Autoregulatory Efficiency Research Articles

Cerebral multi-autoregulation model based enhanced external counterpulsation treatment planning for cerebral ischemic stroke.

Enhanced external counterpulsation (EECP) treatment for cerebral ischemic stroke patients with differing severity of stenosis, is subject to uncertainties due to the varying effects of the cerebral autoregulation mechanism on haemodynamics. The current study reports the development of a cerebral multi-autoregulation (MR) mathematical model, based on cerebral arteriole regulation of neurogenic, vascular smooth muscle reflex and shear stress mechanisms which takes into account the severity of stenosis. The model was evaluated by comparison to authentic clinical measurements of cerebral autoregulatory efficiency. Then it was applied to a 0D/3D geometric multi-scale haemodynamic model of a cerebral artery. Haemodynamic indicators were calculated under different pressurization durations of EECP to evaluate the efficacy for different stenosis lesions. Moderate stenosis of 50% to 60% produced excessive time-averaged wall shear stress in the distal area of the stenosis (>7 Pa) during prolonged pressurization and may result in damage to vascular endothelial cells. However, prolonged pressurization did not result in haemodynamic risk for severe stenosis of 70% to 80%, indicating that the duration of pressurization may be extended with increasing severity of stenosis. The current MR model accurately simulated cerebral blood flow and has relevance to the simulation of cerebral haemodynamics in a clinical setting.

Restoration of afferent arteriolar autoregulatory behavior in ischemia-reperfusion injury in rat kidneys.

Renal autoregulation is critical in maintaining stable renal blood flow (RBF) and glomerular filtration rate (GFR). Renal ischemia-reperfusion (IR)-induced kidney injury is characterized by reduced RBF and GFR. The mechanisms contributing to renal microvascular dysfunction in IR have not been fully determined. We hypothesized that increased reactive oxygen species (ROS) contributed to impaired renal autoregulatory capability in IR rats. Afferent arteriolar autoregulatory behavior was assessed using the blood-perfused juxtamedullary nephron preparation. IR was induced by 60 min of bilateral renal artery occlusion followed by 24 h of reperfusion. Afferent arterioles from sham rats exhibited normal autoregulatory behavior. Stepwise increases in perfusion pressure caused pressure-dependent vasoconstriction to 65 ± 3% of baseline diameter (13.2 ± 0.4 μm) at 170 mmHg. In contrast, pressure-mediated vasoconstriction was markedly attenuated in IR rats. Baseline diameter averaged 11.7 ± 0.5 µm and remained between 90% and 101% of baseline over 65-170 mmHg, indicating impaired autoregulatory function. Acute antioxidant administration (tempol or apocynin) to IR kidneys for 20 min increased baseline diameter and improved autoregulatory capability, such that the pressure-diameter profiles were indistinguishable from those of sham kidneys. Furthermore, the addition of polyethylene glycol superoxide dismutase or polyethylene glycol-catalase to the perfusate blood also restored afferent arteriolar autoregulatory responsiveness in IR rats, indicating the involvement of superoxide and/or hydrogen peroxide. IR elevated mRNA expression of NADPH oxidase subunits and monocyte chemoattractant protein-1 in renal tissue homogenates, and this was prevented by tempol pretreatment. These results suggest that ROS accumulation, likely involving superoxide and/or hydrogen peroxide, impairs renal autoregulation in IR rats in a reversible fashion.NEW & NOTEWORTHY Renal ischemia-reperfusion (IR) leads to renal microvascular dysfunction manifested by impaired afferent arteriolar autoregulatory efficiency. Acute administration of scavengers of reactive oxygen species, polyethylene glycol-superoxide dismutase, or polyethylene glycol-catalase following renal IR restored afferent arteriolar autoregulatory capability in IR rats, indicating that renal IR led to reversible impairment of afferent arteriolar autoregulatory capability. Intervention with antioxidant treatment following IR may improve outcomes in patients by preserving renovascular autoregulatory function and potentially preventing the progression to chronic kidney disease after acute kidney injury.

Autoregulatory Efficiency Assessment in Kidneys Using Deep Learning.

