Editorial Commentary Angiotensin II Infusion Model of Hypertension

There has been a long-standing interest in the possibility that activation of the sympathetic nervous system may contribute to the hypertension induced by angiotensin II (Ang II). This hypothesis is commonly assessed by chronically infusing Ang II and using various tests to determine the sympathetic component to the increase in arterial pressure. Despite a multitude of studies, it is still unclear whether the sympathetic nervous system plays an important role in mediating this form of hypertension. Why the uncertainty? This is largely because of the varied and often times ambiguous experimental approaches to address this issue. More specifically, the uncertainty arises from studies using different animals, different sites of Ang II administration (central, intravenous, and subcutaneous), different rates of Ang II infusion, and different time courses of study. In addition, in most studies, measures of Ang II levels have not been made, making it difficult to determine whether reported effects are physiological, pathophysiological, or pharmacological. In addition, precise measures of sympathetic activity must be made before specific inferences regarding its role in Ang II hypertension can be made. Beyond these considerations, there are additional limitations that impede a clear resolution of this topic. The kidneys play a primary role in mediating long-term changes in arterial pressure, and, therefore, neurogenic mechanisms of hypertension must in some way impair renal excretory function. Because the renal nerves provide an obvious link between alterations in central sympathetic outflow and renal excretory function (Figure), an understanding of the role of neurogenic mechanisms in the maintenance of hypertension depends on measurement of renal sympathetic nerve activity (RSNA) and assessment of the influence of this sympathetic outflow on steady-state levels of arterial pressure. Unfortunately, technical limitations often preclude these chronic determinations. In this regard, the Circulatory Control Laboratory at the University of Auckland (Auckland, New Zealand) has provided unique insight into neurogenic mechanisms of hypertension by developing technology to directly measure RSNA continuously in conscious animals over long time periods (several weeks). To provide greater insight into a possible role of the sympathetic nervous system in mediating Ang II hypertension, they report in the current issue of Hypertension continuous radiotelemetric recordings of RSNA in rabbits chronically infused with Ang II while maintained on a high-salt intake.1 An alternate approach that has been used successfully in experimental and clinical studies to determine regional specific sympathetic activity, including RSNA, has been to measure the spillover of norepinephrine (NE) to plasma.2,3 In regard to the kidneys, renal NE spillover captures a “snapshot” of RSNA at any given point in time. In clinical studies, measurements of organ-specific NE spillover have shown that the control of sympathetic activity to organs is differentially regulated, and the progression of primary hypertension is associated with early and sustained activation of RSNA. The importance of this latter observation has been highlighted recently by studies showing that bilateral renal denervation and chronic suppression of RSNA by baroreflex activation have appreciable blood pressure–lowering effects in human subjects with resistant hypertension and in animals with clinically relevant hypertension.4–6 The ability to directly measure RSNA continuously by telemetry from chronically implanted electrodes placed around the renal nerves has been a tour de force of the Circulatory Control Laboratory at the University of Auckland. Using this technology, they identified previously the confounding effect of sustained baroreflex activation in studies designed to investigate the role of sympathetic activation in mediating Ang II hypertension. In rabbits subjected to a rate of Ang II infusion that had immediate pressor effects, these investigators clearly showed marked suppression of RSNA throughout a 7-day period of Ang II hypertension.7 Furthermore, when this study was repeated in another group of rabbits after sinoaortic denervation, suppression of RSNA did not occur, indicating that this renal sympathoinhibition was mediated by baroreflex activation attributed to the increase in arterial pressure.8 However, because RSNA did not increase after sinoaortic denervation, this study did not support the hypothesis that Ang II can act centrally to increase RSNA even in the absence of sympathetic inhibition by baroreflex activation. These elegant studies are consistent with earlier findings in dogs made hypertensive by chronic infusion of Ang II hypertension. In one of these studies, the snapshot technology provided by measurement of renal NE spillover demonstrated sustained suppression of renal NE spillover in chronic Ang II hypertension.3 Subsequent studies by this same group further supported the hypothesis that the sustained suppression of RSNA was mediated by chronic The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS. Correspondence to Thomas E. Lohmeier, Department of Physiology, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216-4505. E-mail [email protected] (Hypertension. 2012;59:539-541.) © 2012 American Heart Association, Inc.