Histological Characterisation of a Sheep Model of Mild Traumatic Brain Injury: A Pilot Study.

Large animal models of mild traumatic brain injury (mTBI) are needed to elucidate the pathophysiology of mechanical insult to a gyrencephalic brain. Sheep (ovis aries) are an attractive model for mTBI because of their neuroanatomical similarity to humans; however, few histological studies of sheep mTBI models have been conducted. We previously developed a sheep mTBI model to pilot methods for investigating the mechanical properties of brain tissue after injury. Here, we sought to histologically characterize the cortex under the impact site in this model. Three animals received a closed skull mTBI with unconstrained head motion, delivered with an impact stunner, and 3 sham animals were anesthetized but did not receive an impact. Magnetic resonance imaging (MRI) of the brain was performed before and after the impact and revealed variable degrees of damage to the skull and brain. Fluorescent immunohistochemistry revealed regions of hemorrhage in the cortex underlying the impact site in 2 of 3 mTBI sheep, the amount of which correlated with the degree of damage observed on the post-impact MRI scans. Labeling for microtubule-associated protein 2 and neuronal nuclear protein revealed changes in cellular anatomy, but, unexpectedly, glial fibrillary acidic protein and ionized calcium-binding adaptor molecule 1 labeling were relatively unchanged compared to sham animals. Our findings provide preliminary evidence of vascular and neuronal damage with limited glial reactivity and highlight the need for further in-depth histological assessment of large animal mTBI models.

Atlas-Free Automatic Segmentation of Sheep Brain MRI.

Automated 3D brain segmentation methods have been shown to produce fast, reliable, and reproducible segmentations from magnetic resonance imaging (MRI) sequences for the anatomical structures of the human brain. Despite the extensive experimental research utility of large animal species such as the sheep, there is limited literature on the segmentation of their brains relative to that of humans. The availability of automatic segmentation algorithms for animal brain models can have significant impact for experimental explorations, such as treatment planning and studying brain injuries. The neuroanatomical similarities in size and structure between sheep and humans, plus their long lifespan and docility, make them an ideal animal model for investigating automatic segmentation methods.This work, for the first time, proposes an atlas-free fully automatic sheep brain segmentation tool that only requires structural MR images (T1-MPRAGE images) to segment the entire sheep brain in less than one minute. We trained a convolutional neural network (CNN) model - namely a four-layer U-Net - on data from eleven adult sheep brains (training and validation: 8 sheep, testing: 3 sheep), with a high overall Dice overlap score of 93.7%.Clinical relevance- Upon future validation on larger datasets, our atlas-free automatic segmentation tool can have clinical utility and contribute towards developing robust and fully automatic segmentation tools which could compete with atlas-based tools currently available.

The Safety of Micro-Implants for the Brain.

Technological advancements in electronics and micromachining now allow the development of discrete wireless brain implantable micro-devices. Applications of such devices include stimulation or sensing and could enable direct placement near regions of interest within the brain without the need for electrode leads or separate battery compartments that are at increased risk of breakage and infection. Clinical use of leadless brain implants is accompanied by novel risks, such as migration of the implant. Additionally, the encapsulation material of the implants plays an important role in mitigating unwanted tissue reactions. These risks have the potential to cause harm or reduce the service of life of the implant. In the present study, we have assessed post-implantation tissue reaction and migration of borosilicate glass-encapsulated micro-implants within the cortex of the brain. Twenty borosilicate glass-encapsulated devices (2 × 3.5 × 20 mm) were implanted into the parenchyma of 10 sheep for 6 months. Radiographs were taken directly post-surgery and at 3 and 6 months. Subsequently, sheep were euthanized, and GFAP and IBA-1 histological analysis was performed. The migration of the implants was tracked by reference to two stainless steel screws placed in the skull. We found no significant difference in fluoroscopy intensity of GFAP and a small difference in IBA-1 between implanted tissue and control. There was no glial scar formation found at the site of the implant's track wall. Furthermore, we observed movement of up to 4.6 mm in a subset of implants in the first 3 months of implantation and no movement in any implant during the 3-6-month period of implantation. Subsequent histological analysis revealed no evidence of a migration track or tissue damage. We conclude that the implantation of this discrete micro-implant within the brain does not present additional risk due to migration.

