Intracranial mechanisms for preserving brain blood flow in health and disease.

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 ischaemia. 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 ischaemic 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 ischaemia 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/ischaemia and ICP and play a major role in determining the long-term level of sympathetic outflow and arterial pressure, to optimize cerebral perfusion.

The rhythmicity of sympathetic nerve activity.

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.

Heart-rate variability and cardiac autonomic function in diabetes.

Cardiac autonomic function was measured in 25 subjects with insulin-dependent diabetes mellitus and 11 control subjects. Autonomic integrity was assessed with standard tests of autonomic function and a new technique of measuring heart-rate variability (HRV) for 24 h. All of the diabetic subjects were selected on the basis of peripheral or autonomic neuropathy or long-term poorly controlled diabetes. They were divided into groups according to presence or absence of vagal neuropathy based on the results of standard tests of autonomic function. Thirteen diabetic subjects had normal autonomic function tests (group 1), and vagal neuropathy was detected in 12 diabetic subjects (group 2). All subjects were monitored by ambulatory electrocardiograph, and the recordings were played back through an analyzer that identified and timed successive pulse (R-R) intervals. HRV was measured from the standard deviation of the successive differences between R-R intervals. HRV was significantly reduced in group 1 (mean +/- SE 73 +/- 9 ms) and group 2 (65 +/- 12 ms) diabetic subjects compared with the control group (138 +/- 10 ms). The standard tests of autonomic function did not distinguish the vagal dysfunction noted with HRV monitoring in group 1 diabetic subjects compared with control subjects. Measurement of 24-h HRV can detect small changes in cardiac autonomic function compared with currently available tests.

Circadian variation of heart rate variability.

STUDY OBJECTIVE: The aim of the study was to examine the circadian variation in heart rate variability and to test the hypothesis that the variation is due to vagal influence. DESIGN: Human subjects, some with vagal neuropathy, underwent ambulatory 24 h electrocardiographic monitoring, the recordings being played back through an analyser which identified and timed successive pulse (R-R) intervals. Heart rate variability was measured for each 30 min period over 24 h as the standard deviation of the successive differences between R-R intervals, which filtered out low frequency components of heart rate variability that were not autonomic in origin. Modelled curves of heart rate variability were compared using analysis of variance. SUBJECTS: The subjects were aged between 33 and 65 years and were matched in three groups for age and sex. There were 11 healthy controls, 12 insulin dependent diabetics and seven alcoholics with vagal neuropathy. RESULTS: A significant circadian variation in heart rate variability was present, characterised by a rise during sleep. Mean heart rate variation was significantly reduced in groups with vagal neuropathy, although the amplitude of the cycle and time of peak variability was not significantly different. The circadian variation was sustained regardless of the degree of vagal neuropathy. CONCLUSIONS: The cycle of heart rate variability is not dependent on vagal interaction. It may be due to fluctuations in sympathetic activity affecting beat to beat variability.

Baroreflex control of heart rate and cardiac hypertrophy in angiotensin II-induced hypertension in rabbits.

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 on a group of seven rabbits during a normotensive period, during the early phase of angiotensin II (Ang II)-induced hypertension II week) (50 ng/kg per minute i.v. 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 < .05). Thus, although Ang II infusion produced an initial deficit in the baroreflex control of heart rate, this effect became less as the hypertension continued. Furthermore, although cardiac hypertrophy developed, its presence did not appear to be sufficient to produce a decrease in barosensitivity independent of raised arterial pressure.

Sympathetic modulation of blood pressure variability.

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.

Mechanism of ethanol-induced vasodilation.

