Arterial Pressure Research Articles

Ascorbic Acid Infusion Improves Cerebrovascular Reactivity in Middle-Aged and Older Adults

Aging is associated with reductions in cerebrovascular reactivity (CVR) and cerebrovascular conductance (CVC), which may contribute to the development of neurodegenerative disease and stroke. In the peripheral vasculature, increased oxidative stress is linked to vascular dysfunction and is ameliorated following infusion of the antioxidant ascorbic acid (AA). However, oxidative stress’ effect on cerebrovascular function in humans is not entirely understood. PURPOSE: To determine whether oxidative stress reduces CVR and CVC in middle-aged and older adults (MA/O). We hypothesized that AA infusion would increase CVR and CVC in MA/O but not young adults (YA). METHODS: Young (18-29 years) and middle-aged and older (55-79 years) adults were recruited for two identical experimental visits. Each visit consisted of the same measures performed both before and after the infusion of either AA or saline (SAL). Middle cerebral artery blood velocity (MCAv) was recorded using a transcranial Doppler ultrasound probe. CVR was tested using a hypercapnia protocol that was achieved with a computer-based gas blender that increased the subjects’ end-tidal partial pressure of carbon dioxide (PETCO2) 9 mmHg above baseline for a 3-minute period. CVR was defined as the percent change in MCAv during hypercapnia divided by the absolute change in PETCO2. CVC was defined as the percent of CVR normalized for the changes in mean arterial blood pressure. Two-way ANOVAs were used to assess the effects of AA and SAL on CVR and CVC. Fisher’s LSD tests were used to assess main and interaction effects when necessary. RESULTS: 8 YA (25 + 2 years) and 14 MA/O (65 + 6 years) completed the experimental visits. There was a significant main effect of condition (pre/post) on CVR following SAL infusion (p = 0.016), and a significant age x condition interaction effect on CVR following AA infusion (p = 0.016). There were no significant main or interaction effects on CVC following SAL infusion, but there was a significant age x condition interaction effect on CVC following AA infusion (p = 0.012). Post hoc testing indicated that the difference in CVR following SAL infusion was due to an increase in YA (3.0 + 0.5 %/mmHg pre vs. 3.8 + 1.1 %/mmHg post, p = 0.047), whereas the difference in CVR following AA infusion was due to an increase in MA/O (3.3 + 1.7 %/mmHg pre vs. 4.1 + 1.9 %/mmHg post, p = 0.006). The difference in CVC was indicated to be due to both lower baseline CVC in MA/O (2.3 + 0.4 %/mmHg YA pre vs. 1.3 + 1.1 %/mmHg MA/O pre, p = 0.019) and an increase in CVC in MA/O following AA infusion (1.3 + 1.1 %/mmHg pre vs. 2.0 + 0.5 %/mmHg post, p = 0.047). CONCLUSION: Our main finding is that AA infusion restores CVR and CVC in MA/O, but not YA. This finding suggests that age-related increases in oxidative stress may impair cerebrovascular function. Supported by NIH Grant P20 GM113125. 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.

Association of initial assessment variables and mortality in severe pediatric traumatic brain injury

BackgroundPredictive scales have been used to prognosticate long-term outcomes of traumatic brain injury (TBI), but gaps remain in predicting mortality using initial trauma resuscitation data. We sought to evaluate the...

Exercise Mitigates Angiotensin II-Mediated Sympathetic Nerve-Macrophage Interaction in Aortic Adventitia Leading to Vascular Remodeling

Large artery stiffness is a significant risk factor for cardiovascular diseases. Our previous study suggested that angiotensin II (Ang II) stimulates sympathetic innervation in aortic adventitia (AA) leading to elevated mean arterial blood pressure and increased arterial fibrosis, while voluntary wheel-running (VWR) reduces them. The aim of this study is to explore mechanism under Ang II-induced the aortic remodeling through sympathetic nerves and immune cell interactions using transcriptomics. We isolated cells in AA from Ang II (1.5 mg/kg/day) vs. Vehicle (Saline) infused C57BL/6 male mice (n=3 of each group), and we performed single-cell RNA-sequencing (scRNAseq). We profiled 23,419 cells after quality control and filtering steps and annotated 9 cell types in the AA employing a uniform manifold approximation and projection (UMAP) to visualize the remaining cells and the Leiden cluster algorithm. Firstly, we identified the Adrb2 gene for β2-adrenergic receptor (β2-ADR) was predominantly expressed in macrophages/monocytes as compared to other cell types, and significantly more expressed in macrophages vs. monocytes (adjusted p-value, <0.05). We validated the transcriptomic results using immunostaining for β2-ADR and synapsin with CD68 in AA. In addition, Ang II increased AA macrophage proportion which displays M1 phenotype (pro-inflammatory) (adjusted p-value, <0.05). These findings suggest that Ang II promotes M1 like macrophages which interact with sympathetic nerves in AA. Next, we performed Gene Ontology (GO) enrichment test in macrophages and fibroblasts. Ang II Macrophages were enriched in GO terms with inflammation and cytokines, and Ang II fibroblasts were enriched in GO terms involved in extracellular matrix deposition. The GO results indicate that Ang II induced inflammatory macrophages activates fibroblasts to accumulate ECM deposition in AA. Congruent with the scRNAseq results, we found that number of macrophages, ECM accumulation, and vascular stiffness measured by pulse wave velocity were increased with Ang II vs. Vehicle (all, p <0.05), whereas interestingly VWR ameliorated the Ang II effects. This study provides the evidence that Ang II promotes aortic remodeling by interaction between sympathetic nerves and macrophage which results in ECM deposition in AA using transcriptomics approach, while VWR countermeasure to these detrimental effects. 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.