A method to evaluate dynamic cerebral pressure-flow relationships in the conscious rat.

The classic dogma of cerebral autoregulation is that cerebral blood flow is steadily maintained across a wide range of perfusion pressures. This has been challenged by recent studies suggesting little to no "autoregulatory plateau" in the relationship between cerebral blood flow and blood pressure (BP). Therefore, the mechanisms underlying the cerebral pressure-flow relationship still require further understanding. Here, we present a novel approach to examine dynamic cerebral autoregulation in conscious Wistar rats (n = 16) instrumented to measure BP and internal carotid blood flow (iCBF), as an indicator of cerebral blood flow. Transient reductions in BP were induced by occluding the vena cava via inflation of a chronically implanted intravascular silicone balloon. Falls in BP were paralleled by progressive decreases in iCBF, with no evidence of a steady-state plateau. No significant changes in internal carotid vascular resistance (iCVR) were observed. In contrast, intravenous infusions of the vasoactive drug sodium nitroprusside (SNP) produced a similar fall in BP but increases in iCBF and decreases in iCVR were observed. These data suggest a considerable confounding influence of vasodilatory drugs such as SNP on cerebrovascular tone in the rat, making them unsuitable to investigate cerebral autoregulation. We demonstrate that our technique of transient vena cava occlusion produced reliable and repeatable depressor responses, highlighting the potential for our approach to permit assessment of the dynamic cerebral pressure-flow relationship over time in conscious rats.NEW & NOTEWORTHY We present a novel technique to overcome the use of vasoactive agents when studying cerebrovascular dynamics in the conscious rat. Our method of vena cava occlusion to reduce BP was associated with decreased iCBF and no change in iCVR. In contrast, comparable BP falls with intravenous SNP increased iCBF and reduced iCVR. Thus, the dynamic cerebral pressure-flow relationship shows a narrower, less level autoregulatory plateau than conventionally thought. We confirm our method allows repeatable assessment of cerebrovascular dynamics in conscious rats.

Intracranial baroreflex is attenuated in an ovine model of renovascular hypertension.

We have previously shown that elevations in intracranial pressure (ICP) within physiological ranges in normotensive animals increase arterial pressure; termed the intracranial baroreflex. Hypertension is associated with alterations in reflexes which maintain arterial pressure however, whether the intracranial baroreflex is altered is not known. Hence, in the present study, we tested the hypothesis that in hypertension, physiological increases in ICP would not be accompanied with an increase in arterial pressure. Renovascular hypertension was associated with no change in heart rate, renal blood flow or ICP levels compared to the normotensive group. ICV infusion of saline produced a ramped increase in ICP of 20 ± 1 mmHg. This was accompanied by an increase in arterial pressure (16 ± 2 mmHg) and a significant decrease in renal vascular conductance. ICV infusion of saline in the hypertensive group also increased ICP (19 ± 2 mmHg). However, the increase in arterial pressure was significantly attenuated in the hypertensive group (5 ± 2 mmHg). Ganglionic blockade abolished the increase in arterial pressure in both groups to increased ICP. Our data indicates that physiological increases in ICP lead to increases in arterial pressure in normotensive animals but this is severely attenuated in renovascular hypertension.

Selective optogenetic stimulation of efferent fibers in the vagus nerve of a large mammal.