A convolutional deep neural network is employed to assess renal autoregulation using time series of arterial blood pressure and blood flow rate measurements in conscious rats. The network is trained using representative data samples from rats with intact autoregulation and rats whose autoregulation is impaired by the calcium channel blocker amlodipine. Network performance is evaluated using test data of the types used for training, but also with data from other models for autoregulatory impairment, including different calcium channel blockers and also renal mass reduction. The network is shown to provide effective classification for impairments from calcium channel blockers. However, the assessment of autoregulation when impaired by renal mass reduction was not as clear, evidencing a different signature in the hemodynamic data for that impairment model. When calcium channel blockers were given to those animals, however, the classification again was effective.

Characterization of regional differences in cerebral vascular response to breath holding usingBOLD fMRI

AbstractCerebrovascular reactivity (CVR) is a specific indicator of autoregulatory efficiency. Studies have demonstrated that CVR depends on the baseline vascular dilation status between groups. Within the brain, there also exist spatial variations in both the resting cerebral blood flow (CBF) and CVR across different cerebral regions. However, the relationship between the regional CBF and CVR remains unclear. Hence, the primary goal of this study was to investigate the relationship between the resting CBF using pseudocontinuous arterial spin labeling (pCASL) technique and CVR using blood oxygenation level‐dependent (BOLD) technique across different cerebral regions. Eleven male and 14 female young volunteers were recruited in this study. Each subject was asked to perform the breath‐holding challenge to evaluate CVR at 3 T. The resting CBF was measured using pCASL in each subject. The relationships between CBF and CVR across the lobes were evaluated using the Spearman's rank test. The results showed that, for both sexes, the frontal lobe had the maximal resting perfusion but minimal vascular response to hypercapnia, whereas the occipital lobe had the lowest baseline CBF but maximal reactivity to hypercapnia, suggesting low and high autoregulatory efficiencies at high and low resting CBF in the brain, respectively. Sex‐related differences were observed in CBF but not in CVR. These findings may be of clinical interest in the assessment of cerebrovascular reserve and regional‐dependent vascular diseases.

Clinical Implications

Clinical Implications

Influence of connexin45 on renal autoregulation.

Renal autoregulation is mediated by the myogenic response and tubuloglomerular feedback (TGF) working in concert to maintain renal blood flow and glomerular filtration rate despite fluctuations in renal perfusion pressure. Intercellular communication through gap junctions may play a role in renal autoregulation. We examine if one of the building blocks in gap junctions, connexin45 (Cx45), which is expressed in vascular smooth muscle cells, has an influence on renal autoregulatory efficiency. The isolated perfused juxtamedullary nephron preparation was used to measure afferent arteriolar diameter changes in response to acute changes in renal perfusion pressure. In segmental arteries, pressure myography was used to study diameter changes in response to pressure changes. Wire myography was used to study vasoconstrictor and vasodilator responses. A mathematical model of the vascular wall was applied to interpret experimental data. We found a significant reduction in the afferent arteriolar constriction in response to acute pressure increases in Cx45 knockout (KO) mice compared with wild-type (WT) mice. Abolition of TGF caused a parallel upward shift in the autoregulation curve of WT animals but had no effect in KO animals, which is compatible with TGF providing a basal tonic contribution in afferent arterioles whereas Cx45 KO animals were functionally papillectomized. Analysis showed a shift toward lower stress sensitivity in afferent arterioles from Cx45 KO animals, indicating that the absence of Cx45 may also affect myogenic properties. Finally, loss of Cx45 in vascular smooth muscle cells appeared to associate with a change in both structure and passive properties of the vascular wall.

Aging Impairs Renal Autoregulation in Mice.

