Correspondence and requests for reprints to Professor Guido Grassi, Clinica Medica, Ospedale San Gerardo Dei Tintori, Via Donizetti 106, 20052 Monza, Milano, Italy. Tel: +39 233 3357; fax: +39 322 274
Over the years, a number of experimental and clinical investigations have shed light on the key role exerted by the renin–angiotensin and the adrenergic nervous system in the homeostatic control of both blood volume and blood pressure [1,2]. Straightforward evidence has also been provided that these two systems do not independently operate but mutually interact with each other in accomplishing their cardiovascular regulatory functions. In addition, the renin–angiotensin–sympathetic interactions have not only physiological, but also pathophysiological relevance; a reciprocal reinforcement of the favourable as well as unfavourable cardiovascular, renal, metabolic and reflex effects of the two systems being reported in a variety of cardiovascular (essential hypertension, congestive heart failure and ischemic heart disease) and non-cardiovascular (cirrhosis, renal insufficiency and failure) conditions [3–5].
Information on the renin–angiotensin–sympathetic interactions has also been extended to the possible sites (and possible mechanisms) of these interactions (Fig. 1). For example, the observation that intracerebral injection (or local brain application) of angiotensin II triggers a sympathetically mediated blood pressure rise associated with systemic vasoconstriction has suggested a central facilitatory effect of angiotensin II on sympathetic outflow [3,4,6]. Evidence has also been provided that angiotensin II: (i) plays a facilitatory role on the neuroadrenergic transmission across sympathetic ganglia [3,4,7]; (ii) potentiates norepinephrine release from sympathetic nerve terminals via stimulation of presynaptic angiotensinergic receptors [3,4,8]; and (iii) amplifies the alpha-receptor mediated vasoconstrictor responses to exogenously administered or endogenously produced norepinephrine . Furthermore, angiotensin II has been shown to exert inhibitory effects on baroreceptor reflex control of heart rate and sympathetic nerve traffic [4,5]. Two final mechanisms through which the renin–angiotensin and the sympathetic nervous system interact together deserve to be mentioned. The first comes from evidence demonstrating that not only the systemic, but also the local (e.g. tissue vascular) renin–angiotensin system can actively modulate the regional sympathetic neural outflow by facilitating norepinephrine release at presynaptic level and/or by potentiating the postsynaptic response to this adrenergic neurotransmitter. Although mainly documented by animal studies in vitro and in vivo, this local interaction has been recently shown to occur in humans and to take place in a variety of regional cardiovascular districts, such as the forearm and the coronary circulations [10–12]. The second mechanism comes from evidence demonstrating that angiotensin II facilitation of neuroadrenergic outflow depends at least in part on an angiotensin II-mediated inhibition of the adrenergic neurotransmitter re-uptake by sympathetic nerve terminals . Whether this process (which has been documented to occur in several cardiovascular districts, including the mesenteric region and the heart [13,14]) represents a physiological curiosity or has major pathophysiological and therapeutic relevance has yet to be clarified.
The paper by Raasch et al.  in this issue provides an almost conclusive answer to this question, in addition to raising a number of intriguing pathophysiological and therapeutical hypotheses worthy of testing in future studies. The main features and results of the study can be summarized as follows. First, by employing a radiolabelled norepinephrine technique in spontaneously hypertensive rats, the effects of acute and prolonged pharmacological blockade of the renin–angiotensin system via an angiotensin converting enzyme (ACE) inhibitor on the norepinephrine re-uptake process by cardiac sympathetic nerve terminals were evaluated. The results of this first set of experimental data clearly demonstrate that, after both acute and prolonged ACE-inhibitor treatment, an increase in the myocardial re-uptake process does occur. Second, by directly quantifying the myocardial content of endogenous norepinephrine (which is taken as an index of the re-uptake process of the adrenergic neurotransmitter) in the same strain of rats, evidence is provided demonstrating that a 3-month ACE-inhibitor treatment markedly increases the storage process of norepinephrine in myocardial tissue.
Taken together, these results allow the authors to draw a main conclusion, namely that blockade of the renin–angiotensin system stimulates cardiac norepinephrine re-uptake in hypertension. This implies that angiotensin II exerts a number of facilitatory effects on adrenergic function that go beyond stimulation of the central nervous system or ganglionic transmission, thereby involving inhibition of norepinephrine reuptake by sympathetic nerve endings.
Several other intriguing results of the study deserve to be mentioned. First, the study results confirm and expand recent observations collected in humans showing that a reduced norepinephrine re-uptake process in the cardiac district characterizes essential hypertension and obesity-related hypertension and that, in the former condition, this defect is associated with phenotypic evidence of norepinephrine transporter dysfunction . Second, not only norepinephrine, but also the epinephrine re-uptake process is markedly enhanced by ACE inhibition, reinforcing the hypothesis advanced years ago (and recently reappraised) that epinephrine acts as cotransmitter of norepinephrine and that this phenomenon may have pathophysiological relevance in hypertension .
A further interesting, although at first glance puzzling, result of the study is the lack of any relationship between the magnitude of the blood pressure-lowering effects induced by ACE inhibitors and the degree of norepinephrine and epinephrine re-uptake. This result would thus imply that the ‘re-uptake’ does not consistently participate in the antihypertensive effect of this class of compounds. Although the authors seem to have a more probabilistic opinion, the data provided can hardly explain the blood pressure-lowering effects of ACE inhibitors. It should be mentioned, however, that in several previous studies, no relationship at all (or in some cases only a weak one) was found between blood pressure reduction induced by ACE inhibitors and the decrease in several indices of adrenergic tone, such as plasma levels of norepinephrine or sympathetic nerve traffic values [18,19]. Among the several hypotheses advanced to explain this result, a likely one is that the behaviour of the sympathetic responses to a given intervention (in the case of the present study, ACE-inhibitor administration) is not homogeneous in the different cardiovascular districts, and so blood pressure values do not reflect the heterogeneous adrenergic behaviours seen at the level of the various regional circulations.
On the other hand, the improvement in norepinephrine and epinephrine re-uptake by cardiac sympathetic nerve terminals seen after acute and prolonged pharmacological blockade of the renin–angiotensin system has a number of important clinical implications. The results of the study, showing that improved norepinephrine re-uptake was parallelled by a concomitant regression of both vascular and cardiac hypertrophy during ACE-inhibitor treatment, suggest that this process may, at least in part, be involved in the development of hypertension-related cardiovascular structural alterations and participate in the favourable effects induced by ACE-inhibitor treatment on end organ damage. The phenomenon may have also straightforward relevance in the pathophysiology of cardiac dysrhythmias, given the evidence that (i) norepinephrine has pro-arrhythmogenic effects  and (ii) in several cases, ACE inhibitors display anti-arrhythmogenic properties, which cannot entirely be ascribed to the ‘pure’ blockade of the renin–angiotensin system .
A final controversial issue should also be mentioned, namely the contribution of bradykinin to the increase in the norepinephrine re-uptake process seen during ACE-inhibitor administration. Although the observation that re-uptake can be increased by a non-hypotensive dose of an ACE inhibitor weakens the possible role of bradydinin, the concept that an increase in circulating bradykinin (caused by an ACE-inhibitor-dependent reduction of bradykinin breakdown) may favour an increased norepinephrine re-uptake per se should be stressed. Thus, as often happens in research, intriguing data may provide the answer to one question but also raise further queries that call for additional studies.
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