Spontaneous Sympathetic Baroreflex Sensitivity Is Impaired in Patients with Chronic Kidney Disease

Patients with chronic kidney disease (CKD) have chronic overactivation of the sympathetic nervous system that contributes to hypertension and increased cardiovascular risk. The sympathetic baroreflex is a major regulator of sympathetic activity in response to changes in blood pressure; however, limited information is available regarding sympathetic baroreflex control in non-dialysis patients with CKD. In the present study we tested the hypothesis that baroreflex control of muscle sympathetic nerve activity (MSNA) is attenuated in non-dialysis patients with CKD. In 17 sedentary patients with CKD stages III-IV (76% hypertensive and 29% with diabetes) [12 male/5 female, age: 57 ± 13 yr, 13 Black/4 White, systolic/diastolic BP: 122 ± 17/75 ± 7 mmHg, BMI: 31 ± 5 kg/m2, eGFR: 40 ± 14 mL/min/1.73m2] and 9 controls (CON) (89% hypertensive and 22% with diabetes) [7 male/2 female, age: 51 ± 13 yr, 8 Black/1 White, systolic/diastolic BP: 123 ± 6/79 ± 6 mmHg, BMI: 30 ± 6 kg/m2, eGFR: 95 ± 12 mL/min/1.73m2], resting beat-to-beat blood pressure (finger photoplethysmography), heart rate (electrocardiography) and muscle sympathetic nerve activity (MSNA, microneurography) were continuously recorded during 10 min of semi-recumbent rest. Weighted linear regression analysis between MSNA burst incidence and diastolic blood pressure was used to determine the spontaneous sympathetic baroreflex sensitivity (sBRS). Resting MSNA burst incidence was higher in patients with CKD [CKD: 70 ± 19 bursts (100 heart beats)−1. mmHg−1 versus CON: 47 ± 9 bursts (100 heart beats)−1. mmHg−1; p<0.001], and a higher MSNA burst frequency was observed in CKD (CKD: 43 ± 11 bursts. min−1 versus CON: 32 ± 10 bursts. min−1; P=0.021], whereas resting mean arterial blood pressure (91 ± 9 mmHg versus 94 ± 5 mmHg; P=0.317) and heart rate were similar between groups. Patients with CKD had reduced sBRS compared to controls [CKD: -1.37 ± 0.59 bursts (100 heart beats)−1 mmHg−1 versus CON: -2.79 ± 1.33 bursts (100 heart beats)−1 mmHg−1; P=0.013]. The MSNA burst incidence (r = -0.63, p<0.001) and the sBRS (r = -0.57, P=0.002) were significantly associated with the estimated glomerular filtration rate (eGFR). Overall, these preliminary findings suggest an attenuated sympathetic baroreflex sensitivity in patients with CKD compared with age and-comorbidities matched controls, with greater impairment in those with more severe kidney dysfunction. This work was supported by National Institutes of Health Grants R01HL135183 and R61AT010457 (J.P). 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.

Potassium Ion Channel Modulation as a Potential Remedy for Cadmium-induced Hypertension

Objective: Hypertension remains a chief non-communicable lifestyle disease that is negatively associated with dietary cadmium (Cd). The exact mechanism of Cd toxicity and the mitigating role of potassium supplementation are not fully known, hence, this study aimed to investigate their effects on the aorta. Hypothesis: We hypothesized that potassium supplementation can modulate Cd-induced vascular dysfunction. Method: Six cohorts of control, Cd-exposed, and potassium supplemented male Sprague-Dawley rats were selected. Hypertension was induced using cadmium chloride (2.5 or 5 mg/kg b.w.). Blood pressure was measured twice weekly. Reactivity to pharmacological agents with and without potassium ion channel modulation was assessed in thoracic aortic rings after eight weeks, using an organ bath set-up. Data: Statistical analysis was done using one-way analysis of variance and the results were reported as mean ± standard error of the mean. The Games-Howell or Bonferroni post hoc test was used for multiple comparisons. Summary of Results: Cadmium significantly (p<0.05) elevated systolic, diastolic, mean arterial, and pulse pressures, reduced (p<0.001) phenylephrine-induced contraction mostly via BKCa channels, and augmented (p<0.05) sodium nitroprusside-induced relaxation via K-ATP, KV, and KIR channels, without affecting acetylcholine-induced relaxation. Potassium supplementation ameliorated these effects via KIR and BKCa channels. Conclusions: The results indicate that modulation of potassium ion channels in the vasculature might provide therapeutic management for environmentally-induced hypertension and should be further explored. Funding source: The Mona Campus Committee for Research and Publications and Graduate Awards, School for Graduate Studies and Research, University of the West Indies. 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.

Genetic Deletion of Carboxypeptidase N Attenuates Angiotensin II-Induced Hypertension and Target Organ Damage