Impaired renal autoregulation permits more transmission of disturbance in systemic blood pressure, which initiates barotrauma in intrarenal microvasculatures such as glomerular and tubulointerstitial capillaries, contributing to the development of kidney damage and deterioration in renal function, especially under the conditions with high blood pressure. Although it has been postulated that autoregulatory efficiency is attenuated in the aging kidney, direct evidence remains lacking. In the present study, we measured the autoregulation of renal blood flow, myogenic response of afferent arteriole (Af-Art), tubuloglomerular feedback in vivo with micropuncture, as well as tubuloglomerular feedback in vitro in isolated perfused juxtaglomerular apparatus in young and aged C57BL/6 mice. We found that renal blood flow was not significantly changed in response to a defined elevation of renal arterial pressure in young mice but significantly increased in aged mice. Additionally, myogenic response of Af-Art measured by microperfusion with a stepwise increase in perfusion pressure was significantly blunted in the aging kidney, which is associated with the attenuation of intraluminal pressure-induced intracellular calcium increases, as well as the reduced expression of integrin α5 (Itga5) in Af-Art. Moreover, both tubuloglomerular feedback in vivo and in vitro were nearly inactive in the aging kidney, which is associated with the significantly reduced expression of adenosine A1 receptor (A1AR) and suppressed vasoconstrictor response to adenosine in Af-Art. In conclusion, this study demonstrates that aging impairs renal autoregulation with blunted myogenic response and inhibited tubuloglomerular feedback response. The underlying mechanisms involve the downregulations of integrin α5 and A1AR in the Af-Art.

Inhalation anesthesia based on sevofluran in patients with acute pathology of abdominal cavity organs

The use of new inhalation anesthetics in patients with acute abdominal pathology has several advantages. However, the use of inhalation anesthetics, in particular sevoflurane, does not exclude perioperative disorders of energy-structural interactions in the body of patients, manifested by changes in higher cortical functions. The aim of our study is to improve treatment outcomes for patients with acute pathology of the abdominal organs, by giving an energy-protective orientation to the inhalation anesthesia with sevoflurane. Materials, methods and results. The work was performed on the results of perioperative audit of energy-structural interactions in the mass of body cells, reserves, properties and efficiency of autoregulation in 91 patients with acute pathology of the abdominal cavity organs. According to the initial level of energy-structural interactions in the mass of body cells, patients were divided into two groups: with dysfunction and damage. Each group consisted of treatment and control groups. The patients of the control group underwent inhalation anesthesia based on sevoflurane in accordance with the standard protocol. In the treatment group, inhalation anesthesia was supplemented with energy-protective techniques for perioperative management of patients. Analysis of the clinical study showed a close relationship between early manifestations of structural microdamage of brain cells with energy-structural changes in the mass of body cells. Conclusions. The use of energy-protective techniques significantly increases the effectiveness of inhalation anesthesia in patients with dysfunction and damage of energy-structural interactions.

Cerebral autoregulation in migraine with aura: A case control study.

Migraine with aura is independently associated with increased risk of ischemic stroke, especially in younger subjects. This association might be related to an impairment of cerebral autoregulation, which normally maintains cerebral blood flow independent of arterial blood pressure variations. Patients aged 30-55, fulfilling ICHD-3 beta criteria for migraine with aura, were prospectively enrolled and compared with gender- and age-matched healthy controls without a history of migraine. Patients and controls with a history of stroke or any disease potentially impairing cerebral autoregulation were excluded. We assessed cerebral autoregulation with two different methods: Transfer function analysis, and the correlation coefficient index Mx. The transfer function phase and gain reflect responses of cerebral blood flow velocities to relatively fast fluctuations of arterial blood pressure, whereas Mx also reflects responses to slower arterial blood pressure fluctuations. A total of 22 migraine with aura patients (median age [IQR]: 39.5 [12.5] years) and 22 controls (39 [9.75] years) were included. Transfer function parameters and Mx were not different between patients and controls. However, Mx was inversely correlated with age in patients (ρ = -0.567, p = 0.006) and not in controls (ρ = -0.084, p = 0.509). Mx was also inversely correlated with migraine with aura duration (ρ = -0.617, p = 0.002), suggesting improvement of cerebral autoregulation efficiency with disease duration. Cerebral autoregulation did not differ between patients and controls aged 30-55. However, cerebral autoregulation efficiency was strongly correlated with migraine with aura duration. Further studies in younger patients are needed to determine whether cerebral autoregulation is impaired early in the course of disease. NCT02708797.

Renal autoregulation in experimental septic shock and its response to vasopressin and norepinephrine administration.

