The sympathetic nervous system in renovascular hypertension: lead actor or ‘bit’ player?

During recent years, several issues concerning the role of the sympathetic nervous system in the pathophysiology of the hypertensive state have been thoroughly investigated and successfully clarified. An updated picture of the information collected to date on this topic can be summarized as follows. First, in most published reports, essential hypertension is almost invariably characterized by an activation of the sympathetic nervous system, as confirmed by the increased circulating noradrenaline, muscle sympathetic nerve traffic and systemic noradrenaline spillover values reported by different investigators in essential hypertensive patients [1–5]. Second, this adrenergic activation contributes to the development, as well as to the progression, of the hypertensive disorder, directly participating not only in the blood pressure elevation, but also in the pathogenesis of the target organ damage characterizing the disease [6,7]. Third, the hypertension-related increase in adrenergic cardiovascular drive is widespread, involving several circulatory districts, including the cerebral, renal, cardiac and muscular ones, with the only exception being represented by the cutaneous circulation in which sympathetic nerve traffic has been reported to be within the normal range (Table 1) [8,9]. Fourth, the adrenergic overdrive appears to be particularly pronounced in young and middle-aged patients, although recent findings also show its presence in systo-diastolic and isolated systolic hypertension of the elderly [10]. Finally, many mechanisms appear to be responsible for the hypertension-related sympathoexcitation, including: (i) a dysfunction in the reflex influences (stemming from the arterial baroreceptors, the cardiopulmonary volume receptors and the chemoreceptors), which in physiological conditions tonically restrain central sympathetic outflow [11]; (ii) an ‘adrenergic reinforcement’ due to the excitatory effects exerted on sympathetic neural function, both at the central and peripheral level, by various humoral agents (such as angiotensin II, nitric oxide, endothelins, etc.) [11]; and (iii) an interaction between the sympathetic nervous system and metabolic variables (such as insulin) that have been documented to potentiate central sympathetic outflow [11].Table 1: Behaviour of regional sympathetic activity in different pathological conditionsMore scarce and less univocal are the information on the behaviour of the sympathetic nervous system in secondary hypertension. The debate specifically concerns renovascular hypertension, given the agreement about the finding that a central sympathoinhibition usually occurs in primary aldosteronism and in adrenal pheochromocytoma [12,13]. The results of the study by Petersson et al. reported in this issue of the journal [14] and the findings of a previously published study by the same group [15] add further ‘fresh fuel’ to the debate by providing well-documented evidence of an increase in cardiac noradrenaline spillover [14] and in muscle sympathetic nerve traffic [15] in patients with renovascular hypertension. In contrast, in the two above-mentioned studies, the behaviour of systemic ‘net’ secretion of noradrenaline was not univocal, one of them showing elevated values [15] and the other ‘normal’ values [14]. Overall, the study results are in line with previous observations made by another group [12] but in sharp contrast with the findings of the studies performed by Morlin et al. in Sweden [16] and by ourselves in Italy [5]. The present commentary aims to shed light on the possible causes responsible for the discrepancy between the published findings on the behaviour of the sympathetic nervous system in renovascular hypertension. Historical background Dating back almost 25 years, the first report on the behaviour of the sympathetic nervous system in patients with renovascular hypertension was published, providing evidence of 24-h urinary noradrenaline excretion values greater than those found in age-matched essential hypertensive individuals [17]. This was followed by the results of a microneurographic study in which efferent postganglionic sympathetic neural outflow to the skeletal muscle vessels was recorded in nine renovascular hypertensives before and during percutaneous transluminal renal angioplasty, which, in the short-term period, caused a marked increase in sympathetic nerve firing rate [16]. This finding implies that adrenergic cardiovascular drive might be inhibited in this secondary hypertensive state, a conclusion opposite to that achieved in a subsequent study [12] performed in eight renovascular hypertensives who displayed a marked increase in sympathetic activity and blood pressure, where the increase was combined with elevated plasma renin and angiotensin II levels. In a study performed by our group [5] in which the main objective was to assess baroreflex control of adrenergic and vagal tone in essential and secondary hypertensives, we were unable to provide any microneurographic evidence of an increased sympathetic drive in seven renovascular hypertensives. The muscle sympathetic nerve traffic values were indeed superimposable on the ones seen in age-matched normotensive controls and significantly less than those found in age-matched essential hypertensives with a blood pressure rise of similar magnitude, but in this case idiopathic. This finding reinforces the possibility that a sympathoinhibition characterizes this secondary form of hypertension, similar to what has been found in primary aldosteronism and phoeochromocytoma (12,13). Possible explanations for the discrepancy between studies. In their study Petersson et al. investigated the behaviour of systemic and cardiac sympathetic drive (noradrenaline spillover technique) in a group of renovascular hypertensives, comparing the results with those obtained in 19 age-matched healthy normotensives [14]. The main study outcome is represented by the finding that cardiac noradrenaline spillover is markedly enhanced in renovascular hypertension, while the systemic measure is indistinguishable from that characterizing the normotensive state, at variance from that previously reported by the same group [15]. It might, perhaps, be surprising to see different data reported by the same investigators, who are known worldwide for their contribution to our understanding on the role of neurogenic mechanisms in the pathophysiology of hypertension. Similarly, it might also be surprising that the same approach (the microneurographic one) has provided such different results in studies by Morlin et al. [16] and our group [5] on the one hand, and by Miyajima et al. [12] and Johansson et al. [15] on the other. Several plausible explanations may be advanced to explain these discrepant results. First, as properly emphasized by Petersson et al. [14], the heterogeneity of the clinical profile of the renovascular hypertensive states (degree of arterial stenosis, atherosclerotic or fibrodysplastic aetiology) might be responsible for the discrepant results between studies. Second, as shown by Johansson et al. [15] in renovascular hypertensives, the degree of sympathetic activation is closely and directly related to the circulating levels of renin as well as angiotensin II. This explanation also holds true for our findings [5], because the seven renovascular hypertensives studied were characterized by only a moderate degree of renin–angiotensin stimulation. Third, it has been suggested that the participation of the sympathetic nervous system to the blood pressure elevation in renovascular hypertension is a late phenomenon, and is preceded by renin–angiotensin system activation [18]. Fourth, it is possible that, in the time course of the adrenergic alterations occurring in renovascular hypertension, the increase in cardiac sympathetic drive may become evident well before the occurrence of a generalized adrenergic overactivity. This explanation is supported by the finding that, in congestive heart failure, cardiac sympathetic overactivity is an early phenomenon which precedes the generalized adrenergic overactivity seen later in the clinical course of the disease [19]. Finally, because systemic noradrenaline spillover is the net result of the behaviour of the sympathetic drive in different vascular districts [20], the lack of an increase in systemic noradrenaline spillover might reflect the fact that in this condition adrenergic overdrive is not homogeneously distributed over the whole cardiovascular system. As shown in Table 1, however, renovascular hypertension is not the only condition characterized by an heterogeneity in the behaviour of sympathetic cardiovascular influences between different districts, a similar phenomenon also being detectable in obesity, essential hypertension and, at least in part, in congestive heart failure and liver cirrhosis [2,3,5,8,9,12,14,15,19–27].