Changes In Perfusion Pressure Research Articles

Differential Role for the Clock Gene, BMAL1, on Kidney Function in Male versus Female Rats

Many activities of modern life, such as social visits with friends at night, long working hours, jet lag, and shift work cause circadian rhythm disturbances, which increase the risk of renal decline and eventual disease. Chronic kidney disease (CKD) is defined by decreases in glomerular filtration rate (GFR) which is higher during the daytime and lower at night in healthy individuals. Prior studies indicate that processes critical for maintaining blood pressure ( e.g. autoregulation) contribute to this time-of-day-dependence mediated by a molecular timekeeping mechanism known as the molecular circadian clock that resides in all tissues including the kidney. We hypothesized that loss of the molecular clock would impair normal kidney physiology through misalignment of functional rhythms with normal environmental patterns associated with day and night. We used a rat model of circadian disruption to interrogate our hypothesis. Male and female brain and muscle ARNT-like protein 1 knockout (BMAL1 KO) and littermate control (CON) rats aged 12-14 weeks underwent GFR measurements using FITC-labeled sinistrin clearance at two times of the day corresponding to the dark (active) and light (inactive) periods. Following GFR measurements, rats were placed in metabolic cages with food to record water intake and urine excretion over 12h active and inactive periods. Implantable telemeters were used for 24h measurement of systolic and diastolic blood pressure, locomotor activity and body temperature. Autoregulatory behavior was assessed using the isolated juxtamedullary nephron preparation to determine afferent arteriole diameter responses to changes in perfusion pressure. Diurnal measurements of GFR revealed that male BMAL1 KO rats had a significantly lower GFR in the active period as compared to CON males (1.87±0.37 vs 2.55±0.47 ml/min/100g; 2-way ANOVA, p<0.05; n=8-9). As a result, there was no diurnal variation in the KO males as seen in the CON males (Δ GFR 0.63±0.24 vs 0.04±0.21 ml/min/100g/12h CON vs KO respectively) (Sidak post-hoc, p<0.05; n=8-9) in parallel with a lack of diurnal variation in urine volume and Na excretion. Both male (n=8) and female (n=6-9) BMAL1 KO rats also displayed a significantly lower 24h mean arterial pressure (Males; 103±1 vs 107±1 mmHg, p<0.05; Females; 110±1 vs 100±2 mmHg, p<0.05) compared to CON with diurnal variation and autoregulatory reactivity preserved. Male BMAL1 KO rats consumed significantly more water compared to CON (n=5-9, 22.5±5.4 vs 14.7±4.0 mL/12h, p<0.05) concomitant with increased urine excretion (n=5-9, 13.3±6 vs 4.2±0.8 mL/12h, p<0.05) and reduced urine osmolality (n=5-7, 967±398 vs 2140±811 mmol/kg, p<0.05) regardless of time of day. Taken together these data suggest that BMAL1 is necessary for maintaining renal functional rhythms and urine concentrating ability in a sex-dependent manner. R01 DK134562 P01 HL158500. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Time-domain methods for quantifying dynamic cerebral blood flow autoregulation: Review and recommendations. A white paper from the Cerebrovascular Research Network (CARNet).

Cerebral Autoregulation (CA) is an important physiological mechanism stabilizing cerebral blood flow (CBF) in response to changes in cerebral perfusion pressure (CPP). By maintaining an adequate, relatively constant supply of blood flow, CA plays a critical role in brain function. Quantifying CA under different physiological and pathological states is crucial for understanding its implications. This knowledge may serve as a foundation for informed clinical decision-making, particularly in cases where CA may become impaired. The quantification of CA functionality typically involves constructing models that capture the relationship between CPP (or arterial blood pressure) and experimental measures of CBF. Besides describing normal CA function, these models provide a means to detect possible deviations from the latter. In this context, a recent white paper from the Cerebrovascular Research Network focused on Transfer Function Analysis (TFA), which obtains frequency domain estimates of dynamic CA. In the present paper, we consider the use of time-domain techniques as an alternative approach. Due to their increased flexibility, time-domain methods enable the mitigation of measurement/physiological noise and the incorporation of nonlinearities and time variations in CA dynamics. Here, we provide practical recommendations and guidelines to support researchers and clinicians in effectively utilizing these techniques to study CA.