Evidence suggests that septic shock patients with chronic arterial hypertension may benefit from resuscitation targeted to achieve higher blood pressure values than other patients, possibly as a result of altered renal autoregulation. The effects of different vasopressor agents on renal autoregulation may be important in this context. We investigated the effects of arginine vasopressin (AVP) and norepinephrine (NE) on renal autoregulation in ovine septic shock. Sepsis was induced by fecal peritonitis. When shock developed (decrease in mean arterial pressure to <65 mmHg and no fluid responsiveness), animals were randomized to receive NE or AVP in a crossover design. Before the switch to the second vasopressor, the first vasopressor was discontinued for 30 min to ensure complete washout of the first vasopressor. Renal autoregulation was evaluated by recording the change in renal blood flow (RBF) in response to manual, stepwise reductions in renal inflow pressure. In this model, the lower limit of renal autoregulation was not significantly altered 6 h after sepsis induction (59 ± 9 vs. 64 ± 7 mmHg at baseline, P = 0.096). After development of shock, the autoregulatory threshold was lower with AVP than with NE (59 ± 5 vs. 65 ± 7 mmHg, P = 0.010). However, RBF was higher with NE both at the start of autoregulatory measurements (206 ± 58 vs. 170 ± 52 ml/min; P = 0.049) and at the autoregulatory threshold (191 ± 53 vs. 150 ± 47 ml/min; P = 0.008). As vasopressors may have different effects on renal autoregulation, blood pressure management in patients with septic shock should be individualized and take into account drug-specific effects.NEW & NOTEWORTHY Septic shock patients with chronic arterial hypertension may benefit from higher blood pressure targets due to underlying deficits in renal autoregulatory efficiency. The current study is the first to show that the choice of vasopressor agent can differentially affect renal autoregulation. These findings may contribute to more personalized blood pressure management in patients with septic shock.

Internephron Coupling Increases the Efficiency of Dynamic Autoregulation

In the kidney, dynamic autoregulation is provided by the response of the pre‐glomerular vascular resistance to time‐dependent perturbations of blood pressure. The two major autoregulatory mechanisms are the myogenic response, which is activated by afferent arteriole blood pressure, and tubuloglomerular feedback, which is activated by deviations in distal nephron chloride concentration. While the two mechanisms operate primarily on the single nephron level, signals that are transmitted through the supplying vasculature give rise to substantial internephron interactions. To study the impact of internephron coupling, we develop a mathematical model of the nephrovascular tree and apply the model to investigate the extent to which buffering of transient pressure perturbations is achieved. The model consists of coupled nephrovascular units; each unit represents an afferent arteriole, a glomerulus, and a nephron. The model includes superficial and juxtamedullary nephrons. Model simulations indicate effective buffering of pressure perturbations at low frequencies and slight amplification at high frequencies, in agreement with experimental observations of whole organ hemodynamics. Furthermore, the model predicts that internephron coupling increases the autoregulatory efficiency of the neprhovascular tree.Support or Funding InformationNSF DBI‐1300426

Assessing Renal Blood Flow Hemodynamics And Autoregulation In Humans Using Intrarenal Doppler Flow Velocity Measurement

Renal hemodynamics studied in experimental animals (rats, mice, dogs) has revealed that autoregulation of renal blood flow (RBF) is established by myogenic response (MR) and tubuloglomerular feedback (TGF). However, this data has not been available in humans. In this pilot study, we directly measure RBF in humans allowing analysis of MR and TGF characteristics. We assessed RBF at 50 Hz using Doppler-based flow velocity measurements by introducing a FloWire (Volcano) catheter into the renal artery of 5 human subjects who were undergoing cardiac catheterization. RBF was derived from Doppler velocities over 5-10 minutes and renal artery diameter. Renal artery pressure (RAP) was measured in the abdominal aorta at the root of the renal artery. The 5 subjects displayed substantial variations in RAP, allowing assessment of MR and TGF by time series analysis. Overall, RBF showed autoregulatory behaviour (see example). MR and TGF signatures could be identified in the Gain, Coherence and Phase plots. A newly developed method to assess autoregulation efficiency established by MR revealed highly variable efficiency among these 5 individuals. In sum, this approach makes it possible to investigate RBF dynamics, MR and TGF and efficiency of autoregulation in humans. Further studies are directed to develop the analytical methodology for these human samples further and to compare patients with and without heart failure with respect to RBF dynamics. Grant support received from the Univ. of Alberta Hospital Foundation.

