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Sympathetic overdrive is associated with many diseases, but its origin remains an enigma. An emerging hypothesis in the development of cardiovascular disease is that the brain puts the utmost priority on maintaining its own blood supply; even if this comes at the “cost” of high blood pressure to the rest of the body. A critical step in making a causative link between reduced brain blood flow and cardiovascular disease is how changes in cerebral perfusion affect the sympathetic nervous system. A direct link between decreases in cerebral perfusion pressure and sympathetic tone generation in a conscious large animal has not been shown. We hypothesized that there is a novel control pathway between physiological levels of intracranial pressure (ICP) and blood pressure via the sympathetic nervous system. Intracerebroventricular infusion of saline produced a ramped increase in ICP of up to 20 mmHg over a 30-min infusion period (baseline 4.0 ± 1.1 mmHg). The ICP increase was matched by an increase in mean arterial pressure such that cerebral perfusion pressure remained constant. Direct recordings of renal sympathetic nerve activity indicated that sympathetic drive increased with increasing ICP. Ganglionic blockade, by hexamethonium, preventing sympathetic transmission, abolished the increase in arterial pressure in response to increased ICP and was associated with a significant decrease in cerebral perfusion pressure. This is the first study to show that physiological elevations in ICP regulate renal sympathetic activity in conscious animals. We have demonstrated a novel physiological mechanism linking ICP levels with sympathetic discharge via a possible novel intracranial baroreflex.

Hydrocephalus is the single most common pediatric neurosurgical problem worldwide. Current treatment of this life-threatening disorder involves diverting excess fluid from the ventricles of the brain via a prosthetic shunt. While many hydrocephalus sufferers rely heavily on their ventriculo-distal shunt to maintain a healthy intracranial pressure, shunts carry a high risk of failure. Current methods of assessing shunt patency are performed within the hospital, and many patients and their families feel bound to remaining within close proximity of a hospital in order to receive timely medical intervention in the event of a shunt failure. There is a need for a system which can detect shunt malfunction, simply and reliably. We present a novel method of obtaining flow measurements from a piezoresistive pressure transducer. This builds on an earlier development of obtaining simultaneous temperature and pressure measurement from the single ultra-miniature solid-state transducer. The flow measurement system is capable of measurements in the range 0-35 ml/h, typical of the fluid flow rates through a hydrocephalus shunt. Within the flow range 0–14 ml/hour the resolution is 2 ml/hour. For flow rates greater than 16 ml/hour the resolution is 5 ml/hour. Employing a thermal flow sensing technique, the maximum heating of the local fluid is 0.65 ± 0.02 °C. The flow signal is independent of ambient temperature. The sensor would be implanted in the shunt to allow the detection of the flow rate of fluid through it, enabling the clinician to measure the patency of a shunt in real time.

Although cerebral perfusion pressure (CPP) is known to be fundamental in the control of normal brain function, there have been no previous long-term measurements in animal models. The aim of this study was to explore the stability and viability of long-term recordings of intracranial pressure (ICP) in freely moving rats via a telemetry device. We also developed a repeatable surgical approach with a solid-state pressure sensor at the tip of the catheter placed under the dura and in combination with arterial pressure (AP) measurement to enable the calculation of CPP. Telemeters with dual pressure catheters were implanted in Wistar rats to measure ICP and AP. We found that the signals were stable throughout the 28-day recording period with an average ICP value of 6 ± 0.8 mmHg. Significant light-dark differences were found in AP (3.1 ± 2.7 mmHg, P = 0.02) and HR (58 ± 12 beats/min, P = 0.003), but not ICP (0.3 ± 0.2 mmHg, P >0.05) or CPP (2.6 ± 2.8 mmHg, P > 0.05). Use of kaolin to induce hydrocephalus in several rats demonstrates the ability to measure changes in ICP throughout disease progression, validating this new solution for chronic measurement of ICP, CPP, and AP in conscious rats.

There is controversy regarding whether the arterial baroreflex control of renal sympathetic nerve activity (SNA) in heart failure is altered. We investigated the impact of sex and ovarian hormones on changes in the arterial baroreflex control of renal SNA following a chronic myocardial infarction (MI). Renal SNA and arterial pressure were recorded in chloralose-urethane anesthetized male, female, and ovariectomized female (OVX) Wistar rats 6–7 wk postsham or MI surgery. Animals were grouped according to MI size (sham, small and large MI). Ovary-intact females had a lower mortality rate post-MI (24%) compared with both males (38%) and OVX (50%) ( P < 0.05). Males and OVX with large MI, but not small MI, displayed an impaired ability of the arterial baroreflex to inhibit renal SNA. As a result, the male large MI group (49 ± 6 vs. 84 ± 5% in male sham group) and OVX large MI group (37 ± 3 vs. 75 ± 5% in OVX sham group) displayed significantly reduced arterial baroreflex range of control of normalized renal SNA ( P < 0.05). In ovary-intact females, arterial baroreflex control of normalized renal SNA was unchanged regardless of MI size. In males and OVX there was a significant, positive correlation between left ventricle (LV) ejection fraction and arterial baroreflex range of control of normalized renal SNA, but not absolute renal SNA, that was not evident in ovary-intact females. The current findings demonstrate that the arterial baroreflex control of renal SNA post-MI is preserved in ovary-intact females, and the state of left ventricular dysfunction significantly impacts on the changes in the arterial baroreflex post-MI.

Purpose To investigate the potential patient risk and interactions between a prototype implantable pressure monitoring device and a 3T clinical magnetic resonance imaging (MRI) machine to guide device design towards MR Conditional safety approval. Materials and Methods The pressure monitor device contained a catheter-mounted piezo-resistive pressure sensor, rechargeable battery, wireless communication system, and inductive pickup coil. Standard testing methods were used to guide experiments to investigate static field induced force and torque, radiofrequency (RF)-induced heating, image artifacts, and the MR's effect on device function. The specific clinical application of intracranial pressure monitoring was considered. RF-induced heating experiments were supported by numerical modeling of the RF body coil, the device, and experimental phantom. Results Sensing catheter lead length and configuration was an important component of the device design. A short 150 mm length catheter produced a heating effect of less than 2°C and a long 420 mm length catheter caused heating of 7.2°C. Static magnetic field interactions were below standard safety risk levels and the MR did not interfere with device function; however, artifacts have the potential to interfere with image quality. Conclusion Investigation of MR interactions at the prototype stage provides useful implantable device design guidance and confidence that an implantable pressure monitor may be able to achieve MR Conditional safety approval. J. Magn. Reson. Imaging 2015;42:1441–1449.