Objectives: Kininase I transforms bradykinin and kallidin, into kinin B1 receptor (B1R) agonists des-Arg9-BK and des-Arg10-kallidin, respectively. Carboxypeptidase M (CPM) is the membrane bound isoform of kininase I and carboxypeptidase N (CPN) is the isoform located in the plasma. Activation of the B1R has been implicated in the development of hypertension, diabetes and atherosclerosis. Pharmacologic inhibition of kininase I is associated with reductions in B1R expression, inflammation, oxidative stress, and improvements in insulin resistance. B1R can interact with aminopeptidase N (CD13) or high-mobility group box 1 (HMGB1) to mediate an inflammatory response. However, the exact role of kininase I in the development of hypertension and the regulation of these B1R-mediated signaling mechanisms remains unknown. In this study, we hypothesize that gene deletion of CPN will prevent B1R activation, reduce inflammation via interfering with CD13 and HMGB1 signaling, and ultimately attenuate the progression of hypertension and target organ damage. Methods and Results: To test our hypothesis we utilized 12-week-old male and female C57BL/6NJ wild-type (WT) and CPN gene knockout (CPNKO) mice. These mice were infused angiotensin II (Ang II, 600 ng/kg/min) or saline (vehicle) via osmotic minipumps for 2 weeks. Vehicle treated CPNKO and WT mice showed no significant difference in mean arterial blood pressure (MAP) (104 ±7 vs 102 ±5 mmHg, n=5, p≤0.05). Ang II-induced elevations in MAP were significantly reduced in CPNKO mice compared to WT mice infused with Ang II (129 ±8 vs 150 ±6 mmHg, n=5, p≤0.05). Interestingly, we did not find any significant sex differences in MAP in CPNKO groups. Additionally, Ang II treatment significantly increased cardiomyocyte hypertrophy in male and female WT mice, but this effect was blunted in CPNKO mice (n=5, p≤0.05; wheat germ agglutinin staining). Ang II infusion promoted collagen deposition in the aorta of WT male and female mice, but not in CPNKO mice (n=5, p≤0.05; picrosirius red/Masson’s trichrome). In male WT mice, Ang II significantly increased the immunoreactivity of CPM in the heart, but this was abrogated in CPNKO mice infused with Ang II (n=4, p≤0.05). Similarly, B1R was also upregulated in male WT mice hearts when compared to CPNKO mice after Ang II infusions (n=3, p≤0.05). We also found that Ang II significantly increased HMGB1 and CD13 in male WT hearts and brains, but not in CPNKO mice (n=4, p≤0.05). In addition, oxidative stress levels in the brain were significantly increased by Ang II in WT mice and was attenuated in CPNKO mice (n=4, p≤0.05; dihydroethidium staining). Conclusions: Genetic deletion of CPN attenuates Ang II-induced hypertension by reducing B1R mediated reductions in CD13 and HMGB1-mediated inflammatory responses and oxidative stress. Our data suggests that targeting kininase I may be a novel therapeutic target for hypertension and target organ damage. Funding: This study was supported by NHLBI/NIH 5R01HL153115 (S. Sriramula). 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.

Sex differences in the regulation of salt appetite in Spontaneously Hypertensive Rats after loss of interoceptive input from the kidney

The average American consumes 3,400 mg/day of sodium, 1000mg over the American Heart Association’s recommended maximum daily allowance. Excessive salt intake accelerates the progression of many diseases including hypertension, congestive heart failure, and chronic kidney disease. Reducing sodium intake has beneficial effects on a population level and in at risk patients. In previous studies we have shown that afferent renal nerves are involved in the regulation of sodium intake in DOCA hypertensive rats. Like DOCA hypertensive rats, Spontaneously Hypertensive rats (SHR) are a model with increased salt appetite. Here, we tested the hypothesis that afferent renal nerves regulate sodium intake in SHR. Secondarily, it is well documented that estrogens modulate salt intake. To examine the effect of sex on sodium intake we compared salt-appetite between male and female SHR. Bilateral afferent renal denervation (ARDN) was performed using the periaxonal application of 33mM capsaicin. In sham rats the renal arteries were isolated but not treated. Mean arterial blood pressure (MAP) was assessed using radiotelemetry, with the catheter implanted in the femoral artery. Four groups of rats were studied: male SHR-sham (n=9), female SHR-sham (n=3), male SHR+ARDN (n=8) and female SHR+ARDN (n=4). All rats were given ad libitum access to two bottles, one containing dH2O and the other containing 1.8% NaCl. The bottle position was rotated, and fluid intake was recorded daily for 21-days. ARDN caused a significant reduction in 1.8% intake in female but not male SHR rats (p=0.02, female SHR-sham v female SHR-ARDN, p>0.99 male SHR v male SHR-ARDN). This effect was specific for saline intake, water intake was not altered by ARDN in the female SHR (p=0.3). The female SHR drank more saline than male SHR when normalized to body weight (p=0.04 female SHR-sham v male SHR-sham). MAP was not reduced by ARDN in the male SHR (p=0.39), and ongoing studies are examining MAP in response to ARDN in female SHR. The data presented demonstrate for the first time that ARDN decreases salt appetite in female but not male SHR. We also found that baseline saline intake was higher in female SHR than male SHR. In future studies we will examine the renal mechanisms underlying these sex differences. Together, these data suggest that reduced sodium intake may offer an additional therapeutic benefit of renal denervation in female patients with hypertension and cardiovascular disease. LE is funded by R01HL152166; ACV is funded by FAPESP. 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.

The rat telemetry assay and venous catheter access buttons for use in cardiovascular safety pharmacology assessments – Surgical methods, refinements and colony maintenance

IntroductionRat telemetry is the assay of choice to assess the potential effects of novel drug candidates on cardiovascular parameters during early drug discovery. Telemetry device implantation can be combined with venous catheter and access button implantation when intravenous administration of the drug substance is required. MethodsRats (Sprague Dawley or Han Wistar) were implanted with telemetry devices for arterial blood pressure measurement using either direct aortic catheterisation (n = 131) or aortic catheterisation via the femoral artery (n = 17). Bipolar leads for ECG recording were also implanted in some of the animals (n = 102). Femoral vein catheters and access buttons were implanted as a separate surgery after the initial telemetry implantation (n = 43). Results128 animals (86%) were implanted successfully with telemetry devices without any notable surgical or post-surgical problems. When considering the 2 different catheterisation methods separately, the success rate of the direct aortic approach was 88% compared to 76% with the aortic placement via the femoral artery. Lameness was the most common post-surgical problem. Blood loss during surgery and ischaemic patches on the tail were also observed at a low incidence with the direct aortic approach. Catheter pull-out occurred in some rats before the first signal check reducing the overall success rate for blood pressure measurement using the direct aortic approach to 85%. A 95% success rate was observed for catheter and access button implantation. DiscussionA high success rate is possible when implanting telemetry devices in rats with and without venous catheters and access buttons. We have attempted to provide solutions to problems and describe refinements to the procedure which may further improve surgical outcomes.