The mechanism by which ethanol ingestion causes dermal vasodilation is unclear, but it may result from a direct action on central vascular control mechanisms. Forearm blood flow and peripheral skin temperatures were examined in five quadriplegics (lesions above T7) and five control subjects, before and after the ingestion of ethanol (0.75 ml/kg body wt). The lack of vasomotor efferent function was confirmed in the quadriplegics by the absence of vasodilation in response to radiant heating of the torso. There were no significant changes in peripheral temperatures or forearm blood flow after ethanol in the quadriplegics. The control subjects had a significant increase in forearm blood flow (1.12 +/- 0.2 ml.min-1.100 ml-1) and skin temperature (finger 2.4 +/- 0.4 degrees C, toe 3.4 +/- 0.3 degrees C) after ethanol. These data suggest that ethanol may induce peripheral vasodilation by modulation of central vasomotor control mechanisms.

Sympathetic response to stimulation of the pontine A5 region in conscious rabbits.

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.

Chronic renal blood flow measurement in dogs by transit-time ultrasound flowmetry.

To test the validity of transit-time ultrasound flowmetry for chronic measurement of renal blood flow in dogs, we compared this method with the renal clearance of para-aminohippuric acid (CPAH) (corrected for hematocrit), and with direct volumetric measurements. When flow-probes were implanted without silastic sheeting to stabilize the implant, there was significant disparity between the (within-dog) mean levels of renal blood flow estimated by flow-probe and CPAH. In contrast, when the flow-probe implants were stabilized with silicone sheeting, there was close agreement in each dog between the flow rates measured by the two methods. When flow-probes were calibrated volumetrically in situ, there was a close linear relationship between flow derived from the flow-probe and that measured volumetrically (r = 0.98 +/- 0.02). We conclude that valid, chronic measurement of renal blood flow in dogs can be achieved using transit-time ultrasound flowmetry, provided the implant is stabilized with silicone sheeting.

24-hour recordings of blood pressure, heart rate and behavioural activity in rabbits by radio-telemetry: effects of feeding and hypertension.

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.

Differential regulation of the oscillations in sympathetic nerve activity and renal blood flow following volume expansion.

Renal sympathetic nerve activity (RSNA) and renal blood flow (RBF) both show oscillations at various frequencies but the functional significance and regulation of these oscillations is not well understood. To establish whether the strength of these oscillations is under differential control we measured the frequency spectrum of RSNA and RBF following volume expansion in conscious rabbits. Seven days prior to experiment animals underwent surgery to implant an electrode for recording renal nerve activity and a flow probe for recording RBF. Volume expansion (Haemaccel, 1.5 ml min(-1) kg(-1) for 15 min) resulted in a 25 +/- 5% decrease in mean RSNA, paralleled by an increase in RBF to 60 +/- 12 ml min(-1) from resting levels of 51 +/- 11 ml min(-1). Renal denervated rabbits did not show an increase in RBF with volume expansion. Arterial baroreflexes were unaltered by volume expansion. Spectral analysis of the different frequencies in RSNA showed oscillations in RSNA between 0.2 and 0.4 Hz were selectively decreased following volume expansion (14 +/- 3 to 6 +/- 1% of total power in RSNA at < 3 Hz). A corresponding decrease in the strength of oscillations in RBF at this frequency was also seen (20 +/- 6 to 8 +/- 2%). In contrast, the strength of respiratory (0.8-2.0 Hz) and cardiac (3-6 Hz) related rhythms did not change with volume expansion. These results show that selective changes in the different frequency components of RSNA can occur. We suggest that input from cardiopulmonary receptors and/or other vascular beds, and/or altered vascular resistance after volume expansion can reduce the strength of the 0.3 Hz oscillation independent of changes in arterial baroreflex control of RSNA.

Efficient Power-Transfer Capability Analysis of the TET System Using the Equivalent Small Parameter Method.

Transcutaneous energy transfer (TET) enables the transfer of power across the skin without direct electrical connection. It is a mechanism for powering implantable devices for the lifetime of a patient. For maximum power transfer, it is essential that TET systems be resonant on both the primary and secondary sides, which requires considerable design effort. Consequently, a strong need exists for an efficient method to aid the design process. This paper presents an analytical technique appropriate to analyze complex TET systems. The system's steady-state solution in closed form with sufficient accuracy is obtained by employing the proposed equivalent small parameter method. It is shown that power-transfer capability can be correctly predicted without tedious iterative simulations or practical measurements. Furthermore, for TET systems utilizing a current-fed push-pull soft switching resonant converter, it is found that the maximum energy transfer does not occur when the primary and secondary resonant tanks are "tuned" to the nominal resonant frequency. An optimal turning point exists, corresponding to the system's maximum power-transfer capability when optimal tuning capacitors are applied.