The precise roles of hypoxia in the initiation and progression of kidney disease remain unresolved. A major technical limitation has been the absence of methods allowing long-term measurement of kidney tissue oxygen tension (Po2) in unrestrained animals. We developed a telemetric method for the measurement of kidney tissue Po2 in unrestrained rats, using carbon paste electrodes (CPEs). After acute implantation in anesthetized rats, tissue Po2 measured by CPE-telemetry in the inner cortex and medulla was in close agreement with that provided by the “gold standard” Clark electrode. The CPE-telemetry system could detect small changes in renal tissue Po2 evoked by mild hypoxemia. In unanesthetized rats, CPE-telemetry provided stable measurements of medullary tissue Po2 over days 5− 19 after implantation. It also provided reproducible responses to systemic hypoxia and hyperoxia over this time period. There was little evidence of fibrosis or scarring after 3 wk of electrode implantation. However, because medullary Po2 measured by CPE-telemetry was greater than that documented from previous studies in anesthetized animals, this method is presently best suited for monitoring relative changes rather than absolute values. Nevertheless, this new technology provides, for the first time, the opportunity to examine the temporal relationships between tissue hypoxia and the progression of renal disease.

The physiological mechanisms contributing to sex differences following myocardial infarction (MI) are poorly understood. Given the strong relationship between sympathetic nerve activity (SNA) and outcome, we hypothesized there may be a sex difference in SNA responses to MI. In anaesthetized, open-chest male, female and ovariectomized (OVX) female Wistar rats, mean arterial pressure, heart rate and renal SNA were recorded in response to ligation of the left coronary artery. In males, renal SNA increased by 30 ± 6% in the first minute of coronary occlusion (P < 0.05) and remained elevated at 18 ± 7% above baseline (P < 0.05) at 2 h following MI. In response to MI, ovary-intact females displayed no change in renal SNA, whereas OVX females displayed a significant increase, similar to that seen in the males (increases of 43 ± 11% at 1 min and 21 ± 7% at 2 h post-MI, P < 0.05 versus intact females). Arterial baroreflex control of renal SNA had a smaller range in females (ovary intact and OVX) than males; no changes in arterial baroreflex responses were observed 1 h post-MI in males or females. Denervating the arterial baroreceptors abolished the renal SNA response to MI in the males, whereas in ovary-intact females and OVX females the response was unaltered. These findings suggest that ovarian hormones are able to blunt the initial sympathetic activation post-MI in females and that the importance of the arterial baroreflex in mediating initial sympathetic activation post-MI is different between the sexes.

1. Sexual intercourse is associated with an increased risk of death from arrhythmia development, myocardial infarction or stroke. It is unclear whether this increased risk is due to physical exertion alone or whether it is an inherent aspect of sexual activity itself. 2. Using a telemetric approach, we show that sexual activity is associated with transient (8-14 s) but profound increases in renal sympathetic nerve activity (RSNA; up to 22-fold that of baseline) in both male and female rabbits. This increase was significantly greater than that observed during physical exertion (three- to sixfold increase in RSNA). 3. In addition, we observed rapid transitions in male rabbits from tachycardia (422 ± 21 b.p.m.; P < 0.01) to bradycardia (186 ± 28 b.p.m.; P < 0.05) during and immediately following coitus. This suggests simultaneous activation of both the sympathetic and parasympathetic nervous systems. 4. The present study provides the first real-time insight into the extreme variation in neural and cardiovascular function occurring during sexual activity in normal healthy rabbits. Little is known about how the physiological responses to sexual activity may change under disease or drug-treatment states, and these findings may prove of use to these areas in future.

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

Late preterm infants, born between 34 and 36 weeks gestation, have significantly higher morbidity than neonates born at full term, which may be partly related to reduced sensitivity of the arterial baroreflex. The present study assessed baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) in near-term fetal sheep at 123 ± 1 days gestation. At this age, although fetuses are not fully mature in some respects (term is 147 days), sleep-state cycling is established [between high-voltage, low-frequency (HV) and low-voltage, high-frequency (LV) sleep], and neural myelination is similar to the term human infant. Fetal sheep were instrumented to record blood pressure (BP), HR (n = 15) and RSNA (n = 5). Blood pressure was manipulated using vasoactive drugs, phenylephrine and sodium nitroprusside. In both HV and LV sleep, phenylephrine was associated with increased arterial BP and decreased HR. In HV sleep, phenylephrine was associated with a fall in RSNA, from 124 ± 14 to 58 ± 11% (P < 0.05), but no significant change in RSNA in LV sleep. In contrast, the fall in BP after sodium nitroprusside was associated with a significant increase in HR during LV but not HV sleep, and there was no significant effect of hypotension on RSNA. These data demonstrate that in near-term fetal sheep baroreflex activity is only partly active and is highly modulated by sleep state. Critically, there was no RSNA response to marked hypotension; this finding has implications for the ability of the late preterm fetus to adapt to low BP.

Sympathetic nerve activity (SNA) has two main properties, the presence of co-ordinated bursts of activity, indicative of many nerve fibres firing at a similar time, and entrainment of the bursts to the cardiac cycle, due to inhibitory input from baroreceptors to a network of cell groups within the CNS. Although this patterning is used as a 'gold standard' for the identification of successful nerve recordings, the maturation of these basic features of SNA from fetal life to adulthood has not been investigated. Using a telemetry-based nerve amplifier, renal SNA (RSNA) was recorded in preterm (99 ± 1 days gestation; term 147 days) and near-term fetal sheep (119 ± 0 days gestation), without anaesthesia or paralysis, and contrasted with RSNA recorded in adult sheep. All three age groups showed a classic bursting pattern of RSNA and co-ordination of bursts with the cardiac cycle. However, the delay between diastole and the next peak in RSNA was longest in preterm fetuses (319 ± 1 ms), compared with near-term fetuses (250 ± 13 ms), and shortest in the adult sheep (174 ± 38 ms). This was independent of the maturational decrease in heart rate. The near-term fetuses showed a marked but sleep-state-dependent increase in resting RSNA compared with preterm fetuses. Although entrainment with the pressure pulse suggests that the intricate circuitry within the CNS is developed in the preterm fetus, the decrease in the length of the delay suggests continuing maturation of this key feature of RSNA in the last third of gestation and after birth.