Antihypertensive effect of chicken blood peptide hydrolysate in streptozotocin-induced diabetic rats

Chicken blood peptide hydrolysate (CBH) has been reported to exert antioxidant, angiotensin 1-converting enzyme (ACE) inhibitory, and cholesterol-lowering activities. Antihypertensive effect of the CBPH was also demonstrated in spontaneously hypertensive rats. This study aimed to assess the anti-diabetic and antihypertensive effect of the CBH in streptozotocin (STZ)-induced diabetic rats. CBH was prepared from fresh chicken blood collected from an industrial slaughterhouse in Nakhon Ratchasima, Thailand. Adult male Wistar rats were randomly divided into 2 main groups: normal and STZ-induced diabetes mellitus (DM) groups. Five subgroups of each main group were given distilled water, metformin (200 mg/kg), and CBH (300, 600, 1200 mg/kg) by oral gavage for 28 days (n=10 per each group). Fasting blood sugar level and OGTT were evaluated before and at the end of experiment. Each rat underwent monitoring of blood pressure using femoral artery. STZ-induced diabetic rats showed higher fasting blood glucose concentration and area under curve from OGTT than normal rats, which was not reduced by all treatments. STZ-induced diabetic rats showed higher mean arterial blood pressure than normal rats, which was significantly reduced by metformin and CBH (300 and 1200 mg/kg) (p<0.05). The blood pressure-lowering effect of CBH suggested the potential for the application of CBH in the management of diabetic hypertension. However, attention must be paid to concerns about bird flu in certain places and prohibition of the use of blood product. This work was supported by Suranaree University of Technology (SUT), Thailand Science Research and Innovation (TSRI), and National Science Research and Innovation Fund (NSRF) (FF1-111-65-12-30(08)). 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.

Increased Oxygen Saturation Is Associated with Decreased Sympathetic Nervous System Activity in Individuals Given Bacteriotherapy at High Altitude

Exposure to low-oxygen conditions (hypoxia), as encountered at high altitudes and in some pathological conditions, results in the activation of various physiological stressors and acclimatization to hypoxia. Previous studies show that administration of a novel probiotic (SLAB51; O2BOOSTER; Hecto, Seoul, South Korea) improves oxygen saturation in severely hypoxemic COVID-19 patients and in healthy participants upon exposure to simulated and terrestrial hypobaric hypoxic. Whether SLAB51 impacts stress responses such as activation of the sympathetic nervous system during high-altitude exposure has not been evaluated. We hypothesized that SLAB51 treatment and the associated increase in oxygen saturation would reduce metrics of heart rate variability (HRV) at high altitude. Volunteers of Latino ancestry (n=17; eight women, nine men) were recruited and completed sea-level and high-altitude measurements (up to four days at the University of California White Mountain Barcroft Research Station, 12,470 ft / 3,801 m). Participants ingested either the SLAB51 probiotic or a placebo (randomized double-blind procedure) upon arrival and throughout their duration at altitude, and oxygen saturation (SpO2), electrocardiogram (EKG), mean arterial blood pressure (MABP), and heart rate (HR) measurements were collected during a fasted state each morning. We performed HRV analysis based on data from 10 minutes of resting EKG recordings, which included evaluations of low-frequency (LF) and high-frequency (HF) bands and their ratio (LF/HF) as an estimation of sympathetic activity. All values were compared between probiotic and placebo groups at high altitude (mean ± SEM). The two groups did not exhibit differences in LF/HF, MABP, and HR on any of the days spent at high altitude; however, during the first evening at high altitude when the treatment groups exhibited differences in SpO2 (separately reported), the probiotic group exhibited a non-significant trend of lower MABP relative to the placebo group (n = 5, 87.3 ± 2.5 and n = 4, 93.5 ± 3.5, respectively; p = 0.078). Additionally, higher SpO2 associated with lower MABP (R2 = 0.33) across all time points at high altitude in the probiotic group, but the opposite relationship was noted in the placebo group (R2 = 0.30). These data suggest potential differences in sympathetic nervous system activation in probiotic and placebo groups, a finding which warrants further investigation in a larger sample of individuals. SLAB51; O2BOOSTER; Hecto, Seoul, South Korea. 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.