Acute systemic complications in the preterm fetus after asphyxia: role of cardiovascular and blood flow responses.

1. Poor perfusion of the kidneys and gut, and associated functional impairment, are major problems in the first days of life in very preterm infants. These complications can be associated with a substantial mortality and further problems such as reduced kidney growth and chronic renal problems in later childhood. 2. There is very little information, and consequently considerable debate, about how or even whether to improve perfusion of the vital organs of this most vulnerable group of babies. Current treatments simply do not consistently improve babies' perfusion generally or kidney and gut perfusion and function in particular. 3. In this review we critically examine clinical and experimental evidence that suggests that exposure to low oxygen levels before and during birth may be a significant contributor to impaired systemic perfusion, and highlight areas requiring further research. 4. This knowledge is essential to develop and refine ways of improving perfusion of the kidneys and other vital organs in premature babies.

A new model for the generation of sympathetic nerve activity.

1. Sympathetic discharges from multifibre nerve recordings vary in their frequency of occurrence which displays both slow and fast rhythms and in their amplitude which reflects the number of activated fibres. It has been shown that the frequency of occurrence of these rhythms varies according to baroreceptor activity (via blood pressure and heart rate) while the number of activated fibres is independently affected by chemoreceptor activity. 2. A new model is proposed for the generation of sympathetic nerve activity by the central nervous system to account for these results. The upper layer of the model comprises two oscillators, a fast and a slow cycle frequency oscillator, with the balance and occurrence maintained by afferent inputs such as the baroreceptors. 3. It is hypothesized that two central oscillators impinge on a lower layer of the model influencing the number of activated fibres within each postganglionic sympathetic burst. This is independent of the frequency control and affected by separate afferent inputs such a chemoreceptors.

The amplitude and periodicity of synchronized renal sympathetic nerve discharges in anesthetized cats: differential effect of baroreceptor activity.

We applied a computerized peak detection algorithm to recordings of synchronized sympathetic nerve discharges from anesthetized cats to retrieve information about the characteristics of renal nerve activity (RNA) during changes in baroreceptor activity. The algorithm scanned the series of RNA voltages for significant increases followed by significant decreases in a small cluster of voltage values. Once each synchronized RNA peak had been detected, its corresponding amplitude, width and peak-to-peak interval were calculated. The peak-to-peak interval periodicity showed two modes of synchronized discharge, one between 200-500 ms accounting for 47% of intervals, and a higher 20-180 ms frequency (49% of intervals). Baroreceptor stimulation decreased the occurrence of the high frequencies while increasing the probability of the lower frequency components. The overall occurrence of synchronized peaks per second fell linearly to zero with increases in blood pressure. The peak amplitude of RNA was unimodally distributed and was not affected by baroreceptor stimulation until an increase in mean arterial pressure reached a threshold (mean 142 +/- 5 mmHg) whereupon it fell quickly to zero. Sino-aortic vagal denervation did not affect the distribution of peak height. The width of synchronized discharges was also unimodal, mean 82 +/- 1 ms, and was almost unchanged during baroreflex stimulation acting in parallel with changes in the peak amplitude and decreasing at high blood pressures. Sino-aortic vagal denervation did not affect the synchronized width. There was no relationship between the periodicity and amplitude or width of synchronized discharges under all conditions. The results indicate that the periodicity and amplitude of renal synchronized discharges appear to be independent of each other and are differentially affected by baroreceptor input.

Effect of asphyxia on the frequency and amplitude modulation of synchronized renal nerve activity in the cat.