The Role of Nitric Oxide System in The Regulation of Renal Function During Prehypertensive and Hypertensive Period in Fawn‐Hooded Rat

Objective: Fawn-Hooded (FH) rat strain represents unique model of hypertension with renal failure. Normotensive FHL rats serve as a control whereas FHH develop early hypertension and exhibit increased susceptibility to renal disease due to impaired autoregulatory efficiency of the kidney. Aim of this study was to examine the influence of nitric oxide (NO) system in FHL and FHH rats in prehypertensive and hypertensive period. Design and method: 3 and 9 months old FHH and FHL rats were anesthetized, NO synthase inhibitor (L-NAME) were infused via jugular vein in dose 50 μg/kg of body weight and mean arterial pressure (MAP), renal blood flow (RBF), glomerular filtration rate (GFR), urine flow (UF) and sodium excretion responses were measured. Results: FHH rats exhibited significantly higher basal MAP compare to FHL in 3 month (123 ± 2,9 vs. 101 ± 2,5 mmHg) and also in 9 month (141 ± 2,1 vs. 102 ± 2,4 mmHg). Young FHH had higher basal RBF than FHL (6,5 ± 0,2 vs. 5,4 ± 0,5 ml/min/g) although older FHH rats had slightly lower RBF compare to FHL (3,7 ± 0,5 vs. 4,9 ± 0,5 ml/min/g) and also GFR (0,47 ± 0,07 vs. 0,66 ± 0,09 ml/min/g). L-NAME administration led to similar responses in both ages in MAP, RBF and GFR but hypertensive FHH had significantly lower increase in UF (from 3,7 ± 0,4 to 13,6 ± 2,5 µl/min/g) compare to FHL (from 4,4 ± 0,8 to 29,7 ± 2,6 µl/min/g) and also in sodium excretion (from 0,19 ± 0,07 to 1,57 ± 0,54 µmol/min/g) than in FHL (from 0,14 ± 0,08 to 3,77 ± 0,57 µmol/min/g). Conclusions: This study indicates that FHH rats with developed hypertension exhibit impaired renal hemodynamics and tubular function that may be caused by relative NO deficiency in the kidney.

Renal autoregulation in health and disease.

Intrarenal autoregulatory mechanisms maintain renal blood flow (RBF) and glomerular filtration rate (GFR) independent of renal perfusion pressure (RPP) over a defined range (80-180 mmHg). Such autoregulation is mediated largely by the myogenic and the macula densa-tubuloglomerular feedback (MD-TGF) responses that regulate preglomerular vasomotor tone primarily of the afferent arteriole. Differences in response times allow separation of these mechanisms in the time and frequency domains. Mechanotransduction initiating the myogenic response requires a sensing mechanism activated by stretch of vascular smooth muscle cells (VSMCs) and coupled to intracellular signaling pathways eliciting plasma membrane depolarization and a rise in cytosolic free calcium concentration ([Ca(2+)]i). Proposed mechanosensors include epithelial sodium channels (ENaC), integrins, and/or transient receptor potential (TRP) channels. Increased [Ca(2+)]i occurs predominantly by Ca(2+) influx through L-type voltage-operated Ca(2+) channels (VOCC). Increased [Ca(2+)]i activates inositol trisphosphate receptors (IP3R) and ryanodine receptors (RyR) to mobilize Ca(2+) from sarcoplasmic reticular stores. Myogenic vasoconstriction is sustained by increased Ca(2+) sensitivity, mediated by protein kinase C and Rho/Rho-kinase that favors a positive balance between myosin light-chain kinase and phosphatase. Increased RPP activates MD-TGF by transducing a signal of epithelial MD salt reabsorption to adjust afferent arteriolar vasoconstriction. A combination of vascular and tubular mechanisms, novel to the kidney, provides for high autoregulatory efficiency that maintains RBF and GFR, stabilizes sodium excretion, and buffers transmission of RPP to sensitive glomerular capillaries, thereby protecting against hypertensive barotrauma. A unique aspect of the myogenic response in the renal vasculature is modulation of its strength and speed by the MD-TGF and by a connecting tubule glomerular feedback (CT-GF) mechanism. Reactive oxygen species and nitric oxide are modulators of myogenic and MD-TGF mechanisms. Attenuated renal autoregulation contributes to renal damage in many, but not all, models of renal, diabetic, and hypertensive diseases. This review provides a summary of our current knowledge regarding underlying mechanisms enabling renal autoregulation in health and disease and methods used for its study.