Effects of Passive Cycling on Cerebrovascular Reactivity in Acute Brain Injured Patients: A Pilot Study

IntroductionEarly mobilization benefits critically ill patients, but concerns persist, especially in neurologic intensive care unit patients with acute brain injuries. This study assesses early mobility's impact on cerebrovascular autoregulation (CA) and systemic hemodynamics. MethodsThis single-center retrospective study focused on adult neurologic intensive care unit patients undergoing passive cycle ergometry. Data were collected from December 2020 to April 2022. Physical therapists conducted sessions using a standardized protocol, monitoring mean arterial blood pressure (MAP) and intracranial pressure (ICP). The Pressure Reactivity Index (PRx) was calculated as a measure of CA. Statistical analysis included mixed models and repeated measures ANOVA. ResultsEleven patients undergoing continuous physiologic monitoring and early mobility were included, primarily with subarachnoid hemorrhage or intracranial hemorrhage. Median time to protocol initiation was 4 days, with two patients discontinuing due to hemodynamic disturbances. Over a total of 11-hours of neuromonitoring data, passive cycling demonstrated a significant reduction in in heart rate (HR), MAP, and ICP across different rotations per minute (RPM) settings compared to baseline. No significant alterations in PRx or cerebral perfusion pressure (CPP) were noted at various RPM levels. However, a significant difference in PRx emerged between patients who completed the protocol and those who did not, particularly at 10 RPM. DiscussionThis study offers preliminary insights into the impact of early mobility on CA in acute brain injured patients. While passive cycling demonstrates promise in preserving cerebral hemodynamics, its tolerability may not be uniform across all brain-injured patients. These findings highlight the need to determine optimal early mobilization timing and intensity in this population, emphasizing the necessity for larger prospective studies to validate these findings and inform clinical practice. DetailsThis manuscript complies with all instructions to the authors. All coauthors meet the authorship requirements and have reviewed and approved the contents of the manuscript. The manuscript has not been published totally or partly, accepted for publication, or under editorial review for publication elsewhere. We have no conflicts of interest to disclose. STROBE checklist was reviewed prior to the submission of this paper. The manuscript adheres to ethical guidelines and was approved by Cleveland Clinic’s institutional research board for retrospective study. There is no funding to disclose for this study.

Pulmonary Events in ICU patients with hyperoxia: is it possible to relate arterial partial pressure of oxygen to coded diseases? A retrospective analysis

ObjectiveOxygen has been used liberally in ICUs for a long time to prevent hypoxia in ICU- patients. Current evidence suggests that paO2 >300 mmHg should be avoided, it remains uncertain whether an “optimal level” exists. We investigated how “mild” hyperoxia influences diseases and in-hospital mortality. DesignThis is a retrospective study. Setting112 mechanically ventilated ICU-patients were enrolled. Patients or participants112 ventilated patients were included and categorized into two groups based on the median paO2 values measured in initial 24 h of mechanical ventilation: normoxia group (paO2 ≤ 100 mmHg, n = 43) and hyperoxia group patients (paO2 > 100 mmHg, n = 69). InterventionsNo interventions were performed. Main variables of interestThe primary outcome was the incidence of pulmonary events, the secondary outcomes included the incidence of other new organ dysfunctions and in-hospital mortality. ResultsThe baseline characteristics, such as age, body mass index, lactate levels, and severity of disease scores, were similar in both groups. There were no statistically significant differences in the incidence of pulmonary events, infections, and new organ dysfunctions between the groups. 27 out of 69 patients (39.1%) in the “mild” hyperoxia group and 12 out of 43 patients (27.9%) in the normoxia group died during their ICU or hospital stay (p = 0.54). The mean APACHE Score was 29.4 (SD 7.9) in the normoxia group and 30.0 (SD 6.7) in the hyperoxia group (p = 0.62). ConclusionsWe found no differences in pulmonary events, other coded diseases, and in-hospital mortality between both groups. It remains still unclear what the "best oxygen regime" is for intensive care patients.

Protective effects of Dioscin against sepsis-induced cardiomyopathy via regulation of toll-like receptor 4/MyD88/p65 signal pathway.

Dioscin has many pharmacological effects; however, its role in sepsis-induced cardiomyopathy (SIC) is unknown. Accordingly, we concentrate on elucidating the mechanism of Dioscin in SIC rat model. The SIC rat and H9c2 cell models were established by lipopolysaccharide (LPS) induction. The heart rate (HR), left ventricle ejection fraction (LVEF), mean arterial blood pressure (MAP), and heart weight index (HWI) of rats were evaluated. The myocardial tissue was observed by hematoxylin and eosin staining. 4-Hydroxy-2-nonenal (4-HNE) level in myocardial tissue was detected by immunohistochemistry. Superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) activities in serum samples of rats and H9c2 cells were determined by colorimetric assay. Bax, B-cell lymphoma-2 (Bcl-2), toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), phosphorylated-p65 (p-p65), and p65 levels in myocardial tissues of rats and treated H9c2 cells were measured by quantitative real-time PCR and Western blot. Viability and reactive oxygen species (ROS) accumulation of treated H9c2 cells were assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and dihydroethidium staining assays. Dioscin decreased HR and HWI, increased LVEF and MAP, alleviated the myocardial tissue damage, and reduced 4-HNE level in SIC rats. Dioscin reversed LPS-induced reduction on SOD, CAT, GSH, and Bcl-2 levels, and increment on Bax and TLR4 levels in rats and H9c2 cells. Overexpressed TLR4 attenuated the effects of Dioscin on promoting viability, as well as dwindling TLR4, ROS and MyD88 levels, and p-p65/p65 value in LPS-induced H9c2 cells. Protective effects of Dioscin against LPS-induced SIC are achieved via regulation of TLR4/MyD88/p65 signal pathway.