This review examines how the sympathetic nervous system plays a major role in the regulation of cardiovascular function over multiple time scales. This is achieved through differential regulation of sympathetic outflow to a variety of organs. This differential control is a product of the topographical organization of the central nervous system and a myriad of afferent inputs. Together this organization produces sympathetic responses tailored to match stimuli. The long-term control of sympathetic nerve activity (SNA) is an area of considerable interest and involves a variety of mediators acting in a quite distinct fashion. These mediators include arterial baroreflexes, angiotensin II, blood volume and osmolarity, and a host of humoral factors. A key feature of many cardiovascular diseases is increased SNA. However, rather than there being a generalized increase in SNA, it is organ specific, in particular to the heart and kidneys. These increases in regional SNA are associated with increased mortality. Understanding the regulation of organ-specific SNA is likely to offer new targets for drug therapy. There is a need for the research community to develop better animal models and technologies that reflect the disease progression seen in humans. A particular focus is required on models in which SNA is chronically elevated.

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.

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·kg−1·day−1, high NaCl 2.5 g·kg−1·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·l−1·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.

The arterial baroreflex is a fundamental reflex that buffers rapid changes in arterial blood pressure (BP) via regulation of the heart rate and sympathetic nerve activity to the vasculature. In adults a sigmoidal relationship between BP and both heart rate and sympathetic nerve activity is well documented. Its role in blood pressure control before birth is unclear. Preterm babies have a high incidence of low BP, especially in the first few days of life, which could be related, in part, to immaturity of the baroreflex. In the present study, we investigated the baroreflex control of fetal heart rate and renal sympathetic nerve activity (RSNA) in preterm fetal sheep in utero (102 ± 1 days of gestation; term 140 days). Phenylephrine was associated with a significant increase in BP from 38 ± 2 to 58 ± 3 mmHg and a decrease in heart rate (HR) from 177 ± 4 to 116 ± 8 beats per minute (bpm). Sodium nitroprusside was associated with a significant fall in BP from 38 ± 2 to 26 ± 1 mmHg and an increase in HR from 182 ± 4 to 274 ± 8 bpm. However, the time between the 50% changes in BP and HR was significantly greater after hypotension than hypertension (31 ± 8 s vs. 14 ± 5 s, P < 0.05). No significant changes in RSNA occurred with either stimulus. This suggests that there are different maturational tempos for the components of the central autonomic response to altered blood pressure.

SUMMARY 1 Adenosine A1 receptor activation is critical for endogenous neuroprotection from hypoxia–ischaemia, raising the possibility that treatment with A1 receptor agonists may be an effective physiological protection strategy for vulnerable preterm infants. However, the A1 receptor can mediate unwanted systemic effects, including vasoconstriction of the afferent glomerular arteriole. There is limited information on whether this occurs at doses that improve cerebral perfusion in the immature brain. 2 Therefore, in the present study, we examined whether infusion of the selective A1 receptor agonist adenosine amine congener (ADAC) is associated with reduced renal perfusion in chronically instrumented preterm (0.7 gestation) fetal sheep. In the present study, ADAC was given in successive doses of 2.5, 5.0 and 15.0 µg, 45 min apart. 3 Treatment with ADAC was associated with a marked reduction in renal vascular conductance (and blood flow), whereas carotid conductance was increased and there was no significant effect on femoral conductance. In contrast with the stable effects of increasing ADAC dose on vascular conductance, there was a significant dose-related fall in fetal heart rate and blood pressure. 4 In conclusion, these short-term data support the concern that A1 receptor agonist infusion can selectively impair renal perfusion, even at low doses.

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.

The control of blood pressure is a complex mixture of neural, hormonal and intrinsic interactions at the level of the heart, kidney and blood vessels. While experimental approaches to understanding these interactions are useful, it remains difficult to conduct experiments to quantify these interactions as the number of parameters increases. Thus, modelling of such physiological systems can offer considerable assistance. Typical mathematical models which describe the ability of the blood vessels to change their diameter (vasoconstriction) assume linearity of operation. However, due to the interaction of multiple vasocontrictive and vasodilative effectors, there is a significant nonlinear response to the influence of neural factors, particularly at higher levels of nerve activity (often seen in subjects with high blood pressure) which leads to low blood flow rates. This paper proposes a number of nonlinear mathematical models for the relationship between neural influences (sympathetic nerve activity (SNA)) and renal blood flow, using a feedback path to model the predominantly nonlinear effect of local vasoactive modulators such as nitric oxide, which oppose the action of SNA. The model structures are motivated by basic physiological principles, while the model parameters are determined using numerical optimisation techniques using open-loop data collected from rabbits. The models were verified by demonstrating correlation between experimental results and model outputs.

Extensive studies in the adult have demonstrated that the sympathetic nervous system plays a central role in cardiovascular control. The maturation of the sympathetic nervous system before birth is poorly understood. In the present study, we directly recorded renal sympathetic nerve activity (renal SNA) in five preterm fetal sheep (99 ± 1 days gestation; term is 147 days). Recordings were performed in utero using a telemetry-based technique to alleviate movement artifact without anesthesia or paralysis. The preterm fetuses exhibited a coordinated discharge pattern in renal SNA, indicating many individual neurons active at approximately the same time. This is consistent with that observed previously in adult animals, although the frequency of the bursts was relatively low (0.5 ± 0.1 Hz). The discharges in renal SNA were entrained to the cardiac cycle (average delay between diastolic pressure and maximum renal SNA 319 ± 1 ms). The entrainment of the sympathetic discharges to the cardiac cycle indicates phasic baroreceptor input and that the underlying circuits controlling SNA within the central nervous system are active in premature fetuses.

