Carolyn J. Barrett

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.

Tumor Necrosis Factor-Alpha, Interleukin-6, and Interleukin-10 Levels are Altered in Preeclampsia: A Systematic Review and Meta-Analysis

Published reports testing the association between cytokine levels and preeclampsia are conflicting. This comprehensive systematic review and meta‐analysis aimed at testing the association between preeclampsia and maternal circulating tumor necrosis factor‐alpha (TNF‐α), interleukin (IL)‐6, and IL‐10.

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.

High Dietary Salt and Angiotensin II Chronically Increase Renal Sympathetic Nerve Activity A Direct Telemetric Study

Overactivity of the sympathetic nervous system has long been implicated in the hypertensive response to elevated angiotensin II (Ang II) levels. Although recent studies suggest that high dietary salt may alter cardiovascular responses to Ang II, direct evidence demonstrating chronic activation of sympathetic nerve activity is lacking. The objective of this study was to determine whether a low dose of Ang II, on a background of high salt intake, would result in a chronic increase in renal sympathetic nerve activity (RSNA). Arterial pressure and RSNA were recorded via telemetry. Two groups of rabbits were studied: 1 group drank a 0.9% NaCl solution and received Ang II (20 ng/kg per minute for 21 days, Salt+Ang), and the other drank tap water throughout and was not infused with Ang II (Control). In the Salt+Ang group, mean arterial pressure increased over the first week and remain elevated by 18.5±4.1 mm Hg at day 21. RSNA was not significantly different between groups on day 7 but was significantly elevated in the Salt+Ang group on day 21 (13.5±3.2% compared with 6.8±0.8% in the Control group; P<0.05). Baroreflex control of RSNA showed a rightward shift on day 21, but not day 7, and baroreflex responses indicated that RSNA could not be completely suppressed when arterial pressure was increased. No changes were observed in either mean arterial pressure or RSNA variables in the Control group. Our results support the hypothesis that elevated Ang II levels, in conjunction with a high salt diet, have the ability to chronically increase RSNA and, thus, potentially contribute to the maintenance of hypertension.

A real-time algorithm for the quantification of blood pressure waveforms

A real-time algorithm for quantification of biological oscillatory signals, such as arterial blood pressure (BP) is proposed which does not require user intervention and works on waveforms complicated by rapid changes in the mean level, frequency, or by the presence of arrhythmia. The algorithm is based on the continous independent assessment of the refractory period (RP). In the first stage, a sample of the signal is band-pass filtered. During the next stage: 1) the local maxima in the filtered signal are identified and their pulse amplitudes (PA) measured on the side opposite to the possible notch position and 2) those maxima whose PA exceeds some threshold are selected and an array of RP values is formed as a fraction of the moving estimate of the interval between successive selected peaks. Finally, the original signal is analyzed by means of two moving averages (MAs) with short and long averaging time intervals. The true peaks are determined as the maxima between intersections of MAs if the peak-to-peak or the intersection-to-intersection intervals since the previous peak and the previous intersection exceed the R.P. The algorithm proved to be superior against three commercially available heartbeat detectors yielding an error rate of 0.09%.

Quantifying sympathetic nerve activity: problems, pitfalls and the need for standardization

Since the first recording of sympathetic nerve activity (SNA) early last century, numerous methods for presentation of the resulting data have developed. In this paper, we discuss the common ways of describing SNA and their application to chronic recordings. Suggestions on assessing the quality of SNA are made, including the use of arterial pressure wave‐triggered averages and nasopharyngeal stimuli. Calculation of the zero level of the SNA signal from recordings during ganglionic blockade, the average level between bursts and the minimum of arterial pressure wave‐triggered averages are compared and shown to be equivalent. The use of normalization between zero and maximal SNA levels to allow comparison between groups is discussed. We recommend that measured microvolt levels of integrated SNA be presented (with the zero/noise level subtracted), along with burst amplitude and frequency information whenever possible. We propose that standardization of the quantifying/reporting of SNA will allow better comparison between disease models and between research groups and ultimately allow data to be more reflective of the human situation.

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.

Interactions between neural and hormonal mediators of renal vascular tone in anaesthetized rabbits.