Determinants of acute kidney injury during high-power mechanical ventilation: secondary analysis from experimental data

BackgroundThe individual components of mechanical ventilation may have distinct effects on kidney perfusion and on the risk of developing acute kidney injury; we aimed to explore ventilatory predictors of acute kidney failure and the hemodynamic changes consequent to experimental high-power mechanical ventilation.MethodsSecondary analysis of two animal studies focused on the outcomes of different mechanical power settings, including 78 pigs mechanically ventilated with high mechanical power for 48 h. The animals were categorized in four groups in accordance with the RIFLE criteria for acute kidney injury (AKI), using the end-experimental creatinine: (1) NO AKI: no increase in creatinine; (2) RIFLE 1-Risk: increase of creatinine of > 50%; (3) RIFLE 2-Injury: two-fold increase of creatinine; (4) RIFLE 3-Failure: three-fold increase of creatinine;ResultsThe main ventilatory parameter associated with AKI was the positive end-expiratory pressure (PEEP) component of mechanical power. At 30 min from the initiation of high mechanical power ventilation, the heart rate and the pulmonary artery pressure progressively increased from group NO AKI to group RIFLE 3. At 48 h, the hemodynamic variables associated with AKI were the heart rate, cardiac output, mean perfusion pressure (the difference between mean arterial and central venous pressures) and central venous pressure. Linear regression and receiving operator characteristic analyses showed that PEEP-induced changes in mean perfusion pressure (mainly due to an increase in CVP) had the strongest association with AKI.ConclusionsIn an experimental setting of ventilation with high mechanical power, higher PEEP had the strongest association with AKI. The most likely physiological determinant of AKI was an increase of pleural pressure and CVP with reduced mean perfusion pressure. These changes resulted from PEEP per se and from increase in fluid administration to compensate for hemodynamic impairment consequent to high PEEP;

Feasibility of Fluid Responsiveness Assessment in Patients at Risk for Increased Intracranial Pressure.

Background: Effective fluid management is important for patients at risk of increased intracranial pressure (ICP). Maintaining constant cerebral perfusion represents a challenge, as both hypovolemia and fluid overload can severely impact patient outcomes. Fluid responsiveness tests, commonly used in critical care settings, are often deemed potentially hazardous for these patients due to the risk of disrupting cerebral perfusion. Methods: This single-center, prospective, clinical observational study enrolled 40 patients at risk for increased ICP, including those with acute brain injury. Informed consent was obtained from each participant or their legal guardians before inclusion. The study focused on the dynamics of ICP and cerebral perfusion pressure (CPP) changes during the Passive Leg Raise Test (PLRT) and the End-Expiratory Occlusion Test (EEOT). Results: The results demonstrated that PLRT and EEOT caused minor and transient increases in ICP, while consistently maintaining stable CPP. EEOT induced significantly lower ICP elevations, making it particularly suitable for use in high-risk situations. Conclusions: PLRT and EEOT can be considered feasible and safe for assessing fluid responsiveness in patients at risk for increased ICP. Notably, EEOT stands out as a preferred method for high-risk patients, offering a dependable strategy for fluid management without compromising cerebral hemodynamics.

Correlation between early intracranial pressure and cerebral perfusion pressure with 28-day intensive care unit mortality in patients with hemorrhagic stroke.

Hemorrhagic stroke may cause changes in intracranial pressure (ICP) and cerebral perfusion pressure (CPP), which may influence the prognosis of patients. The aim of this study was to investigate the relationship between early ICP, CPP, and 28-day mortality in the intensive care unit (ICU) of patients with hemorrhagic stroke. A retrospective study was performed using the Medical Information Mart for Intensive Care (MIMIC-IV) and the eICU Collaborative Research Database (eICU-CRD), including hemorrhagic stroke patients in the ICU with recorded ICP monitoring. The median values of ICP and CPP were collected for the first 24 h of the patient's monitoring. The primary outcome was 28-day ICU mortality. Multivariable Cox proportional hazards models were used to analyze the relationship between ICP, CPP, and 28-day ICU mortality. Restricted cubic regression splines were used to analyze nonlinear relationships. The study included 837 patients with a 28-day ICU mortality rate of 19.4%. Multivariable analysis revealed a significant correlation between early ICP and 28-day ICU mortality (HR 1.08, 95% CI 1.04-1.12, p < 0.01), whereas early CPP showed no correlation with 28-day ICU mortality (HR 1.00, 95% CI 0.98-1.01, p = 0.57), with a correlation only evident when CPP < 60 mmHg (HR 1.99, 95% CI 1.14-3.48, p = 0.01). The study also identified an early ICP threshold of 16.5 mmHg. Early ICP shows a correlation with 28-day mortality in hemorrhagic stroke patients, with a potential intervention threshold of 16.5 mmHg. In contrast, early CPP showed no correlation with patient prognosis.

Upper cervical sympathectomy in neurovascular pathology.

The effectiveness of upper cervical sympathectomy in the treatment of patients with neurovascular pathology has been discussed in the researcher’s article for many years. However, the indications for this surgery need still to be clarified. The dynamics of cerebral blood flow during sympathetic blockade could not become the significant criterion for determining indications for surgical treatment. A cerebral perfusion pressure change in neurovascular pathology can activate the neurogenic mechanism of cerebral blood flow regulation. The need to search for new methods for the intensity of the autonomic nervous system impact on the cerebral vessels tone (the neurogenic mechanism of cerebral blood flow regulation) to clarify the indications for upper cervical sympathectomy in patients with neurovascular pathology is justified. The review put forward a hypothesis about the relationship between intracranial B-waves amplitude and the state of the neurogenic mechanism of cerebral blood flow regulation.