Microvascular development and remodeling

Skeletal fragility is an important complication of Type 1 Diabetes (T1D), particularly among older adults. Microvascular disease (MVD) has been linked to worse bone health in T1D, suggesting a potential direct pathophysiologic link between vascular disease and bone deficits. However, bone vascular control has not been explored in the context of T1D. Thus, this preliminary work investigates key mechanisms of regulation of the bone vasculature in older adults with T1D. Myogenic vasoconstriction and reactive hyperemia of tibial blood flow were assessed in older healthy adults (n=9, 65 ± 7 yrs) and older adults with T1D (n=10, 63 ± 6 yrs). Myogenic vasoconstriction was assessed in response to leg dependency (two levels of increased arterial transmural pressure obtained by lowering the leg below heart level) and reactive hyperemia was assessed in response to lower leg arterial occlusion via thigh cuff inflation. The initial peak reactive hyperemic response was considered a surrogate of myogenic vasodilation. For both stimuli, tibial blood flow was assessed via NIRS as total hemoglobin (tHb) and whole leg blood flow velocity (LBF) in the popliteal artery of the same leg was measured via Doppler ultrasound. Data are presented as mean±standard error. In response to leg dependency, with increased perfusion pressure, older adults had a tendency for smaller declines in LBF (L1: -3.85 ± 2.01 cm/s; L2: -6.22 ± 4.19 cm/s) compared to older adults with T1D (L1: -6.14 ±2.24 cm/s; L2: -10.4 ± 1.90 cm/s; group p=0.06, level p=0.07). Tibial tHb did not decline in older adults (L1: 1.16 ± 7.27 M; L2: 9.11 ± 13.8 M), but decreased progressively in those with T1D (L1: - 3.40 ± 2.79 M, L2: -6.14 ± 2.24 M, group p<0.01, group*level p=0.07), indicating pronounced tibial myogenic vasoconstriction. In response to reactive hyperemia, LBF increased rapidly with cuff release in both groups (older adults: 50.8 ±22.7cm/s; T1D: 40.0 ± 13.4cm/s). Despite similar responses in LBF, tibial tHb surpassed baseline values in older adults (1.50 ± 5.35M), whereas tibial tHb did not reach baseline values within 5 min post cuff release in T1D (-2.85 ± 5.09M, p=0.09), indicating impaired tibial myogenic vasodilation. Interestingly, older adults with T1D and MVD (n=5) had a stronger tendency for greater tibial myogenic vasoconstriction at both levels and significantly impaired reactive hyperemic response compared to those with no MVD (n=5). Our preliminary results indicate that older adults with T1D have greater myogenic vasoconstriction and impaired reactive hyperemic responses that appear to be worse in the presence of MVD. Alterations in myogenic control act to compromise blood flow regulation, restricting blood flow to bone, and potentially contributing to diabetes-inducted skeletal fragility. NIH NIDDK R01 DK124710. 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.

Antidiabetic activity of egg white protein hydrolysate in streptozotocin-induced diabetic rats

Egg white protein hydrolysate (EWH) has been reported to work as a cardiovascular protective agent. EWH exert antioxidant, vascular relaxing, anti-inflammatory properties and antihypertensive properties. This study aimed to assess the anti-diabetic and antihypertensive effect of the EWH in streptozotocin (STZ)-induced diabetic rats. Adult male Wistar rats were randomly divided into 2 main groups: normal and STZ-induced diabetes mellitus (DM) groups. Five subgroups of each main group were given distilled water, metformin (200 mg/kg), and EWH (300, 600, 1200 mg/kg) by oral gavage for 28 days (n=10 per each group). Fasting blood sugar level and OGTT were evaluated before and at the end of experiment. Each rat underwent monitoring of blood pressure using femoral artery. STZ-induced diabetic rats showed higher fasting blood glucose concentration and area under curve from OGTT than normal rats, which was significantly reduced by 600 mg/kg of EWH (p<0.05). STZ-induced diabetic rats showed higher mean arterial blood pressure than normal rats, which was significantly reduced by metformin (p<0.05). A decrease in hypertension in STZ-induced diabetic rats following EWH, but without significant difference, was observed. EWH may be useful in controlling the blood glucose level in diabetes mellitus and is therefore recommended for further studies. This work was supported by Suranaree University of Technology (SUT), Thailand Science Research and Innovation (TSRI), and National Science Research and Innovation Fund. (NSRF) (FF1-111-65-12-30(08)). 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.

Progesterone Supplementation Improves the Maternal Syndrome of Superimposed Preeclampsia in the Dahl Salt Sensitive Rats

Introduction: Preeclampsia (PE) is characterized by new onset of hypertension after 20 weeks of gestation. It affects 5-7% of all pregnancies in the U.S., and is associated with reduced fetal weight, inflammation and hypertension (HTN). Importantly, 30% of HTN disorders in pregnancy are caused by chronic HTN that is present prior to pregnancy which increases the risk of superimposed PE (SIPE). The mechanisms responsible for the pathogenesis of PE and SIPE are unclear and currently the only treatment is early delivery of the fetus. Progesterone is important for the establishment and maintenance of pregnancy. We have previously shown that progesterone supplementation with 17-hydroxyprogesterone caproate (17-OHPC) improves inflammation, fetal weight and blood pressure in the preclinical RUPP rat model of PE, however the mechanism for this in SIPE is still unknown. Hypothesis: This study was designed to test the hypothesis that 17-OHPC reduces inflammation while improving maternal blood pressure in the preclinical pregnant Dahl Salt Sensitive (DS) rat model of SIPE. Methods: 17-OHPC (3.32mg/kg) or vehicle (Saline) was administrated intraperitoneally on gestation day (GD) 15 to normal pregnant (NP) Sprague-Dawley (SD) and pregnant Dahl Salt Sensitive (DS) rats. On GD 18, Uterine Artery Resistance Index (UARI) was measured by Vevo Doppler Ultrasound and carotid catheters were inserted. On GD 19, mean arterial blood pressure (MAP) and samples were collected. All data are expressed as mean ± standard error means (SEM). Results: MAP was 105±5 mmHg in SD+ Saline rats (n=7) and 105±4 mmHg in SD+17-OHPC rats (n=4), 137±3 mmHg in DS + Saline rats (p<0.05, n=11), which improved to 125±4 mmHg in DS+17-OHPC rats (p<0.05, n=7). Pup and Placenta weights were 2.1± 0.1 g, 0.6 ± 0.1 g in SD + saline rats and significantly reduced to 1.4±0.1 g, 0.5±0.1 g in DS+ Saline rats (p<0.05). Neither placental weight nor pup weight was affected by 17-OHPC. UARI was 0.5 ±0.1 in SD+ Saline rats (n=6) and 0.5 ±0.1 in in SD+17-OHPC (n=4), 0.7±0.1 in DS+Saline rats (n=6, p<0.05), which reduced to 0.5±0.1 in DS+17-OHPC (n=7, p<0.05). TNF-alpha levels were 3.0±1.0 pg/mL in SD+ Saline rats, 11.0±1.2 in DS + Saline rats, which reduced to 4.1±1.6 in DS+17-OHPC (n=4, p<0.05). Importantly, circulating and placental CD4+ T cells were 9.3±3.7 % Gate and 6.4± 1.6 % Gate in SD+ Saline rats (n=4), 38.9 ±2.9 % Gate and 33.1±4.3 % Gate in DS + Saline rats (n=6), which significantly reduced to 26.3 ± 0.1 % Gate and 3.4±1.2 % Gate in DS + 17-OHPC. Conclusion: Collectively, our findings demonstrate that 17-OHPC reduces inflammation and hypertension in the Dahl Salt Sensitive rat model of SIPE. Supported by NIH P20GM121334. 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.

