulation of the CSN as a therapeutic modality for metabolic diseases in humans. The CSN carries sensory information from the carotid bodies, peripheral chemoreceptor organs that respond to changes in blood biochemical modifications such as hypoxia, hypercapnia, acidosis, and hyperinsulinemia. In addition, the CSN also delivers information from carotid sinus baroreceptors—mechanoreceptor sensory neurons directly involved in the control of blood pressure—to the central nervous system. The interaction between these powerful reflex systems—chemoreflex and baroreflex—whose sensory receptors are in anatomical proximity, may be regarded as a drawback to the development of selective bioelectronic tools to modulate the CSN. Herein we aimed to disclose CSN influence on cardiovascular regulation, particularly under hypoxic conditions, and we tested the hypothesis that neuromodulation of the CSN, either by electrical stimuli or surgical means, does not significantly impact blood pressure. Experiments were performed in Wistar rats aged 10–12 weeks. No significant effects of acute hypoxia were observed in systolic or diastolic blood pressure or heart rate although there was a significant activation of the cardiac sympathetic nervous system. We conclude that chemoreceptor activation by hypoxia leads to an expected increase in sympathetic activity accompanied by compensatory regional mechanisms that assure blood flow to regional beds and maintenance of hemodynamic homeostasis. Upon surgical denervation or electrical block of the CSN, the increase in cardiac sympathetic nervous system activity in response to hypoxia was lost, and there were no significant changes in blood pressure in comparison to control animals. We conclude that the responses to hypoxia and vasomotor control short-term regulation of blood pressure are dissociated in terms of hypoxic response but integrated to generate an effector response to a given change in arterial pressure.

Effectiveness of radiofrequency renal denervation in diseases with increased sympathetic nervous system activity

The article discusses the role of sympathetic nervous system hyperactivity in the pathogenesis of various pathologies (hypertension, heart failure, atrial fibrillation, metabolic syndrome, diabetes and systemic inflammatory response syndrome). On the example of large randomized clinical trials using catheter-based radiofrequency ablation, the antihypertensive effect in patients with uncontrolled hypertension has been proven. The first experimental and clinical studies on the effectiveness of renal denervation in reducing the activity of inflammatory markers, the incidence of atrial fibrillation and ventricular arrhythmia episodes, and improving the left ventricular contractility. The first clinical results of the favorable effect of renal denervation on carbohydrate metabolism (insulin resistance and glycemic level) in patients with metabolic syndrome and diabetes have been studied in detail.

Spleen Perfusion as an Index of Gender Impact on Sympathetic Nervous System Response to Exercise

Objective: Sympathetic nervous system (SNS) reaction to exercise is gender dependent. Nevertheless, clinically applicable methods to identify this difference are still missing. An organ largely sensitive to SNS is the spleen whose response to exercise can be easily evaluated, being included in the field of view of myocardial perfusion imaging (MPI). Here, we aimed to verify whether gender interferes with the spleen perfusion and its response to exercise.Methods: For this purpose, we evaluated 286 original scans of consecutive patients submitted to MPI in the course of 2019. Our standard procedure implies a single-day stress-rest sequence with a gap of ≥2 h between the administrations of 180 and 500 MBq of 99mTc-Sestamibi, respectively. Imaging is performed 30 min after radiotracer administration, with scan duration set at 25 and 35 s per view, respectively. Non-gated scans were reconstructed with the filtered back-projection method. A volume of interest was drawn on the spleen and heart to estimate the dose-normalized average counting rate that was expressed in normalized counts per seconds (NCPS).Results: In all subjects submitted to exercise MPI (n = 228), NCPS were higher during stress than at rest (3.52 ± 2.03 vs. 2.78 ± 2.07, respectively; p < 0.01). This effect was not detected in the 58 patients submitted to dipyridamole-stress. The response to exercise selectively involved the spleen, since NCPS in heart were unchanged irrespective of the used stressor. This same response was dependent upon gender, indeed spleen NCPS during stress were significantly higher in the 75 women than in the 153 men (3.86 ± 1.8 vs. 3.23 ± 1.6, respectively, p < 0.01). Again, this variance was not reproduced by heart. Finally, spleen NCPS were lower in the 173 patients with myocardial reversible perfusion defects (summed difference score ≥3) than in the remaining 55, despite similar values of rate pressure product at tracer injection.Conclusion: Thus, exercise interference on spleen perfusion can be detected during MPI. This effect is dependent upon gender and ischemia confirming the high sensitivity of this organ to SNS activation.