We investigated how sympathetic nerve activity and vasoactive hormones interact in controlling renal haemodynamics in pentobarbitone‐anaesthetized rabbits. Renal blood flow was progressively reduced by electrical stimulation (0.5‐3 Hz) of the renal nerves, during renal arterial infusion of saline, vasoconstrictors (angiotensin II and [Phe2,Ile3,Orn8]‐vasopressin), or vasodilators (acetylcholine, adrenomedullin and the nitric oxide donor methylamine hexamethylene NONOate (MAHMA NONOate). A frequency‐rich stimulus was also applied to test whether the vasoactive agents affect the dynamic control of renal blood flow by sympathetic nerve activity. The vasodilators tended to increase renal blood flow, but only the effect of MAHMA NONOate was statistically significant. [Phe2,Ile3,Orn8]‐vasopressin reduced medullary perfusion (by 61 ± 12%) but not renal blood flow or cortical perfusion. Angiotensin II reduced renal blood flow (33 ± 3%) and cortical perfusion (14 ± 5%) but not medullary perfusion. Steady‐state responses of renal blood flow and cortical perfusion during renal nerve stimulation were attenuated during infusion of acetylcholine and [Phe2,Ile3,Orn8]‐vasopressin, while angiotensin II attenuated responses of medullary perfusion, and MAHMA NONOate and adrenomedullin had no significant effects. The dynamic response to sympathetic nerve activity (renal blood flow responded as a low pass filter with a pure time delay of ∼664 ms) was not altered by the vasoactive agents. We conclude that some vasoactive agents can modulate steady‐state renal haemodynamic responses to sympathetic nerve activity in a regionally specific manner, independent of their effects on baseline renovascular tone. However, they have little impact on the dynamic response of renal blood flow to sympathetic nerve activity.

Angiotensin II‐based hypertension and the sympathetic nervous system: the role of dose and increased dietary salt in rabbits

There is accumulating evidence that angiotensin II may exert its hypertensive effect through increasing sympathetic drive. However, this action may be dependent on the dose of angiotensin II as well as salt intake. We determined the effect of different doses of angiotensin II and different levels of salt intake on neurogenic pressor activity. We also examined the effect of renal denervation. New Zealand White rabbits were instrumented to continuously measure arterial pressure. The depressor response to the ganglionic blocker pentolinium tartrate (5 mg kg−1) was used to assess pressor sympathetic drive on days 0, 7 and 21 of a 20 or 50 ng kg−1 min−1 continuous i.v. angiotensin II infusion. A 50 ng kg−1 min−1 infusion caused an immediate increase in pressure (23 ± 5 mmHg), whereas a 20 ng kg−1 min−1 infusion caused a slow increase in pressure, peaking by day 12 (17 ± 4 mmHg). The ganglionic blockade profiles indicated sympathoinhibition in the 50 ng kg−1 min−1 group by day 7 and sympathoinhibition in the 20 ng kg−1 min−1 group at day 21, corresponding to the development of hypertension. Animals receiving increased dietary salt (0.9% NaCl in drinking water), however, showed a similar slow increase in pressure with 20 ng kg−1 min−1 angiotensin II (16 ± 5 mmHg) but no sympathoinhibition at day 21. Bilateral renal denervation delayed the onset but not the extent of hypertension in this group. We conclude that different doses of angiotensin II produce distinct profiles of hypertension and associated changes in pressor sympathetic drive and that increased dietary salt intake disrupts the normal sympathoinhibitory response to angiotensin II‐based hypertension.

A high-salt diet does not influence renal sympathetic nerve activity: a direct telemetric investigation

The importance of dietary salt in the development of hypertension has long been a source of controversy. Recent studies suggest a combination of high-salt and ANG II infusion may increase sympathetic drive; however, the effect of a change in dietary salt alone is unclear. Using telemetry, we recorded renal sympathetic nerve activity (RSNA), arterial pressure (MAP), and heart rate (HR) in seven New Zealand white rabbits before and during a 6-day period of increased salt intake (normal NaCl 0.5 g x kg(-1) x day(-1), high NaCl 2.5 g x kg(-1) x day(-1)) and a second group of seven rabbits with normal salt intake throughout. The responses to stressful stimuli encountered in the laboratory were recorded and compared with rest in control and high-salt groups. Resting MAP, HR, and RSNA were not significantly altered with high salt intake [88 +/- 5 vs. 91 +/- 6 mmHg; 251 +/- 8 vs. 244 +/- 9 beats per minute (bpm); 9.7 +/- and 1.2 vs. 10.8 +/- 1.7 normalized units (nu)] despite significant reductions in plasma renin activity (1.88 +/- 0.18 vs. 1.27 +/- 0.15 nmol ANG I x l(-1) x h(-1); P < 0.05) and ANG II (7.5 +/- 1.2 vs. 4.3 +/- 0.8 pmol/l). Increasing levels of stressful stimuli (resting in home cage, containment in box, handling, and nasopharyngeal activation) in animals on a normal salt diet caused graded increases in MAP (89 +/- 2 mmHg, 95 +/- 2 mmHg, 107 +/- 4 mmHg, and 122 +/- 5 mmHg, respectively) and RSNA (9.7 +/- 0.9 nu; 11.8 +/- 2.7 nu; 31.4 +/- 3.7 nu; 100 nu) but not HR (245 +/- 8 bpm; 234 +/- 8 bpm; 262 +/- 9 bpm; 36 +/- 5 bpm). High dietary salt did not significantly alter the responses to stress. We conclude that a 6-day period of high salt intake does not alter the level of RSNA, with non-neural mechanisms primarily responsible for the observed renin-angiotensin system suppression.