Rohit Ramchandra

What sets the long-term level of renal sympathetic nerve activity: a role for angiotensin II and baroreflexes?

Abstract— Increasing evidence suggests elevated sympathetic outflow may be important in the genesis of hypertension. It is thought that peripheral angiotensin II, in addition to its pressor actions, may act centrally to increase sympathetic nerve activity (SNA). Without direct long-term recordings of SNA, testing the involvement of neural mechanisms in angiotensin II–induced increases in arterial pressure is difficult. Using a novel telemetry-based implantable amplifier, we made continuous recordings of renal SNA (RSNA) before, during, and after 1 week of angiotensin II–based hypertension in rabbits living in their home cages. Angiotensin II infusion (50 ng · kg−1 · min−1) caused a sustained increase in arterial pressure (18±3 mm Hg). There was a sustained decrease in RSNA from 18±2 normalized units (n.u.) before angiotensin II to 8±2 n.u. on day 2 and 9±2 n.u. on day 7 of the angiotensin II infusion (P <0.01) before recovering to 17±2 n.u. after ceasing angiotensin II. Analysis of the baroreflex response showed that although angiotensin II–induced hypertension led to resetting of the relationship between mean arterial pressure (MAP) and heart rate, there was no evidence of resetting of the MAP-RSNA relationship. We propose that the lack of resetting of the MAP-RSNA curve, with the resting point lying near the lower plateau, suggests the sustained decrease in RSNA during angiotensin II is baroreflex mediated. These results suggest that baroreflex control of RSNA and thus renal function is likely to play a significant role in the control of arterial pressure not only in the short term but also in the long term.

Baroreceptor Denervation Prevents Sympathoinhibition During Angiotensin II–Induced Hypertension

Arterial baroreflexes are well established to provide the basis for short-term control of arterial pressure; however, their role in long-term pressure control is more controversial. We proposed that if the sustained decrease in renal sympathetic nerve activity (RSNA) we observed previously in response to angiotensin II–induced hypertension is baroreflex mediated, then the decrease in RSNA in response to angiotensin II would not occur in sinoaortic-denervated (SAD) animals. Arterial pressure and RSNA were recorded continuously via telemetry in sham and SAD rabbits living in their home cages before, during, and after a 7-day infusion of angiotensin II (50 ng · kg−1 · min−1). The arterial pressure responses in the 2 groups of rabbits were not significantly different (82±3 mm Hg sham versus 83±3 mm Hg SAD before angiotensin II infusion, and 101±6 mm Hg sham versus 100±4 mm Hg SAD day 6 of angiotensin II). In sham rabbits, there was a significant sustained decrease in RSNA (53±7% of baseline on day 2 and 65±7% on day 6 of the angiotensin II). On ceasing the angiotensin II, all variables recovered to baseline. In contrast, RSNA did not change in SAD rabbits with the angiotensin II infusion (RSNA was 98±8% of baseline on day 2 and 98±8% on day 6 of the angiotensin II infusion). These results support our hypothesis that the reduction in RSNA in response to a pressor dose of angiotensin II is dependent on an intact arterial baroreflex pathway.

Basis for the preferential activation of cardiac sympathetic nerve activity in heart failure

In heart failure (HF), sympathetic nerve activity is increased. Measurements in HF patients of cardiac norepinephrine spillover, reflecting cardiac sympathetic nerve activity (CSNA), indicate that it is increased earlier and to a greater extent than sympathetic activity to other organs. This has important consequences because it worsens prognosis, provoking arrhythmias and sudden death. To elucidate the mechanisms responsible for the activation of CSNA in HF, we made simultaneous direct neural recordings of CSNA and renal SNA (RSNA) in two groups of conscious sheep: normal animals and animals in HF induced by chronic, rapid ventricular pacing. In normal animals, the level of activity, measured as burst incidence (bursts of pulse related activity/100 heart beats), was significantly lower for CSNA (30 ± 5%) than for RSNA (94 ± 2%). Furthermore, the resting level of CSNA, relative to its maximum achieved while baroreceptors were unloaded by reducing arterial pressure, was set at a much lower percentage than RSNA. In HF, burst incidence of CSNA increased from 30 to 91%, whereas burst incidence of RSNA remained unaltered at 95%. The sensitivity of the control of both CSNA and RSNA by the arterial baroreflex remained unchanged in HF. These data show that, in the normal state, the resting level of CSNA is set at a lower level than RSNA, but in HF, the resting levels of SNA to both organs are close to their maxima. This finding provides an explanation for the preferential increase in cardiac norepinephrine spillover observed in HF.