Finger photopletysmography detects early acute blood loss in compensated blood donors: a pilot study

Objective. Diagnosis of incipient acute hypovolemia is challenging as vital signs are typically normal and patients remain asymptomatic at early stages. The early identification of this entity would affect patients’ outcome if physicians were able to treat it precociously. Thus, the development of a noninvasive, continuous bedside monitoring tool to detect occult hypovolemia before patients become hemodynamically unstable is clinically relevant. We hypothesize that pulse oximeter’s alternant (AC) and continuous (DC) components of the infrared light are sensitive to acute and small changes in patient’s volemia. We aimed to test this hypothesis in a cohort of healthy blood donors as a model of slight hypovolemia. Approach. We planned to prospectively study blood donor volunteers removing 450 ml of blood in supine position. Noninvasive arterial blood pressure, heart rate, and finger pulse oximetry were recorded. Data was analyzed before donation, after donation and during blood auto-transfusion generated by the passive leg-rising (PLR) maneuver. Main results. Sixty-six volunteers (44% women) accomplished the protocol successfully. No clinical symptoms of hypovolemia, arterial hypotension (systolic pressure < 90 mmHg), brady-tachycardia (heart rate <60 and >100 beats-per-minute) or hypoxemia (SpO2 < 90%) were observed during donation. The AC signal before donation (median 0.21 and interquartile range 0.17 a.u.) increased after donation [0.26(0.19) a.u; p < 0.001]. The DC signal before donation [94.05(3.63) a.u] increased after blood extraction [94.65(3.49) a.u; p < 0.001]. When the legs’ blood was auto-transfused during the PLR, the AC [0.21(0.13) a.u.; p = 0.54] and the DC [94.25(3.94) a.u.; p = 0.19] returned to pre-donation levels. Significance. The AC and DC components of finger pulse oximetry changed during blood donation in asymptomatic volunteers. The continuous monitoring of these signals could be helpful in detecting occult acute hypovolemia. New pulse oximeters should be developed combining the AC/DC signals with a functional hemodynamic monitoring of fluid responsiveness to define which patient needs fluid administration.

Enteral Protease Inhibition Preserves Aortic Ultrastructure and Mechanics in Experimental Trauma/Hemorrhagic Shock

Introduction: Vascular compliance of large arteries is often overlooked in acute trauma/hemorrhagic shock (T/HS), as standard interventions, such as vasopressors, typically target systemic vascular resistance (SVR) regulated by small arterioles. However, patients may become refractory to vasopressors, and efforts to raise SVR may not restore mean arterial blood pressure (MAP), which is crucial for organ perfusion. We have previously reported compromised vascular compliance after T/HS in vivo with increased pulse wave velocity and ex vivo with diminished circumferential distensibility, that were both partially mitigated by enteral serine protease inhibition. To further elucidate the mechanisms behind these adverse changes, our aim was to directly assess the material stiffness, extracellular matrix (ECM) morphology, and matrix metalloproteinase (MMP) activity within the aortic wall tissue after T/HS, as well as to evaluate the effectiveness of enteral protease inhibition in this context.Methods: Anesthetized Wistar rats (350 - 400g) underwent laparotomy (trauma) and exsanguination to maintain a MAP of 35-40 mmHg for 90 minutes (shock). Animals were randomly assigned to receive either enteral gabexate mesilate protease inhibitor treatment (GM-treated) or vehicle-only (Untreated) via an orally-inserted catheter; investigators were blinded to the treatment assignation. At the conclusion of the shock period, animals were resuscitated with intravenous Lactated Ringer’s solution (LR) for two hours to achieve and maintain a MAP of at least 60 mmHg. A sham control group was also included for comparison. In all groups, the thoracic aorta was bisected, with one half sectioned for atomic force microscopy and histology and the other half homogenized for gelatin zymography. Liquid-phase force mapping was conducted on random areas (1600 μm2) of the medial layer in triplicate to determine the average Young’s modulus of the tissue. Collagen fibers were stained with picrosirius red, and elastin fibers were stained with Verhoeff Van Gieson. Results: After being subjected to T/HS and LR reperfusion, the aortic media of the Untreated group had a significantly higher average Young’s modulus than that of healthy sham vessels (862.7 kPa vs. 556.5 kPa, p &lt; 0.05). The GM-treated group, however, better preserved its material elasticity (~650 kPa). These stiffness values negatively correlate with corresponding animals’ final MAP values measured at the end of the reperfusion period (r2 = 0.5031), supporting an association between vascular compliance and hemodynamic stability. The area of collagen within the tunica media was found to be significantly decreased in the Untreated compared to the sham group (4.93% vs. 10.26%, p &lt; 0.05), but GM treatment was able to prevent collagen degradation (8.48%). Disruptions in elastin fibers were also observed at a higher frequency in the Untreated T/HS aorta compared to sham controls (3.3 vs. 1.7, p &lt; 0.05) or GM-treated aortas (3.3 vs. 1.6, p &lt; 0.05). Gelatin zymography revealed that enteral GM treatment also significantly attenuated elevated plasma MMP-9 (0.85 vs. 1.97 A.U., p &lt; 0.01) and tissue MMP-2 activity (0.86 vs. 1.80 A.U., p &lt; 0.05) seen following T/HS. Conclusions: Fluid-resuscitated traumatic hemorrhagic shock resulted in ultrastructural and biomechanical alterations in the aorta, indicating a loss in compliance. Enteral gabexate mesilate treatment effectively mitigated these pathological changes to the vasculature, suggesting the potential involvement of serine proteases in aortic ECM remodeling and large artery dysfunction in T/HS. Interventions against central artery impairment may be a promising strategy for improving blood pressure and survival in circulatory shock. Department of Defense Award W81XWH-17-2-0047. 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.

