Metabolic effects of antihypertensive drugs interacting with the sympathetic nervous system

he purpose of this study was to test the hypothesis that heightened sympathetic nervous system (SNS) activity contributes to the mechanism by which hypertension is associated with insulin resistance in humans. We performed frequently sampled intravenous glucose tolerance tests to determine tissue sensitivity to metabolic effects of insulin (SI) and measured plasma norepinephrine (NE) levels in 21 normotensive and 14 hypertensive Caucasian subjects. Compared with the normotensive subjects, hypertensive subjects had decreased SI (5.4 +/- 0.5 vs. 4.0 +/- 0.7 x 10(-5) x min-1 x pM-1; P = 0.03) but similar plasma NE levels (normotensive: 1.82 +/- 0.12 vs. hypertensive: 1.73 +/- 0.16 nM; P = 0.23). In a multiple regression model, only body mass index (BMI) and mean arterial blood pressure (MABP) were significant independent predictors of SI [SI = (-0.513)(BMI) + (-0.058)(MABP) + 23.6; r = 0.748; P = 0.0001]; age, plasma glucose, epinephrine, and NE level did not enter this model. As an additional test of this hypothesis, seven hypertensive subjects were restudied after 10 days of guanadrel therapy to determine whether SI would increase during suppression of SNS activity by guanadrel. Despite a significant reduction in plasma NE levels with guanadrel (baseline: 1.63 +/- 0.18 vs. guanadrel: 0.99 +/- 0.14 nM; P = 0.01), there was no significant change in SI (baseline: 2.97 +/- 0.78 vs. guanadrel: 2.41 +/- 0.54 x 10(-5).min-1 x pM-1; analysis of variance P = 0.57). We conclude that, in the Caucasian population we studied, heightened SNS activity is not essential for the insulin resistance observed in hypertensive humans.

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Abstract 291: Antihypertensive Effect Of Bia 5-1058 a New Selective Peripheral Dopamine β-hydroxylase Inhibitor

Hypertension ◽

10.1161/hyp.60.suppl_1.a291 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Bruno Igreja ◽

Nuno M Pires ◽

Lyndon C Wright ◽

Patrío Soares-da-Silva

Keyword(s):

Blood Pressure ◽

Nervous System ◽

Sympathetic Nervous System ◽

Receptor Antagonist ◽

Antihypertensive Effect ◽

Antihypertensive Drugs ◽

Radio Telemetry ◽

Sympathetic Nerves ◽

Maximum Reduction ◽

Sympathetic Nervous

The sympathetic nervous system can alter blood pressure by modulation of cardiac output, peripheral vascular resistance and renal function. One strategy for controlling sympathetic nerve function is to reduce the biosynthesis of norepinephrine (NE) via inhibition of dopamine β-hydroxylase (DβH; EC 1.14.17.1 ), the enzyme that catalyses the conversion of dopamine (DA) to NE in sympathetic nerves. BIA 5-1058 is a reversible DβH inhibitor that decreases NE levels in peripheral sympathetically innervated tissues slowing down sympathetic nervous system drive, without effect in brain tissues. In freely moving SHR implanted with radio-telemetry transmitters single administration of BIA 5-1058 showed a dose (3, 30 and 100 mg/Kg) and time dependent effect on blood pressure with no significant effect on heart rate (HR) and total activity monitored over a 96-hour period. The maximum reduction on systolic blood pressure (SBP) was -10.8, -21.1 and -35.2 mmHg for 3, 30 and 100 mg/Kg, respectively and the maximum reduction on diastolic blood pressure (DBP) was -9.9, -18.4 and -24.8 mmHg for 3, 30 and 100 mg/Kg, respectively. The antihypertensive effect of BIA 5-1058 (30 mg/Kg) was further evaluated in combination with efficacious doses of well-known antihypertensive drugs, like the ACE inhibitor captopril, the AT1 receptor antagonist losartan, the diuretic hydrochlorothiazide, beta-blocker metoprolol, the alpha-1 receptor antagonist prazosin, and the calcium channel blocker diltiazem. All drugs were administered orally (single dose) in a cross-over design and the effect was monitored for 72 hours. The combination of BIA 5-1058 with any of the tested antihypertensive drugs caused a stronger and prolonged blood pressure decrease than any of the compounds alone.In conclusion, peripheral DβH inhibitors can be used, alone or in combination with others antihypertensive drugs, to reduce blood pressure.