Reinnervation of Renal Afferent and Efferent Nerves at 5.5 and 11 Months After Catheter-Based Radiofrequency Renal Denervation In Sheep

Previous studies indicate that catheter-based renal denervation reduces blood pressure and renal norepinephrine spillover in human resistant hypertension. The effects of this procedure on afferent sensory and efferent sympathetic renal nerves, and the subsequent degree of reinnervation, have not been investigated. We therefore examined the level of functional and anatomic reinnervation at 5.5 and 11 months after renal denervation using the Symplicity Flex catheter. In normotensive anesthetized sheep (n=6), electric stimulation of intact renal nerves increased arterial pressure from 99±3 to 107±3 mm Hg (afferent response) and reduced renal blood flow from 198±16 to 85±20 mL/min (efferent response). In a further group (n=6), immediately after denervation, renal sympathetic nerve activity was absent and the responses to electric stimulation were abolished. At 11 months after denervation (n=5), renal sympathetic nerve activity and the responses to electric stimulation were at normal levels. Immunohistochemical staining for renal efferent (tyrosine hydroxylase) and renal afferent nerves (calcitonin gene–related peptide), as well as renal norepinephrine levels, was normal 11 months after denervation. Findings at 5.5 months after denervation were similar (n=5). In summary, catheter-based renal denervation effectively ablated the renal afferent and efferent nerves in normotensive sheep. By 11 months after denervation the functional afferent and efferent responses to electric stimulation were normal. Reinnervation at 11 months after denervation was supported by normal anatomic distribution of afferent and efferent renal nerves. In view of this evidence, the mechanisms underlying the prolonged hypotensive effect of catheter-based renal denervation in human resistant hypertension need to be reassessed.

Nitric oxide and sympathetic nerve activity in the control of blood pressure.

1. Endothelial dysfunction marked by impairment in the release of nitric oxide (NO) is seen very early in the development of hypertension and is considered important in mediating the impaired vascular tone evident in essential hypertensive patients.

Septic shock induces distinct changes in sympathetic nerve activity to the heart and kidney in conscious sheep

Sepsis and septic shock are the chief cause of death in intensive care units, with mortality rates between 30 and 70%. In a large animal model of septic shock, we have demonstrated hypotension, increased cardiac output, and tachycardia, together with renal vasodilatation and renal failure. The changes in cardiac sympathetic nerve activity (CSNA) that may contribute to the tachycardia have not been investigated, and the changes in renal SNA (RSNA) that may mediate the changes in renal blood flow and function are unclear. We therefore recorded CSNA and RSNA during septic shock in conscious sheep. Septic shock was induced by administration of Escherichia coli, which caused a delayed hypotension and an immediate, biphasic increase in heart rate (HR) associated with similar changes in CSNA. After E. coli, RSNA decreased for over 3 h, followed by a sustained increase (180%), whereas renal blood flow progressively increased and remained elevated. There was an initial diuresis, followed by oliguria and decreased creatinine clearance. There were differential changes in the range of the arterial baroreflex curves; it was depressed for HR, increased for CSNA, and unchanged for RSNA. Our findings, recording CSNA for the first time in septic shock, suggest that the increase in SNA to the heart is not driven solely by unloading of baroreceptors and that the increase has an important role to increase HR and cardiac output. There was little correlation between the changes in RSNA and renal blood flow, suggesting that the renal vasodilatation was mediated mainly by other mechanisms.

Specific control of sympathetic nerve activity to the mammalian heart and kidney

There is a large body of evidence indicating that sympathetic nerves to individual organs are specifically controlled, but only few studies have compared the control of cardiac sympathetic nerve activity (CSNA) with activity in other sympathetic nerves. In this review, changes in sympathetic activity to the heart and kidneys are described during increases in brain [Na+] and in heart failure (HF). In conscious sheep, increases in brain [Na+] increased CSNA and arterial pressure and, conversely, decreased renal sympathetic nerve activity (RSNA), promoting urinary sodium loss. These organ‐specific effects are mediated via a neural pathway that includes an angiotensinergic synapse, the lamina terminalis and the paraventricular nucleus of the hypothalamus. There is also evidence of differential control of SNA in HF. In normal sheep, the resting burst incidence of CSNA was much lower than that of RSNA, whereas in HF they increased to similar, almost maximal levels in both nerves. Arterial baroreflex control of both these nerves was unchanged in HF, but the response of CSNA to changes in blood volume was almost absent. These data indicate that in HF the lower arterial pressure leads to reduced baroreflex inhibition of SNA, which, together with the lack of an inhibitory response to the increased volume and cardiac pressures, would contribute to the sympathoexcitation observed. These studies demonstrate differences in the control of CSNA and RSNA, enabling selective actions on the heart and kidney to restore fluid and electrolyte homeostasis in the case of elevated brain [Na+] and to increase cardiac output in HF.

