Relationships of Adrenoceptor Polymorphisms with Obesity

Obesity, hypertension, and type 2 diabetes are rapidly growing public health problems. Heightened sympathetic nerve activity is a well-established observation in obesity, hypertension, and type 2 diabetes. Human obesity, hypertension, and diabetes have strong genetic as well as environmental determinants. Reduced energy expenditure and resting metabolic rate are predictive of weight gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis. The thermogenic effects of catecholamines in obesity are mainly mediated via the β2, and β3-adrenergic receptors in humans. Further, β2-adrenoceptors importantly influence vascular reactivity and may regulate blood pressure. β-adrenoceptor polymorphisms have also been associated with adrenoceptor desensitization, increased adiposity, insulin resistance, and enhanced sympathetic nervous activity. Many epidemiological studies have shown strong relationships between adrenoceptor polymorphisms and obesity, but the observations have been discordant. This paper will discuss the current topics involving the influence of the sympathetic nervous system and β2- and β3-adrenoceptor polymorphisms in obesity

Advances in Sympathetic Nerve Recording in Humans

In humans, sympathetic activity is commonly assessed by measuring the efferent traffic in the peroneal nerve. The firing activity is the sum of several active neurons, which have the tendency to fire together in a bursting manner. While the estimation of overall sympathetic nervous activity using this multiunit recording approach has advanced our understanding of sympathetic regulation in health and disease no information is gained regarding the underling mechanisms generating the bursts of sympathetic activity. The introduction of single-unit recording has been a major step forward, enabling the examination of specific sympathetic firing patterns in diverse clinical conditions. Disturbances in sympathetic nerve firing, including high firing probabilities, high firing rates or high incidence of multiple firing, or a combination of both may impact on noradrenaline release and effector response, and therefore have clinical implications with regards to the development and progression of target organ damage. Understanding the mechanisms and consequences of specific firing patterns would permit the development of therapeutic strategies targeting these nuances of sympathetic overdrive

Effects of Renal Denervation on Sympathetic Activation, Blood Pressure, and Glucose Metabolism in Patients with Resistant Hypertension

Increased central sympathetic drive is a hallmark of several important clinical conditions including essential hypertension, heart failure, chronic kidney disease, and insulin resistance. Afferent signaling from the kidneys has been identified as an important contributor to elevated central sympathetic drive and increased sympathetic outflow to the kidney and other organs is crucially involved in cardiovascular control. While the resultant effects on renal hemodynamic parameters, sodium and water retention, and renin release are particularly relevant for both acute and long term regulation of blood pressure, increased sympathetic outflow to other vascular beds may facilitate further adverse consequences of sustained sympathetic activation such as insulin resistance, which is commonly associated with hypertension. Recent clinical studies using catheter-based radiofrequency ablation technology to achieve functional renal denervation in patients with resistant hypertension have identified the renal nerves as therapeutic target and have helped to further expose the sympathetic link between hypertension and insulin resistance. Initial data from two clinical trials and several smaller mechanistic clinical studies indicate that this novel approach may indeed provide a safe and effective treatment alternative for resistant hypertension and some of its adverse consequences

Change in Sympathetic Nerve Firing Pattern Associated with Dietary Weight Loss in the Metabolic Syndrome

Sympathetic activation in subjects with the metabolic syndrome (MS) plays a role in the pathogenesis of cardiovascular disease development. Diet-induced weight loss decreases sympathetic outflow. However the mechanisms that account for sympathetic inhibition are not known. We sought to provide a detailed description of the sympathetic response to diet by analyzing the firing behavior of single-unit sympathetic nerve fibers. Fourteen subjects (57 ± 2 years, nine men, five females) fulfilling ATP III criteria for the MS underwent a 3-month low calorie diet. Metabolic profile, hemodynamic parameters, and multi-unit and single-unit muscle sympathetic nerve activity (MSNA, microneurography) were assessed prior to and at the end of the diet. Patients’ weight dropped from 96 ± 4 to 88 ± 3 kg (P < 0.001). This was associated with a decrease in systolic and diastolic blood pressure (−12 ± 3 and −5 ± 2 mmHg, P < 0.05), and in heart rate (−7 ± 2 bpm, P < 0.01) and an improvement in all metabolic parameters (fasting glucose: −0.302.1 ± 0.118 mmol/l, total cholesterol: −0.564 ± 0.164 mmol/l, triglycerides: −0.414 ± 0.137 mmol/l, P < 0.05). Multi-unit MSNA decreased from 68 ± 4 to 59 ± 5 bursts/100 heartbeats (P < 0.05). Single-unit MSNA indicated that the firing rate of individual vasoconstrictor fibers decreased from 59 ± 10 to 32 ± 4 spikes/100 heart beats (P < 0.05). The probability of firing decreased from 34 ± 5 to 23 ± 3% of heartbeats (P < 0.05), and the incidence of multiple firing decreased from 14 ± 4 to 6 ± 1% of heartbeats (P < 0.05). Cardiac and sympathetic baroreflex function were significantly improved (cardiac slope: 6.57 ± 0.69 to 9.57 ± 1.20 ms·mmHg−1; sympathetic slope: −3.86 ± 0.34 to −5.05 ± 0.47 bursts/100 heartbeats·mmHg−1, P < 0.05 for both). Hypocaloric diet decreased sympathetic activity and improved hemodynamic and metabolic parameters. The sympathoinhibition associated with weight loss involves marked changes, not only in the rate but also in the firing pattern of active vasoconstrictive fibers