Exposure to passive heat and cold stress differentially modulates cerebrovascular-CO2 responsiveness.

Heat and cold stress influence cerebral blood flow (CBF) regulatory factors (e.g., arterial CO2 partial pressure). However, it is unclear whether the CBF response to a CO2 stimulus (i.e., cerebrovascular-CO2 responsiveness) is maintained under different thermal conditions. This study aimed to compare cerebrovascular-CO2 responsiveness between normothermia, passive heat, and cold stress conditions. Sixteen participants (8 females; 25 ± 7 yr) completed two experimental sessions (randomized) comprising normothermic and either passive heat or cold stress conditions. Middle and posterior cerebral artery velocity (MCAv, PCAv) were measured during rest, hypercapnia (5% CO2 inhalation), and hypocapnia (voluntary hyperventilation to an end-tidal CO2 of 30 mmHg). The linear slope of the cerebral blood velocity (CBv) response to changing end-tidal CO2 was calculated to measure cerebrovascular-CO2 responsiveness, and cerebrovascular conductance (CVC) was used to examine responsiveness independent of blood pressure. CBv-CVC-CO2 responsiveness to hypocapnia was greater during heat stress compared with cold stress (MCA: +0.05 ± 0.08 cm/s/mmHg/mmHg, P = 0.04; PCA: +0.02 ± 0.02 cm/s/mmHg/mmHg, P = 0.002). CBv-CO2 responsiveness to hypercapnia decreased during heat stress (MCA: -0.67 ± 0.89 cm/s/mmHg, P = 0.02; PCA: -0.64 ± 0.62 cm/s/mmHg; P = 0.01) and increased during cold stress (MCA: +0.98 ± 1.33 cm/s/mmHg, P = 0.03; PCA: +1.00 ± 0.82 cm/s/mmHg; P = 0.01) compared with normothermia. However, CBv-CVC-CO2 responsiveness to hypercapnia was not different between thermal conditions (P > 0.08). Overall, passive heat, but not cold, stress challenges the maintenance of cerebral perfusion. A greater cerebrovascular responsiveness to hypocapnia during heat stress likely reduces an already impaired cerebrovascular reserve capacity and may contribute to adverse events (e.g., syncope).NEW & NOTEWORTHY This study demonstrates that thermoregulatory-driven perfusion pressure changes, from either cold or heat stress, impact cerebrovascular responsiveness to hypercapnia. Compared with cold stress, heat stress poses a greater challenge to the maintenance of cerebral perfusion during hypocapnia, challenging cerebrovascular reserve capacity while increasing cerebrovascular-CO2 responsiveness. This likely exacerbates cerebral hypoperfusion during heat stress since hyperthermia-induced hyperventilation results in hypocapnia. No regional differences in middle and posterior cerebral artery responsiveness were found with thermal stress.

Effect of Hibiscus sabdariffa L. on the Metabolism of Arachidonic Acid in the Isolated Kidney of a Rat Model of Metabolic Syndrome.

The renal system is engaged in metabolic syndrome (MS) and metabolites of arachidonic acid (AA) participate in renal homeostasis and disruption of functionality. Hibiscus sabdariffa L (HSL) is used as a diuretic and could improve renal function. The aim of this study was to assess if treatment with HSL at 2% improves renal function in MS through the metabolites of AA. A total of 24 male Wistar rats were divided into four groups: Group 1, control (C); Group 2, MS with 30% sucrose in drinking water, Group 3, MS plus HSL infusion at 2% (MS+HSL); and Group 4, C+HSL. We evaluated the perfusion pressure changes (∆-PP), the activities of cyclooxygenases (COXs), the percentage of AA, the expressions of PLA2, COX2, COX1, 5-LOX, TAXS and CYP450, and the concentrations of prostaglandins in the kidney from rats with MS. There was a decrease in the ∆-PP, in the activities of COXs, and the expressions of COX2 and CYP450 (p ≤ 0.03, respectively)as well asPGE2, TxB2, and LKB4 (p ≤ 0.01, respectively). However, the percentage of AA and expressions of PLA2 and PGE1 (p = 0.01, respectively) were increased in C and MS+HSL. The HSL treatment improved the function and anatomical structure of the kidneys in the MS rats, through antioxidant molecules, and inhibited the pathways that metabolize the AA including that of PLA2, COX2, 5-LOX, TAXS, and CYP450 while favoring the COX1 pathway. This improves the vascular resistance of renal arterioles.