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Antihypertensive Drugs and the Sympathetic Nervous System

Journal of Cardiovascular Pharmacology ◽

10.1097/fjc.0b013e318135446c ◽

2007 ◽

Vol 50 (5) ◽

pp. 487-496 ◽

Cited By ~ 26

Author(s):

Sara Del Colle ◽

Fulvio Morello ◽

Franco Rabbia ◽

Alberto Milan ◽

Diego Naso ◽

...

Keyword(s):

Nervous System ◽

Sympathetic Nervous System ◽

Antihypertensive Drugs ◽

Sympathetic Nervous

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Renal Denervation Therapy (RDT) in Resistant Hypertension

BIRDEM Medical Journal ◽

10.3329/birdem.v2i2.12325 ◽

2012 ◽

Vol 2 (2) ◽

pp. 104-112

Author(s):

Mohammad Gaffar Amin ◽

Hasna Fahmima Haque

Keyword(s):

Blood Pressure ◽

Nervous System ◽

Sympathetic Nervous System ◽

Renal Artery ◽

Resistant Hypertension ◽

Renal Denervation ◽

Antihypertensive Drugs ◽

Antihypertensive Agents ◽

Radiofrequency Energy ◽

Sympathetic Nervous

Resistant hypertension is defined as blood pressure that remains above therapeutic goal despite the use of three antihypertensive drugs including a diuretic. As much as one third of patients with arterial hypertension are treatmentrefractory as they do not reach sufficient blood pressure control despite combination antihypertensive therapy of significant duration. The hyperactivity of sympathetic nervous system (SNS) in the occurrence of treatment-resistant long standing hypertension has been established both in animal models and in clinical practice. In these patients, the kidneys play a central role as an activator of the sympathetic nervous system. The failure of purely pharmacological approaches to treat resistant hypertension has stimulated interest in invasive device-based treatments based on old concepts. In the absence of orally active antihypertensive agents, patients with severe and complicated hypertension were widely treated by surgical denervation of the kidneys until the 1960s, but this approach was associated with a high incidence of severe adverse events and a high mortality rate. A new catheter system using radiofrequency energy has been developed, allowing an endovascular approach to renal denervation and providing patients, with resistant hypertension, with a new therapeutic option that is minimally invasive and can be performed rapidly under local anaesthesia. With this method the afferent and efferent sympathetic nervous fibers surrounding the renal artery are ablated precisely keeping the renal artery intact. To date, this technique has been evaluated only in open-label trials including small numbers of highly selected resistant hypertensive patients with suitable renal artery anatomy. The available evidence suggests a significant and persistent blood pressure-lowering effect and a very low incidence of short & long term complications with no deleterious effects on renal function. These data, although promising, need confirmation in larger randomized controlled clinical trials with longerterm follow-up.DOI: http://dx.doi.org/10.3329/birdem.v2i2.12325(Birdem Med J 2012; 2(2): 104-112)

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Antihypertensive Drugs and the Sympathetic Nervous System

Journal of Cardiovascular Pharmacology ◽

10.1097/00005344-200000004-00006 ◽

2000 ◽

Vol 35 ◽

pp. S43-S52 ◽

Cited By ~ 20

Author(s):

Ren?? R. Wenzel ◽

Heike Bruck ◽

Georg Noll ◽

Rafael F. Sch??fers ◽

Anton E. Daul ◽

...

Keyword(s):

Nervous System ◽

Sympathetic Nervous System ◽

Antihypertensive Drugs ◽

Sympathetic Nervous

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Endocannabinoid Receptor-1 and Sympathetic Nervous System Mediate the Beneficial Metabolic Effects of Gastric Bypass

Cell Reports ◽

10.1016/j.celrep.2020.108270 ◽

2020 ◽

Vol 33 (4) ◽

pp. 108270 ◽

Cited By ~ 1

Author(s):

Yuanchao Ye ◽

Marwa Abu El Haija ◽

Donald A. Morgan ◽

Deng Guo ◽

Yang Song ◽

...