BACKGROUND: Electrical stimulation applied to individual organs, peripheral nerves, or specific brain regions has been used to treat a range of medical conditions. In cardiovascular disease, autonomic dysfunction contributes to the disease progression and electrical stimulation of the vagus nerve has been pursued as a treatment for the purpose of restoring the autonomic balance. However, this approach lacks selectivity in activating function- and organ-specific vagal fibers and, despite promising results of many preclinical studies, has so far failed to translate into a clinical treatment of cardiovascular disease. OBJECTIVE: Here we report a successful application of optogenetics for selective stimulation of vagal efferent activity in a large animal model (sheep). METHODS AND RESULTS: Twelve weeks after viral transduction of a subset of vagal motoneurons, strong axonal membrane expression of the excitatory light-sensitive ion channel ChIEF was achieved in the efferent projections innervating thoracic organs and reaching beyond the level of the diaphragm. Blue laser or LED light (>10 mW mm-2; 1 ms pulses) applied to the cervical vagus triggered precisely timed, strong bursts of efferent activity with evoked action potentials propagating at speeds of ∼6 m s-1. CONCLUSIONS: These findings demonstrate that in species with a large, multi-fascicled vagus nerve, it is possible to stimulate a specific sub-population of efferent fibers using light at a site remote from the vector delivery, marking an important step towards eventual clinical use of optogenetic technology for autonomic neuromodulation.

Injection Molded Liquid Crystal Polymer Package for Chronic Active Implantable Devices With Application to an Optogenetic Stimulator.

Implanted electronics require protection from the body's fluids to avoid moisture induced failure. This study presents an injection molded liquid crystal polymer (LCP) package to protect active implantable devices for chronic applications, such as in optogenetic research. The technology is applied and assessed through a custom package for a fully implantable optogenetic stimulation system, built on a versatile telemetry system that can incorporate additional stimulating and recording channels. An adapted quasi-steady state model predicts the lifetime of an enclosure, where the definition of the lifetime is the time before the internal relative humidity (RH) reaches a time constant, or 63%RH, a conservative limit to minimize the risk of corrosion. The lifetime of the LCP optogenetic device is 94 days, and can be extended to 326 days with the inclusion of 5% w/v silica gel desiccant. Samples of the LCP optogenetic device containing humidity sensors testing in saline at 38 °C support the RH change predictions. Desiccants inside the implant enclosure can store permeating moisture and prolong the life expectancy of LCP-based implants to years or decades. The results of this study demonstrates the feasibility of providing reliable protection for chronic optogenetic implants, and the technology can be transferred to other applications as an easily-manufactured, cost-effective, radiofrequency compatible alternative to hermetic packaging for chronic studies.

Intracranial pressure influences the level of sympathetic tone.

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.

Renal denervation in male rats with heart failure improves ventricular sympathetic nerve innervation and function.

Heart failure is characterized by the loss of sympathetic innervation to the ventricles, contributing to impaired cardiac function and arrhythmogenesis. We hypothesized that renal denervation (RDx) would reverse this loss. Male Wistar rats underwent myocardial infarction (MI) or sham surgery and progressed into heart failure for 4 wk before receiving bilateral RDx or sham RDx. After additional 3 wk, left ventricular (LV) function was assessed, and ventricular sympathetic nerve fiber density was determined via histology. Post-MI heart failure rats displayed significant reductions in ventricular sympathetic innervation and tissue norepinephrine content (nerve fiber density in the LV of MI+sham RDx hearts was 0.31 ± 0.05% vs. 1.00 ± 0.10% in sham MI+sham RDx group, P < 0.05), and RDx significantly increased ventricular sympathetic innervation (0.76 ± 0.14%, P < 0.05) and tissue norepinephrine content. MI was associated with an increase in fibrosis of the noninfarcted ventricular myocardium, which was attenuated by RDx. RDx improved LV ejection fraction and end-systolic and -diastolic areas when compared with pre-RDx levels. This is the first study to show an interaction between renal nerve activity and cardiac sympathetic nerve innervation in heart failure. Our findings show denervating the renal nerves improves cardiac sympathetic innervation and function in the post-MI failing heart.

Left-Ventricular Energetics in Pulmonary Arterial Hypertension-Induced Right-Ventricular Hypertrophic Failure.