The brain is an exceptionally energetically demanding organ with little metabolic reserve, and multiple systems operate to protect and preserve the brain blood supply. But how does the brain sense its own perfusion? In this review, we discuss how the brain may harness the cardiovascular system to counter threats to cerebral perfusion sensed via intracranial pressure (ICP), cerebral oxygenation and ischemia. Since the work of Cushing over 100 years ago, the existence of brain baroreceptors capable of eliciting increases in sympathetic outflow and blood pressure has been hypothesized. In the clinic, this response has generally been thought to occur only in extremis, to perfuse the severely ischemic brain as cerebral autoregulation fails. We review evidence that pressor responses may also occur with smaller, physiologically-relevant increases in ICP. The incoming brain oxygen supply is closely monitored by the carotid chemoreceptors, however, hypoxia and other markers of ischemia are also sensed intrinsically by astrocytes or other support cells within brain tissue itself, and elicit reactive hyperaemia. Recent studies suggest that astrocytic oxygen signalling within the brainstem may directly affect sympathetic nerve activity and blood pressure. We speculate that local cerebral oxygen tension is a major determinant of the mean level of arterial pressure, and discuss recent evidence that this may be the case. We conclude that intrinsic intra- and extra-cranial mechanisms sense and integrate information about hypoxia/ischemia and intracranial pressure, and play a major role in determining the long-term level of sympathetic outflow and arterial pressure, in order to optimise cerebral perfusion.

A relative deficiency in kidney oxygenation, i.e., renal hypoxia, may contribute to the initiation and progression of acute and chronic kidney disease. A critical barrier to investigate this is the lack of methods allowing measurement of the partial pressure of oxygen in kidney tissue for long periods in vivo. We have developed, validated, and tested a novel telemetric method that can do this. Here we provide details on the calibration, implantation, implementation for data recording, and reuse of this telemetry-based technology for measurement of medullary tissue oxygen tension in conscious, unrestrained rats. This technique provides an important additional tool for investigating the impact of renal hypoxia in biology and pathophysiology.

We have developed a fully implantable telemetry device for use in mice. The telemeter is able to measure biopotential signals (EEG, EMG, ECG) at a sampling rate of 2000 Hz. The device has a volume ...

With increasing evidence that the sympathetic nervous system plays a critical role in the development of hypertension, focus is turning to how these signals translate to a chronic increase in arterial pressure. The kidney's role in the control of salt and water homeostasis makes it an obvious target for such investigations. However, to date many studies have been restricted to experiments that last only a few hours, or at most, a few days, whereas others may use indirect methods of assessing sympathetic activity rather than direct recordings. We review current approaches used to determine the effects of renal sympathetic nerve activity (SNA) on arterial pressure and suggest possible avenues of future investigation. We propose that although afferent inputs, such those as from chemoreceptors and baroreceptors, are important for the short-term control of blood pressure via regulation of SNA to multiple organs, it is highly likely that alternative signals are important for setting the long-term level of renal SNA. Emerging evidence indicates that circulating angiotensin II is a hormone that may act on the central nervous system to regulate renal SNA, renal function, and, therefore, blood pressure. Future studies on the genesis of hypertension should focus more on determining the mediators of long-term levels of renal SNA.

The control of blood pressure is a complex mixture of neural, hormonal and intrinsic interactions at the level of the heart, kidney and blood vessels. While experimental approaches to understanding these interactions remain useful, it remains difficult to conduct experiments to quantify these interactions as the number of parameters increases. Thus modelling approaches can offer considerable assistance. Typical mathematical models which describe the ability of the blood vessels to change their diameter (vasoconstriction) assume linearity of operation. However, due to the interaction of multiple vasocontrictive and vasodilative effectors, there is a significant nonlinear response to the influence of neural factors, particularly at higher levels of nerve activity (often seen in subjects with high blood pressure) which leads to low blood flow rates. This paper proposes a nonlinear mathematical model for the relationship between neural influences (sympathetic nerve activity (SNA) and blood flow, using a feedback path to model the predominently nonlinear effect of local vasoactive modulators such as Nitric Oxide, which oppose the action of SNA. The model, the structure of which is motivated by basic physiological principles, is parameterised using a numerical optimisation method using open-loop data collected from rabbits. The model responses are shown to be in good agreement with the experimental data.

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. 2. Recently, a hypothesis has emerged that NO acting as a neurotransmitter in the brain can modulate levels of sympathetic nerve activity and thereby blood pressure. The NO inhibition model of hypertension has been used to explore the possibility that a decrease in levels of NO can cause an increase in levels of sympathetic nerve activity that can mediate the hypertension. 3. In the present review, we examine the literature regarding the role of NO in setting the mean level of sympathetic nerve activity and blood pressure. Although the acute effects of NO inhibition are well understood, the chronic interaction between the sympathetic nervous system and NO has only been investigated using indirect measures of sympathetic nerve activity, such as ganglionic blockade. This has led to inconsistent results regarding the role of NO in modulating sympathetic nerve activity chronically. 4. Some of the conflicting results may be explained by differences in the 'background' levels of angiotensin (Ang) II. Evidence suggests that NO may interact with AngII and baroreceptor afferent inputs in the central nervous system to set the mean level of sympathetic nerve activity. 5. We suggest chronic NO inhibition can increase sympathetic nerve activity if baroreceptor input is intact and AngII levels are elevated. Although studies exploring the actions of NO or AngII in isolation are useful for gathering initial information, future studies should focus on their interactions and their role in setting the long-term levels of sympathetic activity and blood pressure.

While there is no disputing the critical role of baroreflexes in buffering rapid changes in arterial pressure, their role in long-term pressure control has become an area of controversy. Recent experiments using novel techniques have challenged the traditional view that arterial baroreflexes are not involved in setting chronic arterial pressure levels. Resetting of the arterial baroreflex, often used as an argument against the arterial baroreflex playing a role in long-term pressure control is rarely complete. The arterial baroreflex is just one of the many neural, hormonal, and intrinsic mechanisms involved in arterial pressure control and while the removal of the arterial baroreflex alone has little effect on mean arterial pressure it is too simplistic to suggest that the baroreflex has no role in long-term pressure control. Renal sympathetic nerve activity appears to be particularly resistant to resetting in response to ANG II-induced hypertension. Given the important role of the kidneys in long-term pressure control, we suggest there is a clear need to develop experimental techniques whereby sympathetic nerve activity to the kidneys and other organs can be monitored over periods of weeks to months.