Abstract 124: Renin Cell Identity And Blood Pressure Homeostasis: Exploring The Role Of Endothelial Cell Cross-talk

Our previous studies using an Aortic Coarctation (AoCo) mouse model identified that renin-expressing juxta-glomerular (JG) cells respond to changes in perfusion pressure and Lamin A/C as a component of the renin cell baroreceptor. However, as the mechanisms for transmitting the extracellular pressure to the JG cells are unclear, we hypothesized that the endothelial cells (ECs) act as transducers of signals to the JG cells. Therefore in the current study, we aim 1) to identify the concurrent transcriptomic and epigenomic changes in JG cells and ECs in response to the changes in the perfusion pressure by single-nuclei multiomics approach 2) to define the contribution of EC-specific Lamin A/C (Lmna) in the EC-JG-cells cross-talk. We performed the AoCo surgeries on 3 months (M) old VE-Cad-Cre;Foxd1-Cre;mTmG mice where GFP is expressed simultaneously in Foxd1 and EC-lineage cells. We compared the single-cell gene expression and chromatin accessibility between the left (LK) and the right kidneys (RK) at 72h post-surgeries. Our study revealed: 1) JG cells increased significantly in the LK along with renin gene expression 2) ECs significantly increased by 10.73% in LK with a higher expression for genes promoting EC proliferation, morphogenesis, and immune response 3) JGs of the LK showed enrichment for the motifs Mbd1, Smad1, Smad5 indicating epigenetic changes promoting transcriptional regulation and TgfB1 signaling. Enrichment of Mybl1, Myb, and E2f2 motifs in the ECs of the LK suggests positive regulation of EC proliferation in response to low blood pressure (BP). Furthermore, deletion of the Lmna gene in the EC-lineage affected the BP responses in 4M old Lmna fl/fl ;VE-Cad.Cre mice. The difference between the carotid and femoral mean BP (MBP) measurements was more prominent in the wild type (WT) compared to the mutants at 72h post-AoCo [WT (n=7), Carotid MBP: 69.16±2.24 Femoral MBP: 63.28±2.33, P&lt;0.00001 Mutants (n=4); Carotid MBP: 75.98±3.06 Femoral MBP: 69.75±3.10, P&lt;0.05)]. Our current study shows that ECs undergo transcriptional and epigenetic alterations in response to changes in perfusion pressure. Deletion of Lmna in ECs reduces the differences in the BP between LK and RK, suggesting that it is important for sensing the changes in extracellular pressure.

Critical Care Experience With Clinical Cerebral Autoregulation Testing in Adults With Traumatic Brain Injury.

To describe the setting, feasibility, and safety of static cerebral autoregulation testing in critically injured adults with traumatic brain injury (TBI). Methods: We reviewed static autoregulation testing using transcranial Doppler (TCD) ultrasound in patients > 18 years with TBI ICD codes between January 1, 2014, and December 31, 2021. Adverse events during testing were defined as systemic hypertension (systolic blood pressure (SBP>180 mmHg), bradycardia (HR<40 bpm), and high ICP (>30 mmHg). Impaired and absent cerebral autoregulation was defined as an autoregulatory index (ARI) <0.4 and ARI 0, respectively. We characterized prescribed changes in intracranial pressure (ICP) and cerebral perfusion pressure (CPP) targets by autoregulation testing results. Results: A total of 135 patients, median age 31 (interquartile range (IQR) 24, 43) years, 71.9% male, admission Glasgow coma scale (GCS) score 3 (IQR 3, 5.5), and 70.9% with subdural hematoma from severe (GCS 3-8; 133 (98.5%)) and moderate (GCS 9-12; 2 (1.5%)) TBI, underwent 309 attempted testing. All patients were mechanically ventilated and had ICP monitoring; 246 (80%) had brain tissue oxygen monitoring, and 68 (22%) had an external ventricular drain. The median number of autoregulation tests was two (range 1-3) tests/patient, and the median admission to the first test time was two days (IQR 1, 3). Of 55 (17.8%) tests not completed, systemic hypertension (32, 10.4%), intracranial hypertension (10, 3.2%), and bradycardia (3, 0.9%) were transient. Fifty-three (51%) of the first (n=104) autoregulation tests showed impaired/absent cerebral autoregulation. Impaired/absent autoregulation results at the first test were associated with repeat cerebral autoregulation testing (RR 2.25, 95% CI [1.40-3.60], p=0.0007) than intact cerebral autoregulation results. Pre-testing cerebral hemodynamic targets were maintained (n=131; 86.8%) when cerebral autoregulation was impaired (n=151; RR 1.49, 95% CI [1.25-1.77], p<0.0001). However, 15 (9.9%) test results led to higher ICP targets (from 20 mmHg to 25 mmHg), 5 (3.3%) results led to an increase in CPP target (from 60 mmHg to 70 mmHg), and five out of 131 (3.8%) patients underwent decompressive craniectomy and placement of an external ventricular drain. Intact cerebral autoregulation results (n=43/103, 41.7%) were associated with a change in ICP targets from 20 mmHg to 25 mmHg (RR 3.15, 95% CI [1.97-5.03], p<0.0001). Conclusions: Static cerebral autoregulation testing was feasible, safe, and useful in individualizing the care of patients with moderate-severe TBI receiving multimodal neuromonitoring. Testing results guided future testing, cerebral hemodynamic targets, and procedural decisions. Impaired cerebral autoregulation was very common.

Value of Multimodality Ultrasound in Quantitative Evaluation of the Intra-compartmental Pressure and Perfusion Pressure in Acute Compartment Syndrome in a Rabbit Model.