A computerized peak detection algorithm was used to retrieve new information about changes in the characteristics of renal nerve activity (RNA) with asphyxia in anesthetized cats. The algorithm scanned the series of RNA voltages for significant increases followed by significant decreases in a small cluster of voltage values. Once each synchronized RNA peak had been detected, its corresponding amplitude, width, and peak-to-peak interval were calculated. The peak-to-peak interval showed two rhythms of synchronized discharge: one between 200-500 ms accounting for 38 +/- 3% of intervals and a higher 20-180 ms frequency (52 +/- 5% of intervals). Asphyxia did not change the periodicity distribution despite increases in arterial pressure. The peak amplitude of RNA, reflecting the number of active fibers, was unimodally distributed and was increased 39 +/- 9% with asphyxia. The shape of the distribution was unchanged. The width of the synchronized activity was also unimodally distributed, mean 79 +/- 3 ms, and increased by asphyxia to 99 +/- 5 ms. The results indicate that the control of the periodicity and amplitude of synchronized discharge appear to be independent and are differentially affected by chemoreceptor input.

A new approach to analysis of synchronized sympathetic nerve activity.

Renal sympathetic nerve activity (RSNA) recorded from the multifiber preparation is a continuously fluctuating variable in terms of period and amplitude, reflecting a coordinated tonic level of output from the vasomotor center. Yet current methods of analysis cannot simultaneously measure both of these parameters. A new accurate technique for assessing changes in global sympathetic activity is required. We made a novel application of a computerized peak detection algorithm (Cluster program) to recordings of synchronized sympathetic nerve discharges. The procedure was applied to this new area to retrieve information about the characteristics of synchronized RSNA. Peaks in synchronized RSNA activity were detected from short-term (20 ms) integrated recordings in which voltage changes had been digitized at 200 Hz and stored on computer. The program scanned the data series for significant increases followed by significant decreases in a small cluster of voltage values. The program permits the input of the cluster sample sizes for the test peaks and pre- and postpeak nadirs and also the minimum height to be defined as a peak. Once each synchronized RSNA peak had been detected, its corresponding amplitude, width, and peak-to-peak interval were calculated. The program successfully characterized RSNA in a group of eight cats and yielded results comparable to other analysis techniques. The peak-to-peak interval period showed two modes of synchronized discharge, one related to the cardiac cycle and a faster 8- to 14-Hz frequency. The synchronized peak amplitude and width showed unimodal frequency distributions. The relationship between each of the three variables was examined; only the peak height and width were significantly related to each other.(ABSTRACT TRUNCATED AT 250 WORDS)

Slow oscillations in blood pressure via a nonlinear feedback model.

Blood pressure is well established to contain a potential oscillation between 0.1 and 0.4 Hz, which is proposed to reflect resonant feedback in the baroreflex loop. A linear feedback model, comprising delay and lag terms for the vasculature, and a linear proportional derivative controller have been proposed to account for the 0.4-Hz oscillation in blood pressure in rats. However, although this model can produce oscillations at the required frequency, some strict relationships between the controller and vasculature parameters must be true for the oscillations to be stable. We developed a nonlinear model, containing an amplitude-limiting nonlinearity that allows for similar oscillations under a very mild set of assumptions. Models constructed from arterial pressure and sympathetic nerve activity recordings obtained from conscious rabbits under resting conditions suggest that the nonlinearity in the feedback loop is not contained within the vasculature, but rather is confined to the central nervous system. The advantage of the model is that it provides for sustained stable oscillations under a wide variety of situations even where gain at various points along the feedback loop may be altered, a situation that is not possible with a linear feedback model. Our model shows how variations in some of the nonlinearity characteristics can account for growth or decay in the oscillations and situations where the oscillations can disappear altogether. Such variations are shown to accord well with observed experimental data. Additionally, using a nonlinear feedback model, it is straightforward to show that the variation in frequency of the oscillations in blood pressure in rats (0.4 Hz), rabbits (0.3 Hz), and humans (0.1 Hz) is primarily due to scaling effects of conduction times between species.