Catecholamines are key modulators of ventricular repolarization patterns in the ball python (Python regius)

Ectothermic vertebrates experience daily changes in body temperature, and anecdotal observations suggest these changes affect ventricular repolarization such that the T-wave in the ECG changes polarity. Mammals, in contrast, can maintain stable body temperatures, and their ventricular repolarization is strongly modulated by changes in heart rate and by sympathetic nervous system activity. The aim of this study was to assess the role of body temperature, heart rate, and circulating catecholamines on local repolarization gradients in the ectothermic ball python (Python regius). We recorded body-surface electrocardiograms and performed open-chest high-resolution epicardial mapping while increasing body temperature in five pythons, in all of which there was a change in T-wave polarity. However, the vector of repolarization differed between individuals, and only a subset of leads revealed T-wave polarity change. RNA sequencing revealed regional differences related to adrenergic signaling. In one denervated and Ringer’s solution–perfused heart, heating and elevated heart rates did not induce change in T-wave polarity, whereas noradrenaline did. Accordingly, electrocardiograms in eight awake pythons receiving intra-arterial infusion of the β-adrenergic receptor agonists adrenaline and isoproterenol revealed T-wave inversion in most individuals. Conversely, blocking the β-adrenergic receptors using propranolol prevented T-wave change during heating. Our findings indicate that changes in ventricular repolarization in ball pythons are caused by increased tone of the sympathetic nervous system, not by changes in temperature. Therefore, ventricular repolarization in both pythons and mammals is modulated by evolutionary conserved mechanisms involving catecholaminergic stimulation.

The Impact of α-Adrenoceptors in the Regulation of the Hypotonicity-Induced Increase in Duodenal Mucosal Permeability In Vivo

The duodenal mucosa is regularly exposed to a low osmolality, and recent experiments suggest that hypotonicity increases mucosal permeability in an osmolality-dependent manner. The aim was to examine whether the sympathetic nervous system, via action on α-adrenoceptors, affects the hypotonicity-induced increase in duodenal mucosal permeability. The duodenum of anaesthetised rats was perfused in vivo with a 50 mM NaCl solution in the presence of adrenergic α-adrenoceptor drugs. Studied were the effects on mucosal permeability (blood-to-lumen clearance of 51Cr-EDTA), arterial blood pressure, luminal alkalinisation, transepithelial fluid flux, and motility. Hypotonicity induced a six-fold increase in mucosal permeability, a response that was reversible and repeatable. The α2-adrenoceptor agonist clonidine abolished the hypotonicity-induced increase in mucosal permeability, reduced arterial blood pressure, inhibited duodenal motility, and decreased luminal alkalinisation. The α2-adrenoceptor antagonists, yohimbine and idazoxan, prevented the inhibitory effect of clonidine on the hypotonicity-induced increase in mucosal permeability. The α1-agonist phenylephrine or the α1-antagonist prazosin elicited their predicted effect on blood pressure but did not affect the hypotonicity-induced increase in mucosal permeability. None of the α1- or α2-adrenoceptor drugs changed the hypotonicity-induced net fluid absorption. In conclusion, stimulation of the adrenergic α2-adrenoceptor prevents the hypotonicity-induced increase in mucosal permeability, suggesting that the sympathetic nervous system has the capability to regulate duodenal mucosal permeability.

Reduced prefrontal cortex and sympathetic nervous system activity correlate with fatigue after aHSCT

Long-term fatigue and cognitive dysfunction affects 35% of allogeneic haematopoietic stem cell transplantation (aHSCT) survivors, suggesting a dysfunctional prefrontal cortex. In this study, we assessed prefrontal cortex and sympathetic nervous system activity in aHSCT patients with fatigue (n = 12), non-fatigued patients (n = 12) and healthy controls (n = 27). Measurement of near-infrared spectroscopy and electrodermal activity was carried out at rest and during cognitive performance (Stroop, verbal fluency and emotion regulation tasks). Prefrontal cortex and sympathetic nervous system activity were also analyzed in response to dopamine and noradrenaline increase after a single dose of methylphenidate. Baseline cognitive performance was similar in the two patient groups. However, after methylphenidate, only non-fatigued patients improved in Stroop accuracy and had better verbal fluency task performance compared to the fatigued group. Task-related activation of prefrontal cortex in fatigued patients was lower compared to non-fatigued patients during all cognitive tests, both before and after methylphenidate administration. During the Stroop task, reaction time, prefrontal cortex activation, and sympathetic nervous system activity were all lower in fatigued patients compared to healthy controls, but similar in non-fatigued patients and healthy controls.Reduced prefrontal cortex activity and sympathetic arousal suggests novel treatment targets to improve fatigue after aHSCT.