Pulmonary arterial hypertension (PAH) alters the geometries of both ventricles of the heart. While the right ventricle (RV) hypertrophies, the left ventricle (LV) atrophies. Multiple lines of clinical and experimental evidence lead us to hypothesize that the impaired stroke volume and systolic pressure of the LV are a direct consequence of the effect of pressure overload in the RV, and that atrophy in the LV plays only a minor role. In this study, we tested this hypothesis by examining the mechanoenergetic response of the atrophied LV to RV hypertrophy in rats treated with monocrotaline. Experiments were performed across multiple-scales: the whole-heart in vivo and ex vivo, and its trabeculae in vitro. Under the in vivo state where the RV was pressure-overloaded, we measured reduced systemic blood pressure and LV ventricular pressure. In contrast, under both ex vivo and in vitro conditions, where the effect of RV pressure overload was circumvented, we found that LV was capable of developing normal systolic pressure and stress. Nevertheless, LV atrophy played a minor role in that LV stroke volume remained lower, thereby contributing to lower LV mechanical work output. Concomitantly lower oxygen consumption and change of enthalpy were observed, and hence LV energy efficiency was unchanged. Our internally consistent findings between working-heart and trabecula experiments explain the rapid improvement of LV systolic function observed in patients with chronic pulmonary hypertension following surgical relief of RV pressure overload.

New multimodal data obtained in-vivo from a single ultra-miniature transducer.

Recent advances in multimodal sensing technology and sensor miniaturization technologies are paving the way for a new era in physiological measurement. Traditional approaches have integrated several transducers on a single silicon chip or packaged several sensing elements within a biocompatible catheter. Thermal and electrical cross-talk between sensors, time-lag between parallel measurements, lower yields associated with the increased complexity, and restrictions on the minimum size are challenges presented by these approaches. We present an alternative method which enables simultaneous measurement of temperature, pressure and heart rate to be obtained from a single ultra-miniature solid-state transducer. For the first time multimodal data were obtained from the sensor located within the abdominal aortas of five rats. The catheter-tip sensor interfaces with a fully implanted and inductively powered telemetry device capable of operating for the lifetime of the animal. Results of this study demonstrate good agreement between the core-temperature measurement from the catheter-tip sensor and the reference sensor with mean difference between the two sensors of 0.03 °C ± 0.02 °C (n = 5, 7 days). Real-time data obtained in the undisturbed rat, revealed fluctuations associated with the rest-activity cycle, in temperature, mean arterial pressure and heart rate. The stress response was shown to elicit an elevation in the core temperature of 1.5 °C. This was heralded by an elevation in mean arterial pressure of 35 mmHg and heart rate of 160 bpm. Obtaining multiple parameters from a single transducer goes a considerable way towards overcoming challenges of the prior art.

Recording of intracranial pressure in conscious rats via telemetry.

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.

Arterial baroreceptor reflex control of renal sympathetic nerve activity following chronic myocardial infarction in male, female, and ovariectomized female 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.

Chronic measurement of left ventricular pressure in freely moving rats.

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/dt 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/dt max was 9,444 ± 363 mmHg/s, ranging from 7,870 to 10,558 mmHg/s (n = 7). A circadian variation in dP/dt max and heart rate (HR) was observed with an average increase during the night phase in dP/dt max of 918 ± 84 mmHg/s, and in HR of 38 ± 3 bpm. The ß-adrenergic-agonist isoproterenol, ß1-adrenergic agonist dobutamine, Ca(2+) 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/dt 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.

Tumor necrosis factor-alpha, interleukin-6, and interleukin-10 levels are altered in preeclampsia: a systematic review and meta-analysis.