We examined the roles of cyclooxygenase products and of interactions between the cyclooxygenase and nitric oxide systems in the mechanisms underlying the relative insensitivity of medullary perfusion to renal nerve stimulation (RNS) in anaesthetized rabbits. To this end we examined the effects of ibuprofen and N(G)-nitro-L: -arginine (L-NNA), both alone and in combination, on the responses of regional kidney perfusion to RNS. Under control conditions, RNS produced frequency-dependent reductions in total renal blood flow (RBF; -82+/-3% at 6 Hz), cortical laser-Doppler flux (CLDF; -84+/-4% at 6 Hz) and, to a lesser extent, medullary laser-Doppler flux (MLDF; -46+/-7% at 6 Hz). Ibuprofen did not affect these responses significantly, suggesting that cyclooxygenase products have little net role in modulating renal vascular responses to RNS. L-NNA enhanced RBF (P=0.002), CLDF (P=0.03) and MLDF (P=0.03) responses to RNS. As we have shown previously, this effect of L-NNA was particularly prominent for MLDF at RNS frequencies < or = 1.5 Hz. Subsequent administration of ibuprofen, in L-NNA-pretreated rabbits, did not affect responses to RNS significantly. We conclude that counter-regulatory actions of NO, but not of prostaglandins, partly underlie the relative insensitivity of medullary perfusion to renal nerve activation.

Summary 1. There is strong evidence that the renal medullary circulation plays a key role in long-term blood pressure control. This, and evidence implicating sympathetic overactivity in development of hypertension, provides the need for understanding how sympathetic nerves affect medullary blood flow (MBF). 2. The precise vascular elements that regulate MBF under physiological conditions are unknown, but likely include the outer medullary portions of descending vasa recta and afferent and efferent arterioles of juxtamedullary glomeruli, all of which receive dense sympathetic innervation. 3. Many early studies of the impact of sympathetic drive on MBF were flawed, both because of the methods used for measuring MBF and because single and often intense neural stimuli were tested. 4. Recent studies have established that MBF is less sensitive than cortical blood flow (CBF) to electrical renal nerve stimulation, particularly at low stimulus intensities. Indeed, MBF appears to be refractory to increases in endogenous renal sympathetic nerve activity within the physiological range in all but the most extreme cases. 5. Multiple mechanisms appear to operate in concert to blunt the impact of sympathetic drive on MBF, including counter-regulatory roles of nitric oxide and perhaps even paradoxical angiotensin II-induced vasodilatation. Regional differences in the geometry of glomerular arterioles are also likely to predispose MBF to be less sensitive than CBF to any given vasoconstrictor stimulus. 6. Failure of these mechanisms would promote reductions in MBF in response to physiological activation of the renal nerves, which could, in turn, lead to salt and water retention and hypertension.

1. We investigated how sympathetic nerve activity and renal perfusion pressure (RPP) interact in controlling renal haemodynamics in pentobarbitone-anaesthetized rabbits. 2. Renal blood flow (RBF) was reduced by electrical renal nerve stimulation (0.5-8 Hz), with RPP set using an extracorporeal circuit to 65, 100 and 135 mmHg. 3. Responses of RBF and cortical laser Doppler flux to renal nerve stimulation were blunted by increased RPP. For example, 4 Hz stimulation reduced RBF by 68 +/- 7% with baseline perfusion pressure approximately 65 mmHg, but only by 22 +/- 3% at approximately 135 mmHg. Medullary laser Doppler flux was less responsive than cortical laser Doppler flux to renal nerve stimulation and its response was not dependent on perfusion pressure. 4. When perfusion pressure was clamped at its baseline level during renal nerve stimulation, responses of RBF and cortical laser Doppler flux, but not medullary laser Doppler flux, were still blunted with increased baseline perfusion pressure. 5. A frequency rich stimulus was applied to assess the effects of perfusion pressure on dynamic neural control of RBF. Renal blood flow responded similarly at each level of perfusion pressure, as a low-pass filter with a pure time delay. 6. Our results suggest that, in the rabbit extracorporeal circuit model, increased RPP blunts the ability of steady state renal nerve stimulation to reduce cortical, but not medullary perfusion. However, in this model the level of RPP appears to have little impact on dynamic neural control of RBF.

Although the vascular action of endothelium-derived nitric oxide in modulating arterial pressure is well established, nitric oxide can also act as a neurotransmitter in the central nervous system. In addition, there is evidence for an interaction between nitric oxide and baroreceptor afferent processing; thus, nitric oxide may regulate blood pressure through central modulation of arterial baroreflexes. To test this possible interaction of nitric oxide and baroreflexes in the long-term regulation of blood pressure, we measured arterial pressure and heart rate responses to nitric oxide blockade by using L-NAME (50 mg/kg per day in drinking water) over 7 days in baroreceptor intact and sinoaortic denervated conscious rabbits. In the baroreceptor intact animals, blockade of nitric oxide leads to a significant increase in mean arterial pressure (from 75±2 to 84±3 mm Hg) and decrease in heart rate (from 233±8 to 195±8 bpm) that was sustained over the 7 days of nitric oxide blockade. In the sinoaortic denervated animals, blockade of nitric oxide initially led to a similar increase in arterial pressure (82±3 mm Hg on the second day), but in all sinoaortic denervated animals this increase was not sustained and recovered back to pre–L-NAME levels. This finding indicates that baroreflexes play an important role in the long-term control of blood pressure, and, second, that one mediator of this control is nitric oxide.

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 [Phe 2 ,Ile 3 ,Orn 8 ]-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. [Phe 2 ,Ile 3 ,Orn 8 ]-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 [Phe 2 ,Ile 3 ,Orn 8 ]-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.

