Prejunctional modulation of sympathetic tone by angiotensin II receptor antagonists: are there relevant differences?

More than 100 years after the discovery of renin as the first component of what came to be known as the renin–angiotensin–aldosterone system, the components of this system continue to receive much investigative interest. This ongoing interest clearly is driven by the tremendous clinical success of the first class of drugs interfering with the effects of angiotensin II in patients with cardiovascular diseases [i.e. angiotensin-converting enzyme (ACE) inhibitors]. The development of compounds blocking the effects of angiotensin II at its receptors [1] has provided further insight into the mechanisms of action of angiotensin II. Of these, the facilitation of the sympathetic nervous system by angiotensin II has drawn much attention. Angiotensin II may increase sympathetic outflow from the central nervous system and facilitate ganglionic transmission and prejunctional norepinephrine release in vitro and in animal experiments. Angiotensin II type 1 (AT-1) receptors also exist in the adrenal medulla and their stimulation may result in increased sympatho-adrenal tone [2]. The recognition of the adverse influence of sympathetic activation in cardiovascular conditions such as hypertension, heart failure and renal failure has not surprisingly generated great interest in the potential anti-adrenergic effects of therapies directed against the effects of angiotensin II. Pharmacological studies have shown that angiotensin II acts via two different receptors, termed angiotensin II type 1 (AT-1) and type 2 (AT-2) receptors [3]. Both belong to the A family of the G protein-coupled receptor superfamily. With respect to prejunctional effects of angiotensin II, most studies have found them to be AT-1 receptor mediated. In humans, only one type of AT-1 receptor has been identified, while rodents have two AT-1 receptor genes resulting in the expression of two different AT-1 receptors proteins designated AT–1A and AT-1B [4]. In rats, the AT–1A receptor is the dominant type expressed in vascular smooth muscle cells, heart, liver, kidney and testis whereas the AT-1B receptor is the predominant form in the adrenal cortex and hypopituitary gland [5]. Interestingly, pharmacological studies in the canine pulmonary artery and rat left ventricle suggested that the prejunctional AT-1 receptor may be different from the postjunctional AT-1 receptor and that it might be of the AT-1B type [6]. The hypothesis that the prejunctional AT-1 receptor might be pharmacologically distinguishable from the postjunctional receptor was also supported by studies in the pithed rat model in which different AT-1 receptor antagonists had markedly different potencies with respect to prejunctional sympathetic inhibition and postjunctional AT-1 receptor-mediated vasoconstriction [7,8]. Inasmuch as prejunctional sympathomodulation by angiotensin II is of importance, such a finding might be interpreted to confer an advantage to drugs that block both pre- and postjunctional AT-1 receptors compared to drugs that might not have a sympathomodulating effect in dosages blocking only the postjunctional receptor. In this issue of the journal, Dendorfer et al. [9] provide strong evidence against the hypothesis that pre- and postjunctional AT-1 receptors are pharmacologically distinguishable in the pithed rat model. Measuring AT-1 receptor antagonist-induced reductions of angiotensin II-induced increases of plasma norepinephrine as a measure of prejunctional sympathoinhibiton, as well as inhibition of angiotensin II-induced increases in diastolic blood pressure as an index of postjunctional AT-1 receptor blockade, they found that affinities to pre- and postjunctional AT-1 receptors were in a similar range for each AT-1 receptor antagonist tested. Although the ranking of the affinities for prejunctional effects was the same as that for postjunctional effects, pharmacological potencies, expectedly, differed considerably between the various compounds. The authors also investigated the effects of AT-1 antagonists on sympathetically mediated vasoconstriction and found that AT-1 antagonists, presumably through postjunctional AT-1 receptor-mediated mechanism(s), caused marked reductions in smooth muscle responsiveness to exogenous norepinephrine. How can the differences between this study and previous studies be reconciled? Most studies, including the present one, investigated prejunctional effects in the same experimental model (i.e. the pithed rat). However, an obvious and major difference is the approach chosen for the assessment of prejunctional effects of AT-1 antagonists. Thus, Derndorfer et al. relied on changes of plasma norepinephrine levels induced by angiotensin II infusions compared to changes in blood pressure following thoracolumbar spinal stimulation in previous studies. While the former approach is a direct measurement of exocytotic norepinephrine release from storage vesicles in the sympathetic nerve endings when neuronal and extraneuronal reuptake are pharmacologically blocked (as performed in the current study), blood pressure responses are indirect estimates of sympathetic stimulation only. The observation that AT-1 antagonists reduced vascular smooth muscle responsiveness to exogenous norepinephrine further emphasizes that changes in blood pressure may not precisely reflect changes in sympathetic tone in this model. However, this vascular sympatholytic effect was achieved only with doses of AT-1 receptor antagonists that were higher than those required for complete inhibition of both pre- and postjunctional angiotensin II effects. Although interesting and of potential importance, this finding is in contrast to a recent report describing unchanged vascular smooth muscle responsiveness to exogenous norepinephrine by similar doses of AT-1 receptor antagonists in the pithed rat model [8]. The reason for this discrepancy is not clear. Whether the use of different strains of rats (spontaneously hypertensive versus Wistar–Kyoto rats), as suggested by the authors, can explain this finding awaits further study. Notwithstanding the importance of understanding the pharmacology of AT-1 receptors and AT-1 receptor antagonists, the crucial point in this respect remains the role that prejunctional inhibition and sympathetic modulation by angiotensin II plays in humans. Most studies addressing this problem have been performed in experimental animal preparations and many have used angiotensin II administration in rather high doses. As shown by Derndorfer et al. [9], and also in previous studies [10,11], high dose angiotensin II markedly stimulates neuronal norepinephrine release. When angiotensin II is used in concentrations close to the physiologically relevant range, however, a rather small yet consistent increase in norepinephrine release has been demonstrated [12,13]. In contrast, blockade of angiotensin II receptors under basal conditions had no effects on norepinephrine release in experimental studies [11,12]. Importantly, it should be kept in mind that the AT-1 receptor in humans is encoded by one gene only, and the results from rodents, which have two AT-1 receptor copies, may therefore be difficult to transfer to humans. Because of the constraints inherent to human research, much less information is available in humans. In normal volunteers, infusion of a low dose of angiotensin II into the forearm via the brachial artery resulted in a small increase in norepinephrine release [14]. However, blockade of the renin–angiotensin system in humans often did not produce a decrease of measurements of sympathetic tone under basal conditions [15,16]. It has been reported that blockade of the renin–angiotensin system by the ACE inhibitor captopril reduced plasma adrenaline levels during insulin-induced hypoglycaemia [17], a finding compatible with a modulatory effect of blockade of prejunctional AT-1 receptors in the adrenal medulla during stress. This observation, however, could not be reproduced in another study [18]. Accordingly, the role of angiotensin II in the peripheral modulation of basal sympathetic tone appears to be small; however, it may play a role under conditions of stress, particularly when angiotensin II levels are elevated. Does all this mean that the prejunctional sympathomodulating effects of angiotensin II, and therefore also of AT-1 antagonists, are irrelevant? Before we can answer this question, further studies are needed, particularly in humans, using accurate methodologies, such as systemic and regional norepinephrine spillover rates, to assess the effects of AT-1 receptor antagonists on basal and stimulated sympathetic tone as seen in different cardiovascular diseases. However, regardless of what the ultimate role of prejunctional AT-1 receptors will turn out to be, the current data provide good evidence that it is unimportant which AT-1 receptor antagonist is used to block them. As long as the dose is high enough to block vascular smooth muscle AT-1 receptors, blockade of prejunctional receptors is also achieved.