Artery Catheter Research Articles

Acute stress augments obstructive apneas and related O2-desaturations in urethane-anesthetised rats via disruption of cholinergic modulation

Obstructive sleep apnea (OSA) is a multifactorial respiratory disorder affecting nearly 1 billon of adults worldwide. Anomalies in respiratory control during sleep contribute to airway obstructions and recurrent desaturations; however, the origins of the problem are not well known. Stress disrupts brain function and increases the risk of OSA co-morbidities, including hypertension and obesity. Because, hypothalamic structures regulating the stress response also project to medullary areas regulating cardiorespiratory function and airway motor control, we hypothesised that exposure to a single stress session is suffcient to induce cardiorespiratory disturbances associated with OSA. Experiments were performed in urethane-anesthetised rats; this approach allows sleep-like brain state alternations with significant reductions in upper airway (genioglossus; GG), but not diaphragmatic (DIA), muscle tone during the transition from NREM-like to REM-like states. Adult male rats were either subjected to a 90 min session of immobilisation stress (n = 21) or handled briefly by the experimenter (n = 18). 24h later, rats were anesthetised (urethane, 1.6 g/kg; i.v.) and instrumented to monitor DIA and GG EMG. O2 saturation was measured by pulse oximetry (S pO2). Blood pressure was measured by an arterial catheter. Rats were placed in a supine position and respiratory airflow was measure by a temperature probe near the nares. Obstructive apneas were identified by the absence of airflow in the presence of DIA activity with a S pO2 drop greater than 3%. Stress did not affect distribution of sleep-like states or the state-related changes in phasic GG activity. However, stress augmented the incidence of obstructive apneas (0.5 vs 2.2 events/h; p = 0.05) and doubled the severity of desaturations associated with apneas (-6% vs -12% drop; p = 0.03). Pre-treatment with atropine (0.5 mg/kg) reduced obstructive apneas (drug effect: p = 0.04). Atropine blocked apnea-related O2 desaturations in stressed but not controls (apnea x stress x atropine: p = 0.04). Atropine treatment augmented GG activity; this effect was greater in NREM-like state, especially in stressed rats (atropine x state x stress: p = 0.05). We conclude that, in urethane anesthetised rats, stress disrupts cardiorespiratory control in ways that favor significant obstructive apneas. Disruption of cholinergic modulation of GG activity and cardiovascular function likely contributes to this process. These data point to an important factor in the onset of OSA. While the frequency of apneas was modest we propose that recurrent exposure to stressors or more significant events will worsen the condition over time. Supported by the Canadian Institutes of Health Research and the Foundation of the Québec Heart & Lung Institute. 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.

Renal Function and Survival are Reduced in a Polytrauma Acute Radiation Injury Rat Model with Extremity Trauma and Hemorrhage

The objective of this study was to evaluate whether the presence of radiation injury (RI) decreases survival in an established model of battlefield trauma and hemorrhage in rats. We hypothesized that the addition of radiation to our established traumatic hemorrhage model would increase mortality. Methods: On day zero (D0), male Sprague Dawley rats (n=6/group) received Buprenorphine SR prior to being anesthetized with isoflurane to perform catheterization of a carotid artery. Twenty-four hours later (day 1 or D1), rats were randomly assigned to 1 of 4 groups: 1- sham (no injury; no radiation); 2- RI only; 3- traumatic hemorrhage alone (ET+HEM); or 4- RI combined with traumatic hemorrhage (RI+ET+HEM). For RI and RI+ET+HEM groups, rats were anesthetized and placed inside a cabinet X-ray irradiator (MultiRad 350, Precision, CT) to receive a single sub-lethal X-ray dose of 5.5 Gy, delivered at 1 Gy/min, to induce acute radiation injury. For ET+HEM and RI+ET+HEM groups, under isoflurane, rat then received a unilateral extremity trauma injury. After 90 minutes, a conscious hemorrhage of 37% of the rat estimated blood volume was withdrawn. Rats were monitored for 14 days following injury or sham procedures and provided Buprenorphine SR as needed for pain. Rats remained un-resuscitated and renal function was assessed in vivo by glomerular filtration rate (GFR). GFR was measured with a probe non-invasively and securely strapped to the belly of the rat for about 2.5h. Samples for GFR were collected on D1, day 3 (D3), and day 15 (D15) (or terminal day) from the injury. Result: Sham rats had 100% survival at D15, while RI and ET+HEM rats both had 50% mortality. RI+ET+HEM rats, however, demonstrated 100% mortality by D15; differences in survival proportions were significant (P=0.005). Sham rats showed no significant decrease in GFR (1.0-1.2 ml/min/100g) from D1 to D15. Rats from RI group showed a slight decrease in GFR from D1 to D3 (1.2 to 0.9 ml/min/100g, respectively) at the D3 of measurement. By D15, GFR was 33% lower than D1 in RI group. ET+HEM group showed significant decline in GFR on D1 and D3. However, RI+ET+HEM group showed the most significant decline in GFR ( i.e., >50% lower than sham group on D1 and D3), with little to no improvement over time. Conclusion: We developed a new rodent model of RI+ET+HEM by combining high dose of X-ray irradiation with traumatic hemorrhage, which allows acute (hours) as well as chronic (days) observation. While RI or ET+HEM alone produced significant mortality, the combination of traumatic hemorrhage with RI increased mortality to 100% before D15. Radiation injury combined with extremity trauma and hemorrhage results in significant impairment of renal function. Extremity trauma and hemorrhage impaired renal function more than radiation injury alone. Disclaimer: The views expressed in this abstract are those of the author(s) and do not reflect the offcial policy or position of the U.S. Army Medical Department, Department of the Army, DoD, or the U.S. Government. Supported by Biomedical Advanced Research and Development Authority (BARDA). 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.