Cerebral autoregulation in the microvasculature measured with near-infrared spectroscopy.

Cerebral autoregulation (CA) is the mechanism that allows the brain to maintain a stable blood flow despite changes in blood pressure. Dynamic CA can be quantified based on continuous measurements of systemic mean arterial pressure (MAP) and global cerebral blood flow. Here, we show that dynamic CA can be quantified also from local measurements that are sensitive to the microvasculature. We used near-infrared spectroscopy (NIRS) to measure temporal changes in oxy- and deoxy-hemoglobin concentrations in the prefrontal cortex of 11 human subjects. A novel hemodynamic model translates those changes into changes of cerebral blood volume and blood flow. The interplay between them is described by transfer function analysis, specifically by a high-pass filter whose cutoff frequency describes the autoregulation efficiency. We have used pneumatic thigh cuffs to induce MAP perturbation by a fast release during rest and during hyperventilation, which is known to enhance autoregulation. Based on our model, we found that the autoregulation cutoff frequency increased during hyperventilation in comparison to normal breathing in 10 out of 11 subjects, indicating a greater autoregulation efficiency. We have shown that autoregulation can reliably be measured noninvasively in the microvasculature, opening up the possibility of localized CA monitoring with NIRS.

Changes in the profile of NO synthases affect coronary blood flow autoregulation and myocardial contractile activity during restraint stress in rats.

The efficiency of autoregulation of the coronary blood flow and contractile activity of the myocardium in the presence of inhibitors of constitutive and inducible NO synthases was studied in rats exposed to 6-h restraint stress. Intracoronary administration of S-methylisothiourea (10 μmol/liter), but not L-NAME (60 μmol/liter) fully prevented post-stress increase in the volume coronary blood flow rate, intensity of heart perfusion, and reduction of ventricular developed pressure at all levels of perfusion pressure. Real-time PCR showed 6-fold increased expression of inducible NO-synthase mRNA in the heart tissue against the background of unchanged expression of neuronal and endothelial NO synthases and 2-3-fold elevated content of transcripts of stress-inducible genes Hspa1a and Hspbp1. It was shown that the hypotension of coronary vessels and reduced contractile function of the myocardium are related to NO production by inducible NO synthase in endotheliocytes of coronary vessels and cardiomyocytes.

Monitoring of cerebral autoregulation.

Pressure autoregulation is an important hemodynamic mechanism that protects the brain against inappropriate fluctuations in cerebral blood flow in the face of changing cerebral perfusion pressure (CPP). Static autoregulation represents how far cerebrovascular resistance changes when CPP varies, and dynamic autoregulation represents how fast these changes happen. Both have been monitored in the setting of neurocritical care to aid prognostication and contribute to individualizing CPP targets in patients. Failure of autoregulation is associated with a worse outcome in various acute neurological diseases. Several studies have used transcranial Doppler ultrasound, intracranial pressure (ICP with vascular reactivity as surrogate measure of autoregulation), and near-infrared spectroscopy to continuously monitor the impact of spontaneous fluctuations in CPP on cerebrovascular physiology and to calculate derived variables of autoregulatory efficiency. Many patients who undergo such monitoring demonstrate a range of CPP in which autoregulatory efficiency is optimal. Management of patients at or near this optimal level of CPP is associated with better outcomes in traumatic brain injury. Many of these studies have utilized the concept of the pressure reactivity index, a correlation coefficient between ICP and mean arterial pressure. While further studies are needed, these data suggest that monitoring of autoregulation could aid prognostication and may help identify optimal CPP levels in individual patients.