A Challenged Sympathetic System Is Associated with Retinal Vascular Calibre in a Black Male Cohort: The SABPA Study

Sympathetic system hyperactivity and depression are related to cardiac remodelling in Black men. We investigated whether sympathetic system hyperactivity and depressive symptoms are related to retinal vascular dysregulation. A total of 76 Black and 83 White men (23–68 years of age) from the SABPA study were included. Depressive symptoms, 24h pulse pressure (PP), fasting blood and 24-hour urinary catecholamine data were obtained. Retinal vascular calibre was quantified from digital photographs using standardized protocols. Black men demonstrated increased (p 50 mmHg), hypertension (78.9 % vs 48.4%) and depression (34.2% vs. 13.3%) prevalence compared to White men. Despite lower epinephrine levels, epinephrine was associated with arteriolar narrowing and venular widening in the Black men [Adj R2 −0.37 (95% CI: −0.66, −0.09), p=0.013; Adj R2 0.35 (95% CI: 0.13, 0.57), p=0.003]. This might suggest ß-adrenergic hyporesponsivity to epinephrine, which was accompanied by hyperpulsatile blood pressure in the Black group. In the White group, depressive symptoms and norepinephrine were associated with retinal arteriolar narrowing. A profile of ß-adrenergic hyporesponsivity, indicative of a chronically challenged sympathetic system, was associated with retinal vascular remodelling in Black men. ß-adrenergic hyporesponsivity as a result of chronic stress emphasized central control of the brain on the circulatory system irrespective of the vascular bed

Effect of Central Sympathoinhibition With Moxonidine on Sympathetic Nervous Activity in Polycystic Ovary Syndrome—A Randomized Controlled Trial

Sympathetic nervous system (SNS) activity is increased in polycystic ovary syndrome (PCOS). Moxonidine is a centrally acting sympatholytic drug with known beneficial effects on hypertension, insulin sensitivity, dyslipidemia and inflammation. In this double-blind placebo controlled randomized clinical trial we examined the effect of moxonidine on modulating sympathetic activity and downstream metabolic abnormalities in 48 pre-menopausal women with PCOS (Rotterdam diagnostic criteria), recruited from the community (January 2013–August 2015). Participants received moxonidine (0.2 mg daily initially, up titrated to 0.4 mg daily in 2 weeks) (n = 23) or placebo (n = 25) for 12 weeks. Multiunit muscle sympathetic activity (by microneurography) and plasma noradrenaline levels were measured (primary outcomes). Fasting lipids, insulin resistance, serum androgens, and inflammatory markers were measured as secondary outcomes. Forty three women completed the trial (19 moxonidine, 24 placebo). Mean change in burst frequency (−3 ± 7 vs. −3 ± 8 per minute) and burst incidence (−3 ± 10 vs. −4 ± 12 per 100 heartbeat) did not differ significantly between moxonidine and placebo groups. Women on moxonidine had a significant reduction in hs-CRP compared to placebo group (−0.92 ± 2.3 vs. −0.04 ± 1.5) which did not persist post Bonferroni correction. There was a significant association between markers of insulin resistance at baseline and reduction in sympathetic activity with moxonidine. Moxonidine was not effective in modulating sympathetic activity in PCOS. Anti-inflammatory effects of moxonidine and a relationship between insulin resistance and sympathetic response to moxonidine are suggested which need to be further explored.Clinical Trial Registration Number: (NCT01504321