Keyword(s):

Gastric Bypass ◽

Nervous System ◽

Sympathetic Nervous System ◽

Metabolic Effects ◽

Sympathetic Nervous ◽

Endocannabinoid Receptor

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Relevance of Sympathetic Nervous System Activation in Obesity and Metabolic Syndrome

Journal of Diabetes Research ◽

10.1155/2015/341583 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 133

Author(s):

Alicia A. Thorp ◽

Markus P. Schlaich

Keyword(s):

Metabolic Syndrome ◽

Nervous System ◽

Sympathetic Nervous System ◽

Metabolic Control ◽

Energy Homeostasis ◽

Metabolic Effects ◽

Metabolic Abnormalities ◽

Sympathetic Overactivity ◽

The Metabolic Syndrome ◽

Sympathetic Nervous

Sympathetic tone is well recognised as being implicit in cardiovascular control. It is less readily acknowledged that activation of the sympathetic nervous system is integral in energy homeostasis and can exert profound metabolic effects. Accumulating data from animal and human studies suggest that central sympathetic overactivity plays a pivotal role in the aetiology and complications of several metabolic conditions that can cluster to form the Metabolic Syndrome (MetS). Given the known augmented risk for type 2 diabetes, cardiovascular disease, and premature mortality associated with the MetS understanding the complex pathways underlying the metabolic derangements involved has become a priority. Many factors have been proposed to contribute to increased sympathetic nerve activity in metabolic abnormalities including obesity, impaired baroreflex sensitivity, hyperinsulinemia, and elevated adipokine levels. Furthermore there is mounting evidence to suggest that chronic sympathetic overactivity can potentiate two of the key metabolic alterations of the MetS, central obesity and insulin resistance. This review will discuss the regulatory role of the sympathetic nervous system in metabolic control and the proposed pathophysiology linking sympathetic overactivity to metabolic abnormalities. Pharmacological and device-based approaches that target central sympathetic drive will also be discussed as possible therapeutic options to improve metabolic control in at-risk patient cohorts.

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Uncontrolled Arterial Hypertension: Kidney, Neurohormonal Imbalance, and Approaches to Antihypertensive Drug Therapy

Kardiologiia ◽

10.18087/cardio.2019.12.n547 ◽

2019 ◽

Vol 59 (12) ◽

pp. 64-71

Author(s):

O. B. Kuzmin ◽

N. N. Buchneva ◽

V. V. Zhezha ◽

S. V. Serdyuk

Keyword(s):

Nervous System ◽

Drug Therapy ◽

Sympathetic Nervous System ◽

Arterial Hypertension ◽

Antihypertensive Drug ◽

Antihypertensive Drugs ◽

Mechanisms Of Action ◽

Antihypertensive Drug Therapy ◽

Sodium Reabsorption ◽

Sympathetic Nervous

Resistant and refractory arterial hypertensions are two distinct clinical phenotypes of uncontrolled arterial hypertension (AH), which differ in their sensitivity to antihypertensive drug therapy. The review presents data obtained in clinical studies devoted to elucidating the involvement of disorders of neurohormonal status and renal function in the formation of resistant and refractory arterial hypertension, to and the development of new approaches to increasing the effectiveness of antihypertensive therapy in these patient’s populations. The results of these studies have shown that in patients with uncontrolled arterial hypertension, despite prolonged intake ≥ 3 antihypertensive drugs with different mechanisms of action, including a diuretic, excess sodium reabsorption persists in the distal segments of nephron due to increased aldosterone activity and sympathetic nervous system hyperactivity. In this regard, special attention has been paid to the data of PATHWAY-2, PATHWAY-3 and ReHOT trials that in patients with resistant AH tested the clinical efficacy of spironolactone, amiloride, and antiadrenergic drugs bisoprolol, doxazosin and clonidine, suppressing activity of the sympathetic nervous system.

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