The aim of the present study was to distinguish between the direct effects of the renal nerves on renal function and indirect effects via neurally mediated increased systemic angiotensin II. We applied low-level electrical stimulation (1 Hz) to the left renal nerves in pentobarbitone-anesthetized rabbits for 180 minutes and measured renal blood flow, sodium excretion, and urine flow rate from both the stimulated and the nonstimulated contralateral kidney in the presence and the absence of ACE inhibition (enalaprilat). Stimulation resulted in an angiotensin II–mediated rise in arterial pressure and decreases in renal blood flow, urine flow rate, and sodium excretion on the stimulated side. On the nonstimulated denervated side, we found no change in renal blood flow, but found a decrease in urine flow rate. With ACE inhibition, renal stimulation no longer caused an increase in arterial pressure, the antidiuretic responses of the stimulated kidney were attenuated, and, importantly, the decrease in urine flow rate on the nonstimulated kidney was completely abolished. We therefore propose that although a direct effect of the renal nerves on sodium excretion is clearly present, the antidiuresis and antinatriuresis observed during renal activation is further supported by a neurally mediated increase in systemic angiotensin II.

We tested for regional differences in perfusion responses, within the renal medulla and cortex, to renal nerve stimulation in pentobarbital sodium-anesthetized rabbits. Laser-Doppler flux (LDF) was monitored at various depths below the cortical surface (1-15 mm). Basal cortical LDF (1-3 mm, approximately 200-450 U) was greater than medullary LDF (5-15 mm, approximately 70-160 U), but there were no statistically significant differences in basal LDF within these regions. The background LDF signal during aortic occlusion was similar in the cortex (2 mm, 31 U) and outer medulla (7 mm, 31 U), but slightly greater in the inner medulla (12 mm, 44 U). During electrical stimulation of the renal nerves (0.5-8 Hz), cortical LDF and total renal blood flow were similarly progressively reduced with increasing stimulus frequency. Medullary LDF (measured between 5 and 15 mm) was overall less responsive than cortical LDF. For example, 4-Hz stimulation reduced inner medullary LDF (9 mm) by 19 +/- 6% but reduced cortical LDF (1 mm) by 54 +/- 11%. However, medullary LDF responses to nerve stimulation were similar at all depths measured. Our results indicate that while the vascular elements controlling medullary perfusion are less sensitive to the effects of electrical stimulation of the renal nerves than are those controlling cortical perfusion, sensitivity within these vascular territories appears to be relatively homogeneous.

Summary 1. Chronic administration of angiotensin (Ang) II causes an increase in blood pressure via a multitude of actions, including direct vasoconstriction, hypertrophy and increased sympathetic nerve activity. In the present study, we assessed whether the hypertension resulting from chronic AngII alters the ability of the renal vasculature to respond to sympathetic activity. 2. Angiotensin II was administered for 7 weeks via an osmotic minipump at a dose of 50 ng/kg per min, i.v., to a group of six rabbits. Blood pressure, measured at 0, 1, 2 and 6 weeks after insertion of the pump, increased from 76 ± 2 to 104 ± 6 mmHg at the end of 6 weeks, without any significant change in heart rate. The blood pressure in the control group remained constant at 76 ± 2 mmHg. 3. After 7 weeks, rabbits were anaesthetized and the renal nerves were stimulated at 0.5, 1, 1.5, 2, 3, 5 or 8 Hz for 3 min at their supramaximal voltage (5.5 ± 1.0 V in the normotensive group and 6.5 ± 1.5 V in the hypertensive group) while the renal blood flow (RBF) response was recorded. Under anaesthesia, there was no difference in mean arterial pressure between the normotensive and hypertensive animals (77 ± 2 and 80 ± 7 mmHg, respectively). The resting RBF under these conditions was not significantly different in the hypertensive group (30 ± 4 vs 26 ± 5 mL/min in the normotensive vs hypertensive group, respectively). 4. Stimulation at increasing frequencies was associated with increasing reductions in RBF (e.g. 36 ± 8% at 2 Hz in normotensive rabbits and 48 ± 7% at 2 Hz in hypertensive rabbits). However, there were no significant differences between RBF responses in normotensive and hypertensive rabbits. 5. We conclude that hypertension associated with chronic AngII administration does not alter the response in RBF to electrical stimulation of the nerves.

Multiple forms of acute and chronic kidney disease are associated with renal tissue hypoxia. This has led to the proposition that renal hypoxia is not just a consequence of kidney disease, but rath...

Following myocardial infarction (MI), pathological increases in sympathetic nerve activity (SNA) drive the development and progression of heart failure. The current study investigated the effects of female sex and ovarian hormones on arterial baroreflex and cardiac sympathetic afferent reflex (CSAR) control over renal SNA in MI-induced heart failure. 6 weeks post MI or sham surgery , arterial pressure and renal SNA responses were recorded in chloralose-urethane anesthetized male, female and ovariectomized female (OVX) rats. In male and OVX MI groups, arterial baroreflex control of renal SNA was significantly impaired compared to shams, due mostly to an impaired ability to inhibit SNA. In ovary-intact females, arterial baroreflex control of renal SNA was unaltered in MI animals compared to sham. CSAR mediated increases in renal SNA were significantly augmented in male and OVX MI groups when compared to ovary-intact female MI group. The current study is the first to describe a protective effect of ovarian h...

Although sympathetic nervous activity (SNA) displays oscillations synchronous with the heart beat and respiration, and between 0.1-0.4 Hz, it is apparent that each of these frequencies does not have the same effect on the vasculature. Frequencies above 1 Hz do not produce oscillations in the vasculature but instead contribute to the mean level of vasoconstriction. Slower oscillations in SNA result in a cycle of vasoconstriction and vasodilation within the vasculature, the amplitude of which, generally decreases with increasing frequency. Some studies indicate that, within the same species, differences exist in the frequency responses between vascular beds, such as the skin and gut. This differential responsiveness is also found between the medullary and cortical vasculature regions of the rabbit kidney. Low-pass filter properties have been described in the iliac circulation of rats, and evidence has been provided that noradrenaline reuptake mechanisms are not the frequency limiting step of the vasculature response. Recent studies on isolated rat vascular smooth muscle cells suggest that sympathetic modulation of vascular tone is limited by the alpha-adrenoceptor signal transduction into the cells and not by an intrinsic inability of the cells to contract and relax at higher rates.