Deletion of irisin exacerbate cardiac dysfunction and increase inflammatory response in hemorrhage

Introduction: Irisin plays an important role in regulating tissue stress, cardiac function, and inflammation. The objective of this study is to investigate whether deletion of irisin would exacerbate hemorrhage induced cardiac depression and inflammatory response. Method: Irisin knockout mice was generated by using the CRISPR/Cas-9 genome-editing system. Hemorrhage was induced in mice by achieving a mean arterial blood pressure of 35-45 mmHg for one hour, followed by two hours of resuscitation. Experimental groups were divided as followings: I) WT+Hemorrhage (control, n=6): WT mice were subjected to hemorrhage for 60 minutes followed by resuscitation; II) Irisin −/− +Hemorrhage (n=6): Irisin −/− mice underwent hemorrhage and resuscitation; III) WT +Hemorrhage+Irisin (n=8): The same as the group I except that irisin (50ng/kg) was infused during resuscitation; IV) Irisin −/− +Hemorrhage+ Irisin (n=7): The same as the groups III except that Irisin −/− was used. Cardiac function and hemodynamics were measured using echocardiography and femoral artery catheterization. Systemic cytokine releases were measured using Enzyme-linked immunosorbent assay (ELISA). Histological analyses were used to determine tissue damage in myocardium and skeletal muscles. TUNEL was carried out to assess apoptosis in tissues. Results: As compared to wild type mice, irisin knockout mice attenuated the cardiac function and recovery of hemodynamics, which was associated with the increased release of IL6 and TNF-α in hemorrhage. The infiltration of inflammatory cells and TUNEL positive apoptosis in muscles were increased by deletion of irisin. Irisin treatment demonstrated the profound protection against hemorrhage-induced detrimental effect as compared to control. Furthermore, re-infusion of irisin into irisin-knockout mice rescued mitigated the detrimental effect in hemorrhage by deletion of irisin. Conclusion. Deletion of irisin exacerbate hemorrhage induced cardiac depression and inflammatory response, suggesting critical protection of irisin in modulating hemorrhage. National Institute of General MedicalSciences (R01GM 141339); National Heart, Lung, andBlood Institute Grants (R01 HL089405). 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.

Assessment of the effect of gabapentin on blood pressure in cats with and without chronic kidney disease.

The aim of the present study was to assess the effect of gabapentin on blood pressure (BP) in cats with and without chronic kidney disease (CKD). A randomized, blinded, placebo-controlled crossover study was performed. A total of 29 cats were included: 13 cats with stable CKD (IRIS stage 2-4) and 16 apparently healthy cats (serum creatinine <1.6 mg/dl and urine specific gravity >1.035). The cats were evaluated twice, approximately 1 week apart, and BP (Doppler sphygmomanometry) was obtained 3 h after cats received either a single dose of gabapentin 10mg/kg PO or placebo. For each cat, BP readings were obtained at each visit using the same Doppler and sphygmomanometer unit, and the same cat holder and Doppler operator, in the same location. After administration of a single dose of gabapentin (10 mg/kg PO), BP was significantly lower (median 122 mmHg, range 82-170) than after administration of the placebo (median 150 mmHg, range 102-191; P = 0.001). In the CKD subgroup, BP was significantly lower after administration of gabapentin (median 129 mmHg, range 96-170) than after administration of the placebo (median 155 mmHg, range 102-191; P = 0.008). In the healthy cat subgroup, BP was significantly lower after administration of gabapentin (median 121 mmHg, range 82-139) than after administration of the placebo (median 137 mmHg, range 102-177; P = 0.002). The median change in BP was -12 mmHg (range -95 to 10) for healthy cats and -12 mmHg (range -43 to 21) for cats with CKD (no significant difference between subgroups). Gabapentin may decrease arterial BP in cats with and without CKD and these findings should be taken into account when gabapentin is administered to patients in which measurement of BP is needed.