Role of soluble guanylate cyclase in renal hemodynamics and autoregulation in the rat.

We studied the influence of soluble guanylate (sGC) on renal blood flow (RBF), glomerular filtration rate (GFR), and RBF autoregulation and its role in mediating the hemodynamic effects of endogenous nitric oxide (NO). Arterial pressure (AP), heart rate (HR), RBF, GFR, urine flow (UV), and the efficiency and mechanisms of RBF autoregulation were studied in anesthetized rats during intravenous infusion of sGC activator cinaciguat before and (except GFR) also after inhibition of NO synthase (NOS) by Nω-nitro-L-arginine methyl ester. Cinaciguat (0.1, 0.3, 1, 3, 10 μg·kg(-1)·min(-1), n=7) reduced AP and increased HR, but did not significantly alter RBF. In clearance experiments (FITC-sinistrin, n=7) GFR was not significantly altered by cinaciguat (0.1 and 1 μg·kg(-1)·min(-1)), but RBF slightly rose (+12%) and filtration fraction (FF) fell (-23%). RBF autoregulatory efficiency (67 vs. 104%) and myogenic response (33 vs. 44 units) were slightly depressed (n=9). NOS inhibition (n=7) increased AP (+38 mmHg), reduced RBF (-53%), and greatly augmented the myogenic response in RBF autoregulation (97 vs. 35 units), attenuating the other regulatory mechanisms. These changes were reversed by 77, 78, and 90% by 1 μg·kg(-1)·min(-1) cinaciguat. In vehicle controls (n=3), in which cinaciguat-induced hypotension was mimicked by aortic compression, the NOS inhibition-induced changes were not affected. We conclude that sGC activation leaves RBF and GFR well maintained despite hypotension and only slightly impairs autoregulation. The ability to largely normalize AP, RBF, RBF autoregulation, and renovascular myogenic response after NOS inhibition indicates that these hemodynamic effects of NO are predominantly mediated via sGC.

Reduced speed of microvascular blood flow in hemodialysis patients versus healthy controls: a coherent hemodynamics spectroscopy study

We present a pilot clinical application of coherent hemodynamics spectroscopy (CHS), a technique to investigate cerebral hemodynamics at the microcirculatory level. CHS relies on frequency-resolved measurements of induced cerebral hemodynamic oscillations that are measured with near-infrared spectroscopy (NIRS) and analyzed with a hemodynamic model. We have used cyclic inflation (200 mmHg) and deflation of a pneumatic cuff placed around the subject's thigh at seven frequencies in the range of 0.03 to 0.17 Hz to generate CHS spectra and to obtain a set of physiological parameters that include the blood transit times in the cerebral microcirculation, the cutoff frequency for cerebral autoregulation, and blood volume ratios across the three different compartments. We have investigated five hemodialysis patients, during the hemodialysis procedure, and six healthy subjects. We have found that the blood transit time in the cerebral microcirculation is significantly longer in hemodialysis patients with respect to healthy subjects. No significant differences were observed between the two groups in terms of autoregulation efficiency and blood volume ratios. The demonstration of the applicability of CHS in a clinical setting and its sensitivity to the highly important cerebral microcirculation may open up new opportunities for NIRS applications in research and in medical diagnostics and monitoring.

The effect of LacI autoregulation on the performance of the lactose utilization system in Escherichia coli

The lactose operon of Escherichia coli is a paradigm system for quantitative understanding of gene regulation in prokaryotes. Yet, none of the many mathematical models built so far to study the dynamics of this system considered the fact that the Lac repressor regulates its own transcription by forming a transcriptional roadblock at the O3 operator site. Here we study the effect of autoregulation on intracellular LacI levels and also show that cAMP-CRP binding does not affect the efficiency of autoregulation. We built a mathematical model to study the role of LacI autoregulation in the lactose utilization system. Previously, it has been argued that negative autoregulation can significantly reduce noise as well as increase the speed of response. We show that the particular molecular mechanism, a transcriptional roadblock, used to achieve self-repression in the lac system does neither. Instead, LacI autoregulation balances two opposing states, one that allows quicker response to smaller pulses of external lactose, and the other that minimizes production costs in the absence of lactose.