The aim of the work described here was to investigate the feasibility of using multimodality ultrasound in quantitative evaluation of the intra-compartmental pressure (ICP) and perfusion pressure (PP) changes in acute compartment syndrome (ACS). Infusion technique was used to increase the ICP of the anterior compartment of 10 rabbits from baseline to 20, 30, 40, 50, 60, 70 and 80 mmHg. The anterior compartment was evaluated with conventional ultrasound, shear wave elastography (SWE) and contrast-enhanced ultrasound (CEUS). The shape of the anterior compartment, shear wave velocity (SWV) of the tibialis anterior (TA) muscle and CEUS parameters of the TA muscle were measured. When the ICP exceeded 30 mmHg, the shape of the anterior compartment did not expand significantly with increasing ICP. There was a strong correlation between the SWV of TA muscle and measured ICP (ρ=0.927). Arrival time (AT), time to peak (TTP), peak intensity (PI) and area under the curve (AUC) were significantly correlated with PP (AT, ρ=-0.763; TTP, ρ=-0.900; PI, ρ=0.665; AUC, ρ=0.706), whereas mean transit time (MTT) was not. Multimodality ultrasound can be used to quantitatively evaluate ICP and PP and, thus, could provide more information for the rapid diagnosis and monitoring of ACS.

Evaluation of biological activity of some pyridine derivatives on perfusion pressure and their interaction with the M2 muscarinic receptor

AbstractThe aim of this study was to evaluate the biological activity of some pyridine derivatives (compounds 1 to 15) on perfusion pressure in an isolated rat heart model. Furthermore, theoretical interaction of pyridine derivatives with the M2 muscarinic receptor was determined using acetylcholine, AF‐DX 116 and the 3uon protein as theoretical tools in a docking model. Results showed that pyridine derivatives 6, 9, and 13 decreased perfusion pressure compared to control conditions and compounds 1‐5, 7, 8, 10‐12, 14, and 15. Furthermore, theoretical data indicates that different amino acid residues are involved in the interaction of pyridine derivatives with the protein surface. Other data indicate that the inhibition constant was lower for compounds 6, 9 and 13 compared to acetylcholine and AF‐DX 116. In conclusion, all these data suggest that pyridine derivatives 6, 9 and 13 can produce changes in perfusion pressure possibly through activation of the M2 muscarinic receptor, and this phenomenon could depend on the different functional groups involved in its chemical structure.

ASSOCIATION OF OCULAR PERFUSION PRESSURE AND CEREBROSPINAL FLUID PRESSURE WITH CHANGES IN DIABETIC RETINOPATHY.

To investigate the association between mean ocular perfusion pressure (MOPP), estimated cerebrospinal fluid pressure (CSFP), and changes in diabetic retinopathy (DR) in a Northeastern Chinese population with Type 2 diabetes. A total of 1,322 subjects from the Fushun Diabetic Retinopathy Cohort Study were enrolled. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and intraocular pressure (IOP) were recorded. MOPP was calculated by the following formula: MOPP = 2/3 [DBP + 1/3 (SBP - DBP)] - IOP, and CSFP was estimated according to the following formula: CSFP = 0.44 × body mass index + 0.16 × DBP - 0.18 × age - 1.91. New development, progression, and regression of DR were graded based on fundus photographs at baseline and during follow-up examinations with a mean interval of 21.2 months using the modified Early Treatment Diabetic Retinopathy Study criteria. Increasing MOPP was associated with the incidence of DR in the multivariate model (per 1-mmHg increase: relative risk, 1.06; 95% confidence interval, 1.02-1.10; P = 0.007) and showed a borderline negative association with DR regression (per 1-mmHg increase: relative risk, 0.98; 95% confidence interval, 0.97-1.00; P = 0.053). However, MOPP was not associated with progression of DR. Cerebrospinal fluid pressure was not associated with new development, progression, or regression of DR. The MOPP, but not the CSFP, was found to influence the development, but not the progression of DR in this Northeastern Chinese cohort.

Assessment of renal sympathetic control using invasive pressure and flow velocity measurements in humans.