We have developed a system for long-term continuous monitoring of cardiovascular parameters in rabbits living in their home cage to assess what role renal sympathetic nerve activity (RSNA) has in regulating renal blood flow (RBF) in daily life. Blood pressure, heart rate, locomotor activity, RSNA, and RBF were recorded continuously for 4 wk. Beginning 4–5 days after surgery a circadian rhythm, dependent on feeding time, was observed. When averaged over all days RBF to the innervated and denervated kidneys was not significantly different. However, control of RBF around these mean levels was dependent on the presence of the renal sympathetic nerves. In particular we observed episodic elevations in heart rate and other parameters associated with activity. In the denervated kidney, during these episodic elevations, the increase in renal resistance was closely related to the increase in arterial pressure. In the innervated kidney the renal resistance response was significantly more variable, indicating an interaction of the sympathetic nervous system. These results indicate that whereas overall levels of RSNA do not set the mean level of RBF the renal vasculature is sensitive to episodic increases in sympathetic nerve activity.

This article focuses on how sympathetic nerve activity (SNA) contributes to the variability seen in blood pressure. Specifically, it examines the following questions: why do oscillations occur at certain frequencies, why do only certain frequencies of oscillations in SNA induce oscillations in the vasculature, and what may be the functional purpose of these oscillations.

Blood pressure contains a distinct low-frequency oscillation often termed the Mayer wave. This oscillation is caused by the action of the sympathetic nervous system on the vasculature and results from time delays in the baroreflex feedback loop for the control of sympathetic nerve activity (SNA) in response to changes in blood pressure. In this study, we used bilateral renal denervation to test the hypothesis that it is SNA to the kidney that contributes a large portion of the vascular resistance associated with changes in the strength of the slow oscillation in blood pressure. In conscious rabbits, SNA and blood pressure were measured during hemorrhage (blood withdrawal at 1.35 ml · min−1 · kg−1 for 20 min). Spectral analysis identified a strong increase in power at 0.3 Hz in SNA and blood pressure in the initial compensatory phase of hemorrhage before blood pressure started to fall. However, in a separate group of renal denervated rabbits, although the power of the 0.3-Hz oscillation under control conditions in blood pressure was similar, it was not altered during hemorrhage. Wavelet analysis revealed the development of low-frequency oscillations at 0.1 Hz in both intact and denervated animals. In conclusion, we propose that changes in the strength of the oscillation at 0.3 Hz in arterial pressure during hemorrhage are primarily mediated by sympathetic activity directed to the kidney.

The effects of inhibiting the neural activity in the pontine A5 region on renal sympathetic responses to baroreflex and/or chemoreflex activation were examined in conscious rabbits. Eight rabbits were chronically instrumented with guide cannulas for bilateral microinjections into the A5 area and an electrode for measuring renal sympathetic nerve activity (RSNA). Baroreflex curves were obtained under conditions of normoxia and hypoxia (10% O2 + 3% CO2) after injections into the A5 region of the GABA receptor agonist muscimol or vehicle solution. Under normoxia, injections of muscimol did not affect resting RSNA or blood pressure but increased the range of the RSNA baroreflex by 24 and 33% at doses of 175 or 875 pmol, respectively, without affecting the reflex gain. Hypoxia alone increased resting RSNA by 63%, as well as the range and gain of the RSNA baroreflex by 53 and 89%, respectively, without affecting blood pressure. However, under hypoxia, muscimol increased resting RSNA by 37 and 47% but decreased the gain of the RSNA baroreflex by 19 and 34% at doses of 175 or 875 pmol, respectively, without affecting the reflex range. The effects of muscimol on RSNA were mediated via changes in the amplitude of the sympathetic bursts, whereas burst frequency remained unaffected. These data suggest that the A5 region has a little tonic influence on RSNA in conscious rabbits but serves to limit the renal sympathetic responses to baroreceptor unloading or chemoreceptor stimulation. The different changes in the baroreflex range and gain evoked by muscimol under normoxia and hypoxia indicate that the A5 modulatory action may depend on the activity of the afferent inputs to this region.

Studies in anaesthetized animals have shown that the pontine A5 noradrenergic region plays an important role in the sympathetic control of arterial pressure (AP). The aim of this study was to develop, in conscious rabbits, a technique for microinjections into the A5 region and examine the effects of stimulation of this region on renal sympathetic nerve activity (RSNA). In preliminary mapping experiments on four anaesthetized rabbits, electrical stimulation of the A5 region induced a pressor response ranging between 25 and 75 mmHg while unilateral injection of glutamate (100 nmol) did not change AP. The mapping experiments were used to enable guide cannulae implantation for subsequent microinjections into the A5 region. In six conscious rabbits, unilateral injection of glutamate (100 nmol) caused a consistent increase in RSNA (+45%) but did not change AP. In another eight rabbits, bilateral injection of glutamate (0.3, 3, 30 nmol) into the A5 region dose-dependently increased RSNA by 13%, 30% and 40%, respectively. In four rabbits, angiotensin II (0.3, 3, 30 pmol) injected bilaterally into the A5 region increased RSNA by 5%, 22% and 28%, respectively. In all animals the increase in RSNA was mainly mediated by increasing amplitude of sympathetic synchronized bursts while their frequency remained unchanged. However, both glutamate and angiotensin II did not change AP indicating that the sympathoexcitatory response to the A5 stimulation might be relatively confined to the renal bed. Using a novel microinjection technique developed for conscious rabbits, we found that the A5 region may provide an important excitatory and possibly selective input to the renal sympathetic preganglionic neurons.

This review focuses on that most engaging feature of the sympathetic nervous system, its rhythmicity. In particular examining the nature of sympathetic nerve activity (SNA), its characteristics, the frequencies of these rhythms and possible mechanisms responsible for their generation. Sympathetic activity can be thought of as a complex output of the central nervous system providing subtle control over end organ function. This control is exerted in a number of frequency bands including rhythms related to the cardiac and respiratory cycles, 10 Hz, and between 0.2 and 0.4 Hz. The generation and control over the occurrence of each of these rhythms is likely to be quite separate. Although afferent feedback from sources such as baroreceptors can explain some of the rhythmical properties in each case there is good evidence for inherent generation of aspects of these rhythms. A variety of brainstem cell groups are thought to be involved in their generation with the rostral ventrolateral medulla, although unlikely to be solely responsible for tone generation, an important regulator of overall activity. SNA also varies in the number of nerves recruited to fire in each synchronized discharge. Little is known about this control other than it appears to be quite separate from the control over the timing of discharges. Spinal cord mechanisms are possibly involved. SNA frequencies above 0.7 Hz do not appear to directly induce oscillations in innervated vasculature, however, are likely to contribute to setting the level of vasconstrictive tone. Slower frequencies appear to directly cause oscillations in blood flow.

