Essential hypertension, obesity and the activity of the sympathetic nervous system are characterized by a complex and yet only partially understood relationship with each other. Indeed the mechanisms underlying the association between obesity and arterial hypertension, and in particular the role played in this context by the sympathetic nervous system, are still a matter of considerable debate.
One of the few clearly established findings in this field is probably the association between hypertension and an enhanced sympathetic cardiovascular modulation . This includes the demonstration that an increased sympathetic activity is evident since the pre-hypertensive phase, leading first to cardiovascular hyper-reactivity to a number of stimuli and then to sustained hypertension. It also includes the evidence that an enhanced sympathetic activity accompanies hypertension, probably because of the reduced baroreflex sensitivity which is typical of this condition.
Also, the association between obesity and hypertension is supported by a considerable amount of evidence [2,3]. However, the ‘chicken-or-egg’ question on whether it is obesity that induces hypertension or hypertension that facilitates weight gain has not yet received a conclusive answer . Indeed, evidence supporting both possibilities is available. On one side, it has been shown that an increase in body weight may lead to a number of cardiovascular, renal and metabolic disorders (including hyperinsulinemia and hypertension), the combination of which is known as ‘metabolic syndrome', ‘Syndrome X’ or ‘insulin resistance syndrome’ [2–5]. Although the precise sequence of these events remains to be clarified, there is no doubt concerning the strong association between central obesity, insulin resistance and the risk of developing arterial hypertension. On the other side, it has also been suggested that subjects with higher blood pressure levels are prone to gain more weight over time than subjects with similar baseline weight but lower blood pressure [6–8]. A proposed explanation is that, in individuals prone to develop hypertension, the increase in sympathetic activity results in a down-regulation of β-adrenergic receptors. In turn, this is responsible for a reduced thermogenic response, reducing the ability of hypertensive subjects to dissipate calories, and thus facilitating an increase in weight . This hypothesis is supported by the report that treatment with β-adrenergic receptor blockers is associated with initial weight gain, at least during the first few months .
The association of an increased sympathetic activity with obesity, while being frequently reported in obese hypertensive patients, does not seem to invariably occur in those obese subjects who do not develop hypertension . As mentioned above, the sympathetic nervous system is among the most important mechanisms of essential hypertension. It has also been proposed that higher levels of sympathetic activity characterize the hypertension associated with obesity. There is less consistent agreement, however, on the fact that a sympathetic hyperactivity characterises also obese people with no evidence of hypertension. An incentive to study sympathetic nerve activity in obesity was indeed initially provided by quite a different view, i.e. that in human obesity, the sympathetic nervous system is underactive. According to this view, a diminished sympathetic activity in basal resting conditions, and a reduced sympathetic response to external stimuli, may cause a reduction in energy expenditure, a positive energy balance and an increase in body weight [11,12]. More recent evidence argues against this hypothesis [13,14], and an opposing suggestion has been made by Landsberg, who hypothesized that sympathetic neural activation occurs with chronic overeating [15,16]. While this may facilitate energy balance and weight stabilization by increasing energy expenditure, it may have adverse consequences, including an increased chronic sympathetic nerve activity, which may contribute to the development of a high blood pressure condition.
In fact, the occurrence of a systematic increase in sympathetic activity in obese subjects remains a controversial issue. On the one hand, it is believed that an increase in body weight invariably leads to increased sympathetic neural activity through increased insulin resistance or through increased leptin levels [1,16–18]. The opposing view is that an increased sympathetic activity is not a feature of all obese subjects, but seems to affect only those who develop an obstructive sleep apnea syndrome [19,20], a condition clearly characterized by an increased sympathetic activity and an alteration in reflex cardiovascular autonomic modulation [21–23].
Rumantir et al.  have shown that the picture is even more complex because, in obese normotensive or hypertensive subjects, norepinephrine spillover may be at the same time increased, unchanged or decreased in different body districts, thus emphasizing that regional differences in sympathetic activity may occur, as shown also in congestive heart failure or hypertension [24–27]. A further aspect of this complexity is the reported occurrence of changes in cardiovascular autonomic modulation during the time course of obesity development. As shown by spectral analysis of blood pressure and heart rate variability , the development of abdominal obesity induced by a high-fat diet in dogs is characterized by a biphasic change in cardiovascular autonomic modulation. An early and long-lasting decrease in high frequency heart rate spectral components, suggesting a decrease in parasympathetic cardiac modulation, is associated with an early but transient increase in low frequency heart rate and blood pressure spectral components, indicating and early but transient increase in sympathetic cardiovascular modulation.
In this issue of the journal, the study by Pelat et al.  introduces an additional element of complexity, by drawing our attention on the possibility that the changes in autonomic neural activity observed in the arterial hypertension induced by a weight gain following a high-fat diet in dogs may be mediated by complex changes both in the number and function of autonomic receptors. In a previous study by Sharma et al. mentioned above , it was shown that treatment with β-adrenergic blockers may facilitate weight gain through changes in energy metabolism. Pelat et al. focus on the possible changes in number and function of α2-adrenoceptors induced by an increase in body weight. This was performed: (i) by evaluating the pressor responses to acute clonidine administration under autonomic blockade aimed at investigating the status of post-synaptic alpha2-adrenoceptors; (ii) by evaluating changes in plasma catecholamine levels during an acute yohimbine challenge to assess the function of pre-synaptic and central α2-adrenoceptors; and (iii) by evaluating the number and affinity of alpha2-adrenoceptors on platelet membranes.
The main result of this study is that post-synaptic vascular α2-adrenoceptor function, assessed by the pressor response to clonidine, is not modified by a high-fat diet. In contrast, both presynaptical and/or central α2-adrenoceptors are functionally impaired, and there is a decreased platelet α2-adrenoceptors density under this diet regimen. This is associated with an increase in noradrenaline plasma levels.
This study is not immune from methodological limitations. The number of experimental animals included is rather small (six high-fat diet and six control dogs only); the reproducibility of the responses to pharmacological challenges may not always be optimal; and the reported changes in α2-adrenoceptors status were seen over a 9-week diet change, with no information on whether these changes persist over longer time intervals.
Notwithstanding these problems, which are partly counterbalanced by the great care in implementing an adequate methodological approach to the assessment of either pre-synaptic, post-synaptic and platelet α2- adrenoceptor function, the study emphasizes the need for a wider perspective when assessing the changes in cardiovascular autonomic modulation associated with obesity-related hypertension.
In fact, the results of the study by Pelat et al., and those of a previous study by their group on M2 muscarinic receptor down-regulation in the same model of canine obesity-related hypertension, clearly suggest that the hormonal changes associated with obesity, such as hyperinsulinemia and the increase in leptin plasma levels, are not only associated with changes in autonomic neural efferent traffic, but also are associated with changes in the density and function of autonomic receptors. These changes might be either directly or indirectly involved in the development of obesity-associated arterial hypertension, and this is an issue that deserves to be further addressed in future studies.
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