Renal sympathetic innervation is important in the control of renal and systemic hemodynamics and is a target for pharmacological and catheter-based therapies. The effect of a physiological sympathetic stimulus using static handgrip exercise on renal hemodynamics and intraglomerular pressure in humans is unknown. We recorded renal arterial pressure and flow velocity in patients with a clinical indication for coronary or peripheral angiography using a sensor-equipped guidewire during baseline, handgrip, rest, and hyperemia following intrarenal dopamine (30 μg/kg). Changes in perfusion pressure were expressed as the change in mean arterial pressure, and changes in flow were expressed as a percentage with respect to baseline. Intraglomerular pressure was estimated using a Windkessel model. A total of 18 patients (61% male and 39% female) with a median age of 57 yr (range: 27-85 yr) with successful measurements were included. During static handgrip, renal arterial pressure increased by 15.2 mmHg (range: 4.2-53.0 mmHg), whereas flow decreased by 11.2%, but with a large variation between individuals (range: -13.4 to 49.8). Intraglomerular pressure increased by 4.2 mmHg (range: -3.9 to 22.1 mmHg). Flow velocity under resting conditions remained stable, with a median of 100.6% (range: 82.3%-114.6%) compared with baseline. During hyperemia, maximal flow was 180% (range: 111%-281%), whereas intraglomerular pressure decreased by 9.6 mmHg (interquartile range: 4.8 to 13.9 mmHg). Changes in renal pressure and flow during handgrip exercise were significantly correlated (ρ = -0.68, P = 0.002). Measurement of renal arterial pressure and flow velocity during handgrip exercise allows the identification of patients with higher and lower sympathetic control of renal perfusion. This suggests that hemodynamic measurements may be useful to assess the response to therapeutic interventions aimed at altering renal sympathetic control.NEW & NOTEWORTHY Renal sympathetic innervation is important in the homeostasis of systemic and renal hemodynamics. We showed that renal arterial pressure significantly increased and that flow decreased during static handgrip exercise using direct renal arterial pressure and flow measurements in humans, but with a large difference between individuals. These findings may be useful for future studies aimed to assess the effect of interventions that influence renal sympathetic control.

Lady's Bedstraw as a Powerful Antioxidant for Attenuation of Doxorubicin-Induced Cardiotoxicity.

This study aimed to examine the effects of a 14-day treatment with lady's bedstraw methanol extract on doxorubicin-induced cardiotoxicity through functional, biochemical and histological examinations. We used 24 male Wistar albino rats divided into the following groups: control (CTRL), doxorubicin (DOX), and DOX + GVE (Galium verum extract). GVE was administered orally at a dose of 50 mg/kg per day for 14 days, while a single dose of doxorubicin was injected into the DOX groups. After accomplishing treatment with GVE, cardiac function was assessed, which determined the redox state. During the autoregulation protocol on the Langendorff apparatus, ex vivo cardiodynamic parameters were measured. Our results demonstrated that the consumption of GVE effectively suppressed the disturbed response of the heart to changes in perfusion pressures caused by administration of DOX. Intake of GVE was associated with a reduction in most of the measured prooxidants in comparison to the DOX group. Moreover, this extract was capable of increasing the activity of the antioxidant defense system. Morphometric analyses showed that rat hearts treated with DOX showed more pronounced degenerative changes and necrosis compared to the CTRL group. However, GVE pretreatment seems to be able to prevent the pathological injuries caused by DOX injection via decrease in oxidative stress and apoptosis.

Quantification of Cerebral Vascular Autoregulation Immediately Following Resuscitation from Cardiac Arrest.

Cerebral vascular autoregulation is impaired following resuscitation from cardiac arrest (CA), and its quantification may allow assessing CA-induced brain injury. However, hyperemia occurring immediately post-resuscitation limits the application of most metrics that quantify autoregulation. Therefore, to characterize autoregulation during this critical period, we developed three novel metrics based on how the cerebrovascular resistance (CVR) covaries with changes in cerebral perfusion pressure (CPP): (i)θCVR, which quantifies the CVR vs CPP gradient, (ii) a CVR-based transfer function analysis, and (iii) CVRx, the correlation coefficient between CPP and CVR. We tested these metrics in a model of asphyxia induced CA and resuscitation using seven adult male Wistar rats. Mean arterial pressure (MAP) and cortical blood flow recorded for 30min post-resuscitation via arterial cannulation and laser speckle contrast imaging, were used as surrogates of CPP and cerebral blood flow (CBF), while CVR was computed as the CPP/CBF ratio. Using our metrics, we found that the status of cerebral vascular autoregulation altered substantially during hyperemia, with changes spread throughout the 0-0.05Hz frequency band. Our metrics push the boundary of how soon autoregulation can be assessed, and if validated against outcome markers, may help develop a reliable metric of brain injury post-resuscitation.

Effects of positive end-expiratory pressure on cerebral hemodynamics in acute brain injury patients.

