Neural mechanisms in human obesity-related hypertension

Baker Medical Research Institute and Alfred Baker Medical Unit, Alfred Hospital, Melbourne, Australia.
Journal of Hypertension (Impact Factor: 4.72). 09/1999; 17(8):1125-33. DOI: 10.1097/00004872-199917080-00012
Source: PubMed


Two hypotheses concerning mechanisms of weight gain and of blood pressure elevation in obesity were tested. The first hypothesis is that in human obesity sympathetic nervous system underactivity is present, as a metabolic basis for the obesity. The second hypothesis, attributable to Landsberg, is that sympathetic nervous activation occurs with chronic overeating, elevating blood pressure. These are not mutually exclusive hypotheses, since obesity is a heterogeneous disorder.
Whole body and regional sympathetic nervous system activity, in the kidneys and heart, was measured at rest using noradrenaline isotope dilution methodology in a total of 86 research voluteers in four different subject groups, in lean and in obese people who either did, or did not, have high blood pressure.
In the lean hypertensive patients, noradrenaline spillover for the whole body, and from the heart and kidneys was substantially higher than in the healthy lean volunteers. In normotensive obesity, the whole body noradrenaline spillover rate was normal, mean renal noradrenaline spillover was elevated (twice normal), and cardiac noradrenaline spillover reduced by approximately 50%. In obesity-related hypertension, there was elevation of renal noradrenaline spillover, comparable to that present in normotensive obese individuals but not accompanied by suppression of cardiac noradrenaline spillover, which was more than double that of normotensive obese individuals (P<0.05), and 25% higher than in healthy volunteers. There was a parallel elevation of heart rate in hypertensive obese individuals.
The sympathetic underactivity hypothesis of obesity causation now looks untenable, as based on measures of noradrenaline spillover, sympathetic nervous system activity was normal for the whole body and increased for the kidneys; the low sympathetic activity in the heart would have only a trifling impact on total energy balance. The increase in renal sympathetic activity in obesity may possibly be a necessary cause for the development of hypertension in obese individuals, although clearly not a sufficient cause, being present in both normotensive and hypertensive obese individuals. The discriminating feature of obesity-related hypertension was an absence of the suppression of the cardiac sympathetic outflow seen in normotensive obese individuals. Sympathetic nervous changes in obesity-related hypertension conformed rather closely to those expected from the Landsberg hypothesis.

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    • "The procedure was abandoned because it was associated with side-effects and the advent of effective antihypertensive drugs. Further support for a role for the renal nerves in hypertension is the finding that renal noradrenaline spillover is increased in young adult hypertensive patients and in obesity-related hypertension (Esler et al. 1989; Rumantir et al. 1999). "
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    ABSTRACT: Renal denervation reduces blood pressure in animals with experimental hypertension and recently catheter based renal denervation was shown to cause a prolonged decrease in blood pressure in patients with resistant hypertension. However, the randomised, sham controlled Symplicity HTN-3 trial failed to meet its primary efficacy end point, but there is evidence that renal denervation was incomplete in many patients. Currently there is little information regarding the effectiveness of catheter based renal denervation and of the extent of reinnervation. We assessed the effectiveness of renal nerve denervation with the Symplicity Flex catheter and functional and anatomical reinnervation at 5.5 and 11 months post-denervation. In anaesthetised, non-denervated sheep there was a high level of renal sympathetic nerve activity (RSNA), and electrical stimulation of the renal nerve increased blood pressure and reduced heart rate (afferent response) and caused renal vasoconstriction and reduced renal blood flow (efferent response). Immediately after renal denervation, RSNA and the responses to electrical stimulation were absent, indicating effective denervation. By 11 months after denervation, RSNA was present and the responses to electrical stimulation were normal, indicating reinnervation. Anatomical measures of renal innervation by sympathetic efferent nerves (tissue noradrenaline and tyrosine hydroxylase) and afferent sensory nerves (calcitonin gene related peptide) demonstrated large decreases one week post-denervation, but normal levels at 11 months post-denervation. In summary, catheter based renal denervation is effective, but reinnervation occurs. Studies of central and renal changes post-denervation are required to understand the causes of the prolonged hypotensive response to catheter based renal denervation in human hypertension. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Experimental physiology 01/2015; 100(5). DOI:10.1113/expphysiol.2014.079871 · 2.67 Impact Factor
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    • "mic forearm exercise in younger adults with MetSyn and age - matched healthy control subjects to uncover any potential between - group differences ( which , if present , would complicate data interpretation ) . In line with previous findings , resting MSNA was higher in adults with MetSyn when compared with age - matched healthy control subjects ( Rumantir et al . 1999 ; Huggett et al . 2004 ; Lambert et al . 2007 ) . This increase in basal MSNA may be the result of higher concentrations of plasma leptin , insulin and / or inflammation commonly observed in adults with MetSyn ( Smith & Minson , 2012 ) . Importantly , MSNA remained at resting levels during low - intensity dynamic forearm exercise in bot"
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    ABSTRACT: Background. Alpha-adrenergic-mediated vasoconstriction is greater during simulated exercise in animal models of metabolic syndrome (MetSyn) when compared with control animals. In attempt to translate such findings to humans, we hypothesized adults with MetSyn (n = 14, 35±3 years) would exhibit greater α-adrenergic responsiveness during exercise when compared with age-matched healthy controls (n = 16, 31±3 years). Methods. We measured muscle sympathetic nerve activity (MSNA, microneurography) and forearm blood flow (FBF, Doppler ultrasound) during dynamic forearm exercise (15% of maximal voluntary contraction). Alpha-adrenergic agonists (phenylephrine and clonidine) and antagonist (phentolamine) were infused intra-arterially to assess α-adrenergic receptor responsiveness and restraint, respectively. Results. Resting MSNA was ∼35% higher in MetSyn adults (p<0.05) but did not change in either group with dynamic exercise. Clonidine-mediated vasoconstriction was greater in MetSyn adults (p<0.01). Group differences in vascular responses to phenylephrine and phentolamine were not detected (p>0.05). Interestingly, exercise-mediated vasodilation was greater in MetSyn (p<0.05). Conclusion. Adults with MetSyn exhibit greater resting MSNA and clonidine-mediated vasoconstriction, yet preserved functional sympatholysis and higher exercise blood flow during low-intensity handgrip exercise when compared with age-matched healthy controls. These results suggest adults with MetSyn exhibit compensatory vascular control mechanisms capable of preserving blood flow responses to exercise in the face of augmented sympathetic adrenergic activity.This article is protected by copyright. All rights reserved
    Experimental physiology 03/2014; 99(9). DOI:10.1113/expphysiol.2014.078048 · 2.67 Impact Factor
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    • "The sympathetic drive to skeletal muscles and kidneys is increased in obese patients (Alvarez et al., 2002; Kuniyoshi et al., 2003; Huggett et al., 2004). This increase in sympathetic activation has been considered a key factor in the development of obesity-related hypertension in these patients (Rumantir et al., 1999; Masuo et al., 2000), even though some authors have demonstrated that in humans the BP and heart rate (HR) response to mental stress was similar in lean and obese humans (Kuniyoshi et al., 2003). "
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    Neuroscience 01/2014; 262. DOI:10.1016/j.neuroscience.2013.12.053 · 3.36 Impact Factor
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