Discharge properties of cardiac and renal sympathetic nerves and their impaired responses to changes in blood volume in heart failure

Sympathetic nerve activity (SNA) consists of discharges that vary in amplitude and frequency, reflecting the level of recruitment of nerve fibers and the rhythmic generation and entrainment of activity by the central nervous system. It is unknown whether selective changes in these amplitude and frequency components account for organ-specific changes in SNA in response to alterations in blood volume or for the impaired SNA responses to volume changes in heart failure (HF). To address these questions, we measured cardiac SNA (CSNA) and renal SNA (RSNA) simultaneously in conscious, normal sheep and sheep in HF induced by rapid ventricular pacing. Volume expansion decreased CSNA (-62 +/- 10%, P < 0.05) and RSNA (-59 +/- 10%, P < 0.05) equally (n = 6). CSNA decreased as a result of a reduction in burst frequency, whereas RSNA fell because of falls in burst frequency and amplitude. Hemorrhage increased CSNA (+74 +/- 9%, P < 0.05) more than RSNA (+21 +/- 5%, P < 0.09), in both cases because of increased burst frequency, whereas burst amplitude decreased. In HF, burst frequency of CSNA (from 26 +/- 3 to 75 +/- 3 bursts/min) increased more than that of RSNA (from 63 +/- 4 to 79 +/- 4 bursts/min). In HF, volume expansion caused no change in CSNA and an attenuated decrease in RSNA, due entirely to decreased burst amplitude. Hemorrhage did not significantly increase SNA in either nerve in HF. These findings support the concept that the number of sympathetic fibers recruited and their firing frequency are controlled independently. Furthermore, afferent stimuli, such as changes in blood volume, cause organ-specific responses in each of these components, which are also selectively altered in HF.

The low frequency power of heart rate variability is neither a measure of cardiac sympathetic tone nor of baroreflex sensitivity.

The lack of noninvasive approaches to measure cardiac sympathetic nerve activity (CSNA) has driven the development of indirect estimates such as the low-frequency (LF) power of heart rate variability (HRV). Recently, it has been suggested that LF HRV can be used to estimate the baroreflex modulation of heart period (HP) rather than cardiac sympathetic tone. To test this hypothesis, we measured CSNA, HP, blood pressure (BP), and baroreflex sensitivity (BRS) of HP, estimated with the modified Oxford technique, in conscious sheep with pacing-induced heart failure and in healthy control sheep. We found that CSNA was higher and systolic BP and HP were lower in sheep with heart failure than in control sheep. Cross-correlation analysis showed that in each group, the beat-to-beat changes in HP correlated with those in CSNA and in BP, but LF HRV did not correlate significantly with either CSNA or BRS. However, when control sheep and sheep with heart failure were considered together, CSNA correlated negatively with HP and BRS. There was also a negative correlation between CSNA and BRS in control sheep when considered alone. In conclusion, we demonstrate that in conscious sheep, LF HRV is neither a robust index of CSNA nor of BRS and is outperformed by HP and BRS in tracking CSNA. These results do not support the use of LF HRV as a noninvasive estimate of either CSNA or baroreflex function, but they highlight a link between CSNA and BRS.

The role of the paraventricular nucleus of the hypothalamus in the regulation of cardiac and renal sympathetic nerve activity in conscious normal and heart failure sheep

•  Heart failure is associated with large increases in sympathetic nerve activity to organs like the heart and kidney and this increase is detrimental to patients. •  We explored the role played by the paraventricular nucleus of the hypothalamus (PVN), a central brain region, in mediating the increase in sympathetic drive during heart failure. •  We show that neurons in the PVN selectively mediate changes in sympathetic drive to the kidney, but not to the heart when blood volume is increased. •  In addition, neurons in the PVN do not contribute to the resting levels of sympathetic drive to the heart during normal conditions or in heart failure. •  Our data demonstrates striking differences in the central mechanisms that control sympathetic drive to the heart and kidney during heart failure.