Background: Cerebral autoregulation is the mechanism that allows to maintain the stability of cerebral blood flow despite changes in cerebral perfusion pressure. Maneuvers which increase intrathoracic pressure, such as the application of positive end-expiratory pressure (PEEP), have been always challenged in brain injured patients for the risk of increasing intracranial pressure (ICP) and altering autoregulation. The primary aim of this study is to assess the effect of PEEP increase (from 5 to 15cmH2O) on cerebral autoregulation. Secondary aims include the effect of PEEP increase on ICP and cerebral oxygenation. Material and Methods: Prospective, observational study including adult mechanically ventilated patients with acute brain injury requiring invasive ICP monitoring and undergoing multimodal neuromonitoring including ICP, cerebral perfusion pressure (CPP) and cerebral oxygenation parameters obtained with near-infrared spectroscopy (NIRS), and an index which expresses cerebral autoregulation (PRx). Additionally, values of arterial blood gases were analyzed at PEEP of 5 and 15cmH2O. Results are expressed as median (interquartile range). Results: Twenty-five patients were included in this study. The median age was 65years (46-73). PEEP increase from 5 to 15cmH2O did not lead to worsened autoregulation (PRx, from 0.17 (-0.003-0.28) to 0.18 (0.01-0.24), p = 0.83). Although ICP and CPP changed significantly (ICP: 11.11 (6.73-15.63) to 13.43 (6.8-16.87) mm Hg, p = 0.003, and CPP: 72.94 (59.19-84) to 66.22 (58.91-78.41) mm Hg, p = 0.004), these parameters did not reach clinically relevant levels. No significant changes in relevant cerebral oxygenation parameters were observed. Conclusion: Slow and gradual increases of PEEP did not alter cerebral autoregulation, ICP, CPP and cerebral oxygenation to levels triggering clinical interventions in acute brain injury patients.

Regulation of Renin-Angiotensin System Activity and Blood Pressure by Vascular Smooth Muscle Cullin-3

Mutations in the ubiquitin ligase scaffold protein Cullin 3 (CUL3) in smooth muscle cells (SMCs) cause vascular dysfunction, arterial stiffness, and severe hypertension. We hypothesized that conditional deletion of CUL3 in SMCs causes severe hypertension through a renin-angiotensin system (RAS)-dependent mechanism. Mice carrying a conditional allele of CUL3 were bred to mice expressing a tamoxifen-inducible CRE-recombinase driven by a smooth muscle promoter (ISM-CRE, control). Tamoxifen was administered to generate smooth muscle CUL3 knockout (S-CUL3KO). Primary aortic SMCs were used to elucidate the contribution of CUL3 to intracellular angiotensin II-mediated calcium flux. Calcium response in SMCs was analyzed via ratiometric confocal fluorescent microscopyS-CUL3KO mice demonstrated hypertension following three weeks of tamoxifen, mean arterial pressure (MAP) was 108±1 vs. 140±1 mmHg (ISM-CRE vs. S-CUL3KO). Aorta from S-CUL3KO mice exhibited impaired vasorelaxation to acetylcholine (ACh, max relaxation: 84±4% vs. 16±9%, p&lt;0.05) and sodium nitroprusside (SNP, max relaxation: 95±3% vs. 56±9%, p&lt;0.05). Captopril administration (7 days) markedly reduced MAP to 84±0.3 mmHg and improved vasorelaxation in response to both ACh (72±6%) and SNP (91±4%) in S-CUL3KO mice, suggesting RAS-dependency of the hypertension. Additionally, candesartan treatment (7 days) substantially decreased MAP from 138±1 to 96±3 mmHg suggesting that hypertension in S-CUL3KO group is angiotensin type-1 receptor mediated. Q-PCR and RNAScope analyses demonstrated no difference in renin expression in the kidney between the S-CUL3KO and control mice suggesting a blunting of the baroreceptor mechanism regulating renin mRNA expression. Equilibrium angiotensin II plasma levels in both groups were not different (2517±352 and 2379±549 pmol/L, p&gt;0.05). Preliminary data demonstrated that acute application of 10 μM of angiotensin II to S-CUL3KO SMCs resulted in a sustained increase in intracellular calcium which was abolished by a preincubation with 2 μM of candesartan.Our data suggest that CUL3 may play a vital role in baroreceptor mechanism in the kidney and regulate angiotensin II response in SMCs which are essential for responding to changes in perfusion pressure. Ultimately, understanding CUL3 target proteins may benefit the development of novel treatments for hypertension. R35 HL144807 (to CDS). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

High-mobility group box 1 impairs renal microvascular autoregulatory responses in male and female rats