Renal sympathetic nerve activity (RSNA) is postulated to influence renal function in selective ways with changes in renal hemodynamics only occurring during high stimulus intensities. The aim of this study was to determine the renal blood flow (RBF) response to a number of stimuli designed to increase RSNA by a modest amount and assess the possibility that different afferent stimuli produce differential levels of vasoconstriction by differentially altering the pattern of RSNA. Experiments were performed in eight conscious rabbits subjected to 20 min periods of three stimuli noise stress, air jet stress or hypoxia (10% O2). RSNA was significantly increased 12 +/- 4, 31 +/- 8 and 14 +/- 5% (means of 20 min periods +/- SEM) and these effects were mirrored in the significant changes in RBF over the period of each stimuli with mean reductions of 8 +/- 1, 10 +/- 3 and 8 +/- 4% during noise, air jet stress and hypoxia respectively. Changes in plasma renin activity did not occur without changes in RBF. With regard to the pattern of RSNA discharges, hypoxia selectively increased the amplitude (number of recruited nerves) while noise and air jet stress increased both the amplitude and frequency of discharges. The role of the renal nerves in these responses and in providing a tonic level of vasoconstriction within the kidney, was demonstrated in experiments on a group of eight renal denervated animals. The renal denervated rabbits had greater resting RBF than the intact rabbits (54 +/- 1 denervated vs. 38 +/- 1 ml min(-1) intact), and RBF was not altered by any of the afferent stimuli. We conclude that small changes in RSNA, irrespective of the stimulus, modulate renal blood flow.

We used radio-telemetry to measure 24-hour rhythms of systolic, diastolic and mean blood pressure, heart rate and behavioural activity in conscious rabbits, which were maintained under normal day/night rhythms and restricted feeding. Over three consecutive days, all variables showed little change between day-period and night-period, except for a pronounced rise in the afternoon, coinciding with the presentation of pellet food. Mean blood pressure increased during this period from baseline values between 78-82 mm Hg to a peak of 89-91 mm Hg. At the same time heart rate rose from baseline values of 147-161 b/min to a peak of 206-234 b/min and behavioural activity scores rose from 11-31 counts/h to a peak of 52-81 counts/h. Changing the time at which pellet food was presented to the rabbits from the early afternoon to the early morning, caused a complete and immediate shift of the peak of blood pressure and heart rate to the morning period. Chronic intravenous infusion of angiotensin II caused a significant increase in blood pressure (24-hour average: 80 +/- 1 vs. 114 +/- 7 mm Hg) but did not alter basal heart rate or behavioural activity. The increase in heart rate and blood pressure seen with food presentation was attenuated with angiotensin II infusion. These data show that in rabbits diurnal changes in blood pressure, heart rate and activity were determined to a large extent by timed feeding. In addition, in rabbits with angiotensin-induced hypertension the food-induced changes in blood pressure and heart rate were blunted.

Abstract The cardiac hypertrophy observed in hypertension is thought to be responsible for the accompanying deficiency in the baroreflex control of heart rate. In this study, we assessed the baroreflex relationship between heart rate and arterial pressure in a group of seven rabbits during a normotensive period, during the early phase of angiotensin II (Ang II)–induced hypertension (1 week) (50 ng/kg per minute IV via osmotic minipumps), after 7 weeks of continuous hypertension, then 2 days after Ang II was stopped, and finally 7 days after Ang II. Left ventricles were weighed for measurement of left ventricular weight–body weight ratio. One week of intravenous Ang II infusion produced hypertension (mean arterial pressure from 80±2 up to 115±8 mm Hg), with significantly increased heart rate and hematocrit. The heart rate–arterial pressure baroreflex curve was shifted to the right, with a significant 45% reduction in the gain of the reflex (−6.4±1.5 to −3.5±0.2 beats per minute/mm Hg). After 7 weeks of Ang II, arterial pressure was still elevated (112±4 mm Hg) and the gain of the baroreflex curve still somewhat attenuated, although it was no longer markedly different from normotensive levels (gain, −5.09±0.95, 20% reduction from normotensive level). Two days after the Ang II infusion was stopped, arterial pressure had returned to normotensive levels, although hematocrit and heart rate remained elevated. At this time, the baroreflex curve was similar to prehypertensive control levels, with no further changes when measured again 7 days after Ang II. Cardiac hypertrophy was present when measured at 7 days after angiotensin (left ventricular weight–body weight ratio: 1.78±0.05 versus 1.35±0.04 g/kg, hypertensive versus normotensive, P

Measurements of left ventricular pressure (LVP) in conscious freely moving animals are uncommon, yet could offer considerable opportunity for understanding cardiovascular disease progression and treatment. The aim of this study was to develop surgical methods and validate the measurements of a new high-fidelity, solid-state pressure-sensor telemetry device for chronically measuring LVP and dP/d t in rats. The pressure-sensor catheter tip (2-Fr) was inserted into the left ventricular chamber through the apex of the heart, and the telemeter body was implanted in the abdomen. Data were measured up to 85 days after implant. The average daytime dP/d t max was 9,444 ± 363 mmHg/s, ranging from 7,870 to 10,558 mmHg/s ( n = 7). A circadian variation in dP/d t max and heart rate (HR) was observed with an average increase during the night phase in dP/d t max of 918 ± 84 mmHg/s, and in HR of 38 ± 3 bpm. The β-adrenergic-agonist isoproterenol, β1-adrenergic agonist dobutamine, Ca2+ channel blocker verapamil, and the calcium sensitizer levosimendan were administered throughout the implant period, inducing dose-dependent time course changes and absolute changes in dP/d t max of −6,000 to +13,000 mmHg/s. The surgical methods and new technologies demonstrated long-term stability, sensitivity to circadian variation, and the ability to measure large drug-induced changes, validating this new solution for chronic measurement of LVP in conscious rats.