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: 4.22). 09/1999; 17(8):1125-33. DOI: 10.1097/00004872-199917080-00012
Source: PubMed

ABSTRACT 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 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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    ABSTRACT: Rats fed a high fat diet (HFD) present an exaggerated endocrine response to stress conditions, which, like obesity, show a high correlation with cardiovascular diseases. Meanwhile the GABAergic neurotransmission within the dorsomedial hypothalamus (DMH) is involved in the regulation of the physiological responses during emotional stress. Here we evaluated the influence of obesity, induced by a HFD, on the cardiovascular responses induced by air jet stress in rats, and the role of the GABAergic tonus within the DMH in these changes. Our results showed that consumption of a HFD (45% w/w fat) for 9 weeks induced obesity and increases in baseline mean arterial pressure (MAP) and heart rate (HR). Moreover, obesity potentiated the stress responsiveness, evidenced by the greater changes in MAP and HR induced by stress in obese rats. The injection of muscimol into the DMH reduced the maximal increases in HR and MAP induced by stress in both groups; however, the reduction in the maximal increases in MAP in the HFD group was less pronounced. Moreover, the injection of muscimol into the DMH of obese rats was less effective in reducing the stress-induced tachycardia, since the HR attained the same levels at the end of the stress paradigm as after the vehicle injection. Injection of bicuculline into DMH induced increases in MAP and HR in both groups. Nevertheless, obesity shortened the tachycardic response to bicuculline injection. These data show that obesity potentiates the cardiovascular response to stress in rats due to an inefficient GABAA-mediated inhibition within the DMH.
    Neuroscience 01/2014; 262. DOI:10.1016/j.neuroscience.2013.12.053 · 3.33 Impact Factor
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    • "However, subsequent studies have shown the opposite in humans: that baseline sympathetic activity is increased in obesity [26], [53]. Although the question has not been totally resolved, the general consensus to date is that obesity is associated with sympathetic overactivity, and that this elevated sympathetic tone represents the body's compensatory response aimed at achieving weight stabilization [54], [55]. Food intake triggers the release of insulin which acts to regulate glucose metabolism. "
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    ABSTRACT: The prevalence of obesity is growing at an alarming rate, placing many at risk for developing diabetes, hypertension, sleep apnea, or a combination of disorders known as metabolic syndrome. The evidence to date suggests that metabolic syndrome results from an imbalance in the mechanisms that link diet, physical activity, glucose-insulin control, and autonomic cardiovascular control. There is also growing recognition that sleep-disordered breathing and other forms of sleep disruption can contribute significantly to autonomic dysfunction and insulin resistance. Chronic sleep deprivation resulting from sleep-disordered breathing or behavioral causes can lead to excessive daytime sleepiness and lethargy, which in turn contribute to increasing obesity. Analysis of this complex dynamic system using a model-based approach can facilitate the delineation of the causal pathways that lead to the emergence of the metabolic syndrome. In this paper, we provide an overview of the main physiological mechanisms associated with obesity and sleep-disordered breathing that are believed to result in metabolic and autonomic dysfunction, and review the models and modeling approaches that are relevant in characterizing the interplay among the multiple factors that underlie the development of the metabolic syndrome.
    12/2012; DOI:10.1109/RBME.2012.2232651
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    • "In addition, MetSyn adults exhibit increased muscle sympathetic nerve activity (MSNA), which has been linked to increased rates of cardiovascular morbidity and mortality (Lambert et al. 2007). The exact mechanisms behind this increase are unknown; however, a rise in MSNA may occur in response to changes in body composition, altered insulin signalling, changes in central autonomic regulation and/or stiffening of receptive fields (Scherrer & Sartori, 1997; Rumantir et al. 1999; Esler et al. 2006). Chronic sympathetic activation can affect neurovascular coupling, resulting in altered noradrenaline release, α-adrenergic receptor number, receptor affinity and/or downstream signalling (Gurdal et al. 1995; Mita et al. 2010). "
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    ABSTRACT: Young healthy adults exhibit an inverse linear relationship between muscle sympathetic nerve activity (MSNA) and α-adrenergic responsiveness. This balance may be reversed in metabolic syndrome (MetSyn) given animal models exhibit increased sympathetic activity and α-mediated vasoconstriction. We hypothesized humans with MetSyn would demonstrate increased α-adrenergic vasoconstriction and the inverse relationship between MSNA and adrenergic responsiveness would be lost. We measured MSNA (microneurography of the peroneal nerve) and forearm blood flow (FBF, Doppler ultrasound) in 16 healthy control subjects (31±3 years) and 14 adults with MetSyn (35±3 years; p>0.05) during local administration of α-adrenergic agonists (phenylephrine, PE α1; clonidine, CL α2). MSNA was greater in MetSyn subjects when compared with healthy controls (p<0.05). A group difference in vasoconstriction to PE was not detected (p=0.08). The level of α1-mediated vasoconstriction was inversely related to MSNA in control subjects (r=0.5, p=0.04); this balance between MSNA and α1-responsiveness was lost in adults with MetSyn. MetSyn subjects exhibited greater vasoconstriction to CL infusion when compared with healthy controls (p<0.01). A relationship between MSNA and α2-mediated vasoconstriction was not detected in either group. In summary, altered neurovascular control in human MetSyn is receptor-specific. The observed uncoupling between MSNA and α1-adrenergic responsiveness and increased α2 -vasoconstriction may lead to reduced FBF, altered flow distribution, and/or severe hypertension with the progression toward diabetes and cardiovascular disease.
    The Journal of Physiology 10/2012; DOI:10.1113/jphysiol.2012.239780 · 4.54 Impact Factor
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