High-mobility group box 1 (HMGB1) is a nuclear protein that functions as a paracrine signaling molecule when released from the nucleus of stressed or injured cells into the interstitial fluid. Secreted HMGB1 can activate toll-like receptor 4 (TLR4) and we showed that activation of renal TLR4 causes autoregulatory dysfunction. In addition, microvascular function is seriously compromised in hypertension but the specific mechanisms involved are poorly defined. We tested the hypothesis that HMGB1 negatively influences renal microvascular autoregulatory capability by activating TLR4. Experiments were performed in male rats using the blood-perfused juxtamedullary nephron technique. Three groups were studied: control, HMGB1 (~1.25 μg/ml in the blood perfusate) and HMGB1+LPS-RS (TLR4 blocker; ~10 μg/ml in the blood perfusate). Afferent arteriole autoregulatory behavior was assessed in these groups by increasing perfusion pressure from 65 to 170 mmHg in 15 mmHg increments. Starting diameters of male arterioles, measured at 100 mmHg, were similar across all three groups (15.3±0.7; 15.1±0.2 and 15.3±0.1 μm, respectively). When perfusion pressure increased from 65 to 170 mmHg, control arteriole diameter decreased to 69±3% of baseline (P&lt;0.05; n=6), exhibiting normal pressure-induced autoregulatory vasoconstriction. Afferent arteriole diameters in kidneys receiving HMGB1 remained unchanged at 97±1% over the same pressure range (n=9; P&gt;0.05 vs. baseline; P&lt;0.05 compared to control kidneys), indicating significant loss of autoregulatory behavior. In the HMGB1+LPS-RS group, afferent arteriole responses were similar to normal controls and decreased to 76±1% (n=6; P&lt;0.05 vs baseline; P&lt;0.05 vs. HMGB1) over the same pressure range, signifying normalization of autoregulatory behavior by TLR4 blockade. There are few published data on the response of female afferent arterioles to the change in perfusion pressure, so we conducted separate experiments using females in two groups of rats, (normal kidneys with or without HMGB1 in the perfusate blood). Baseline diameters of female arterioles (100 mmHg) were similar across both groups (14.7±0.4 and 14.2±0.3 μm, respectively) and were similar to baseline diameters in males (P&gt;0.05). Increasing perfusion pressure from 65 to 170 mmHg decreased female control arteriole diameter to 78±1% (P&lt;0.05 vs baseline; n=6), reflecting normal autoregulatory vasoconstriction resembling that observed in males. Afferent arteriole diameters in female kidneys receiving HMGB1 actually became slightly larger to 103±1% (P&lt;0.05 vs baseline; P&lt;0.05 vs control kidneys; n=6) by 170 mmHg, indicating significant loss of autoregulatory reactivity and that female renal microvessels respond to HMGB1 similarly to males. These data demonstrate that HMGB1 exposure can impair afferent arteriole autoregulatory capability in male and female rats and suggests that impairment involves HMGB1-dependent TLR4 activation. Study supported by NIH (DK044628). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Aortic stiffness and impairments in cerebrovascular function in cancer survivorship

An established consequence of anti-cancer treatment is increased aortic stiffness, which impairs the aortic damping of cardiac-generated pulsatile pressure and blood flow. These increased pulsations may result in vascular injury in the microcirculation of target end organs like the brain. The aim of the present study was to determine the ramifications of elevated aortic stiffness on cerebral macro- and microvascular pulsatility and autoregulatory function in cancer survivors. We hypothesized that cerebrovascular pulsatility would be enhanced, and cerebrovascular reactivity (CVR) to elevations in arterial CO 2 would be impaired, both in the large and small cerebral vessels in patients with a history of cancer and anti-cancer treatment versus healthy age- and sex-matched non-cancer controls. Aortic arch pulse wave velocity (aaPWV), a regional measure of stiffness in the proximal aorta, was calculated from echocardiographic views of the aortic valve and the descending aortic arch. Subjects then breathed room air for 60s followed by ~2 minutes of rebreathing with simultaneous collection of end-tidal pressure of CO 2 (P ET CO 2 ). Middle cerebral artery blood flow velocity (MCAv) was assessed using transcranial doppler. Oxygenated (oxy-[Hb]) and deoxygenated (deoxy-[Hb]) cerebral microvascular hemoglobin concentrations were monitored using two near-infrared spectroscopy probes placed over the prefrontal cortices. Pulsatility was assessed at baseline using Gosling’s Pulsatility Index (PI) for both the microvasculature and MCA. To account for changes in perfusion pressure, MAP was collected via finger plethysmography and cerebrovascular conductance indices were calculated for both oxy-[Hb] (CVCi oxy ) and MCAv (CVCi MCA ). CVR was calculated as the slope of CVCi oxy and CVCi MCA over P ET CO 2 during rebreathing. Six women were recruited (n = 3/group). Age was similar between the healthy non-cancer controls (HC) and patients with a history of cancer and anti-cancer treatment (CS) (31.0 ± 7 vs. 32.7 ± 13 years). Baseline ventilatory (P ET CO 2 ), central and cerebral hemodynamics were also similar (all p &gt; 0.05). aaPWV was significantly elevated in CS compared to HC (5.3 ± 0.6 vs. 3.1 ± 1.1 m/s, p = 0.04). Cerebral microcirculation PI in CS was significantly elevated (0.04 ± 0.01 vs. 0.02 ± 0.01, p = 0.02), but MCA PI was not different (p &gt; 0.05). CVR-CVCi oxy was impaired in CS (-3.6 ± 2.8 vs. 1.5 ± 0.5 nM·mmHg -1 /mmHg, p = 0.03), and CVR-CVCi MCA was similarly reduced (-0.05 ± 0.06 vs. 0.15 ± 0.01 mm/sec·mmHg -1 /mmHg, p &lt; 0.01). The increase in MAP during hypercapnia was similar between groups. Consistent with our hypothesis, both CVR-CVCi oxy and CVR-CVCi MCA were attenuated in patients with a history of anti-cancer treatment. Additionally, the microvascular pulsatility was greater in CS. This suggests an impaired cerebrovascular function, possibly related to increased transmission of pulsatility into the brain, in the years following cancer diagnoses and treatment. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.