The angiotensin II-sympathetic nervous system connection.

Abstract

The renin–angiotensin system (RAS) and the sympathetic nervous system (SNS) are closely interrelated. Stimulation of the SNS results in an increased renal renin release through activation of beta-adrenergic receptors within the kidney. By contrast, there is compelling evidence that angiotensin II within the central nervous system (CNS) activates the SNS through interaction with AT1-receptors at sites that are involved in the cardiac and sino-aortic baroreflex control of sympathetic nerve activity [1–5]. For example, Ito and Sved [1] showed that bilateral injection of peptidic angiotensin receptor antagonists into the rostral ventrolateral medulla caused a pronounced fall in resting arterial pressure, comparable to the decrease observed after blockade of spinal sympathetic outflow. As the principal roles of the RAS and SNS are to maintain blood pressure and body fluid homeostasis, a positive interaction between these systems may be advantageous in conditions where sodium deprivation and hypotension are impending, but disadvantageous in conditions accompanied by avid sodium and fluid retention. Angiotensin II within the CNS is known to be a tonic stimulus of renal sympathetic nerve activity (RSNA) [2–4]. It has been shown that CNS angiotensin II resets the baroreceptor reflex relationship between arterial pressure and RSNA to the right, meaning that for each level of blood pressure, RSNA is increased [2]. In the present issue of the journal, and as a logical extension of their previous work, DiBona and Jones [6] report on angiotensin II–induced modulation of the baroreceptor reflex control of RSNA, blood pressure and heart rate. Similar to their previous studies, activation or inhibition of the endogenous RAS was obtained by feeding rats a low, normal or high sodium diet. With rats in balance on these diets, inhibitory responses of blood pressure, heart rate and RSNA to standardized electrical stimulation (0.5–16 Hz) of the afferent vagal (cardiac) and aortic depressor nerves were measured. If angiotensin II had diminished the gain of baroreflex-mediated modulation of SNS activity, a smaller decrease of blood pressure, heart rate and RSNA in response to standardized stimulation of afferent baroreflex nerves was to be expected in animals on a low sodium diet, and an elevated activity of the endogenous RAS compared to animals on a high sodium diet and a low activity of the RAS. However, this appeared not to be the case. With the high, normal and low sodium intake, inhibitory responses of blood pressure, heart rate and RSNA to afferent vagal nerve stimulation did not differ, whereas the inhibitory response of RSNA, but not blood pressure or heart rate, to aortic depressor nerve stimulation was actually greater in the low sodium group compared to the normal or high sodium groups at higher (> 4 Hz) stimulation frequencies. This does not mean that endogenous angiotensin II failed to attenuate the baroreceptor reflex control of RSNA. In a second series of experiments, an approximately 50% augmentation of the inhibitory response of RSNA to vagal and sinoaortic afferent baroreflex stimulation in low sodium, but not in normal or high sodium diet rats, could be demonstrated after systemic administration of the AT1-receptor antagonist candesartan. Surprisingly, pressor and cardioinhibitory responses to afferent baroreflex stimulation after candesartan administration were not augmented, and candesartan had only a minimal effect on baseline RSNA. The results of this study confirm previous observations that endogenous angiotensin II within the CNS inhibits the baroreflex control of RSNA through stimulation of AT1-receptors. They also indicate that the systemically administered AT1-receptor antagonist candesartan has access to these receptors, as was previously demonstrated for losartan [2]. The obvious question that arises is how to explain the discrepant effects of angiotensin II on RSNA on the one hand and blood pressure and heart rate on the other hand? According to the authors, RSNA is a direct measure of SNS, whereas blood pressure and heart rate are indirect measures which are also influenced by other factors. Although this is true, an augmented vasodepressor and cardioinhibitory response to afferent baroreflex stimulation after AT1-receptor blockade is still to be expected if angiotensin II within the CNS is an important modulator of overall SNS activity. Thus, an alternative conclusion could be that CNS angiotensin II preferentially increases RSNA, but has little effect on the SNS activity directed to the vasculature or heart. Measurement of sympathetic nerve activity to various vascular beds and the heart should provide an answer. Another possibility is that the reduction in blood pressure after administration of candesartan obscured the detection of a potential inhibitory effect of angiotensin II on baroreflex-mediated blood pressure modulation. After intravenous administration of candesartan, but before afferent baroreflex stimulation, blood pressure in the low sodium diet rats decreased by approximately 25%. In response to either cardiac or sinoaortic afferent baroreflex stimulation, blood pressure decreased by approximately 20%. On top of this overall 45% decrease in blood pressure, the demonstration of an additional fall in blood pressure may be cumbersome because other mechanisms likely counteract any further decline in blood pressure. The observation that baseline RSNA was only minimally affected by candesartan suggests that, in this model CNS, angiotensin II has little tonic stimulatory effect on RSNA. The crucial question is whether the findings observed in rodents have their clinical correlate in man. It is well-known that agents which interfere with the RAS, such as angiotensin converting enzyme (ACE) inhibitors, AT1-receptor antagonists and renin-inhibitors, contrary to directly acting vasodilators, do not increase heart rate. Furthermore, it has been shown that ACE-inhibitors and AT1 receptor antagonists, despite the fall in blood pressure, do not increase and, in some circumstances, even decrease central sympathetic outflow as assessed by muscle sympathetic nerve activity [5–8]. These findings strongly favour the idea that, in man, central sympathetic outflow is also modulated by these agents, most likely by acute resetting of the baroreceptor reflex [9]. Although the observations are limited, to date, there is no evidence that interference with the RAS results in a decrease in RSNA in man. In a study performed in patients with renovascular hypertension, a suitable model in which to study the interaction between angiotensin II and the SNS, acute ACE inhibition was associated with a 44% increase in renal noradrenaline spillover, whereas total body noradrenaline and muscle sympathetic nerve activity did not change [10]. Obviously, additional studies are required to clarify this unexpected finding.