PROBLEM: Published reports testing the association between cytokine levels and preeclampsia are conflicting. This comprehensive systematic review and meta-analysis aimed at testing the association between preeclampsia and maternal circulating tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-10. METHOD OF STUDY: A systematic literature search of studies reporting maternal circulating TNF-α, IL-6, and IL-10 in women with preeclampsia and normotensive pregnant women was conducted yielding 41, 28, and 12 eligible reports, respectively. RESULTS: Both mild preeclampsia and severe preeclampsia were associated with elevated TNF-α [mean difference (MD) = 7.34 pg/mL, 95% CI 5.02-9.66 and MD = 7.91 pg/mL, 95% CI 4.72-11.10, respectively] and IL-6 (MD = 61.01 pg/mL, 95% CI 14.24-107.77 and MD = 28.54 pg/mL, 95% CI 15.90-41.17, respectively) in the third trimester. Preeclampsia was also associated with elevated levels of IL-10 (MD = 5.54, 95% CI 0.69-10.38). The systematic review of studies reporting median data was in consensus with the parametric data. CONCLUSION: This systematic review and meta-analysis with accompanying summary of non-parametric data shows elevated maternal circulating TNF-α, IL-6, and IL-10 levels in preeclampsia.

Necrotic trophoblast debris increases blood pressure during pregnancy.

Preeclampsia is a major disease of human pregnancy characterised by hypertension and proteinuria. These signs are preceded by systemic maternal endothelial dysfunction. Hypertension in preeclampsia appears to be triggered by a placental factor, which leads to endothelial activation/dysfunction. One potential placental trigger for preeclampsia is necrotic trophoblast cell debris shed from the placenta into maternal blood. The larger trophoblast debris is trapped in the maternal pulmonary vessels and is hypothesised to be cleared by endothelial cells. Phagocytosis of necrotic but not apoptotic trophoblast debris by endothelial cells leads to their activation in vitro. We hypothesised that intravenous injection of necrotic trophoblast debris would induce hypertension in pregnant rats. Virgin female Wistar rats were surgically implanted with telemetry devices to monitor arterial blood pressure and chronic intravenous catheters to allow delivery of necrotic trophoblast debris. After recovery, the rats were mated and, from day 6 of gestation until parturition, they were given five consecutive daily injections per week of 5×10(6) necrotic Jeg-3 cells per kilo bodyweight. Control rats received vehicle injections. The normalised mean arterial blood pressure of rats receiving injections of necrotic trophoblast debris was higher than control rats during the third week of gestation, while mean arterial blood pressure decreased less from the pre-pregnancy baseline compared to control rats. These results suggest that necrotic trophoblast debris has a hypertensive effect which manifests in late gestation in Wistar rats and supports the theory that necrotic trophoblast debris may trigger the symptoms of preeclampsia.

Effects of sex and ovarian hormones on the initial renal sympathetic nerve activity response to myocardial infarction.

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.

Renal sympathetic nerve activity during asphyxia in fetal sheep.

The sympathetic nervous system (SNS) is an important mediator of fetal adaptation to life-threatening in utero challenges, such as asphyxia. Although the SNS is active well before term, SNS responses mature significantly over the last third of gestation, and its functional contribution to adaptation to asphyxia over this critical period of life remains unclear. Therefore, we examined the hypotheses that increased renal sympathetic nerve activity (RSNA) is the primary mediator of decreased renal vascular conductance (RVC) during complete umbilical cord occlusion in preterm fetal sheep (101 ± 1 days; term 147 days) and that near-term fetuses (119 ± 0 days) would have a more rapid initial vasomotor response, with a greater increase in RSNA. Causality of the relationship of RSNA and RVC was investigated using surgical (preterm) and chemical (near-term) denervation. All fetal sheep showed a significant increase in RSNA with occlusion, which was more sustained but not significantly greater near-term. The initial fall in RVC was more rapid in near-term than preterm fetal sheep and preceded the large increase in RSNA. These data suggest that although RSNA can increase as early as 0.7 gestation, it is not the primary determinant of RVC. This finding was supported by denervation studies. Interestingly, chemical denervation in near-term fetal sheep was associated with an initial fall in blood pressure, suggesting that by 0.8 gestation sympathetic innervation of nonrenal vascular beds is critical to maintain arterial blood pressure during the rapid initial adaptation to asphyxia.

Cardiovascular and autonomic responses to sexual activity in the rabbit.

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.

High dietary salt and angiotensin II chronically increase renal sympathetic nerve activity: a direct telemetric study.

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