Increases of renal sodium transporters before and after the occurrence of the hypertension in spontaneously hypertensive rats

Background: Adult spontaneously hypertensive rats (SHR) have increases of renal sodium transporters associated with hypertension. It remains to be determined whether the increases of renal sodium transporters are precede by occurrence of hypertension and reflected by urine exosomal sodium transporters that may serve as non-invasive biomarkers for the effcacy of anti-hypertensive drugs. Methods: 1. Male WKY rats and SHRs were aged of 4, 7 and 10 weeks respectively (n=5/group). 2. Additional 3 sets of 10-week-old rat (n=5/group) were administered by a 7-day intraperitoneal injections of furosemide (NKCC2 inhibitor, 5mg/kg), hydrochlorothiazide (NCC2 inhibitor, 30mg/kg) and amiloride (ENaC inhibitor, 10mg/kg) respectively. 3. The systolic blood pressure (SBP) was measured with a catheter in carotid artery of rats under anesthesia. Tail-cuff methods were used to monitor the drug responses. 4. All rats were rationally fed 0.4% NaCl agar-gelled diet for 7 days. 5. Exosomes were extracted with ultracentrifuge from the urines. Results: SHRs (4 weeks) exhibited similar SBP. The renal NKCC2, the major apical sodium transporters in thick ascending limb, was more than doubled in SHRs (215±14 % of WKY, student t-test, p<0.05, same as below) while the other sodium transporters were normal. However, SHRs had a higher SBP than WKY at ages of 7 (157±10 vs 125±14, mmHg) and 10 weeks (192±8 vs 128±12). There were no differences for the all age groups in heart rate, body weight, urine volume, urine Na+ and Cl− excretion, and serum Cr, K+, Na+, and Cl− concentration between rat strains. At 10-weeks old, renal (161±24) and urine exosomal (159±21, corrected by UCr, same as below) NKCC2 were higher in SHR than WKY. Frusemide normalized SBP on day 1 (day 0: 190±18 vs 138±13; day 1: 149±13 vs 128±16) in SHR; Renal (129±9) and urine-exosomal (137±12) NCC were higher in SHR than WKY. Hydrochlorothiazide normalized SBP in SHR on day 1 (day 0: 206±4 vs 140±9; day 1: 159±11 vs 144±11). Renal (α:134±16; β:137±25) and urine-exosomal (α:153±13; β:158±12) ENaCs were higher in SHR than WKY. Amiloride diminished the difference in SBP between rat strains on day 1 (day 0: 188±18 vs 138±11; day 1: 164±16 vs 147±7). Conclusions: The increase of renal NKCC2 precedes the elevation of SBP in SHRs. Urine exosomal NKCC2, NCC, ENaCs may reflect their renal levels and be indicative of the corresponding inhibitors on the hypertension model. Natural Science Foundation of China 81970605. 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.

Microcirculatory Evaluation of Crystalloids, Fresh Frozen Plasma, Hemoglobin Based Oxygen Carriers, and Pack Red Blood Cells in Trauma Hemorrhagic Shock

Introduction: The prehospital management of traumatic injuries has significantly evolved since the establishment of emergency medical services in the 1970s. Initially focused on using crystalloid solutions, experiences in military and civilian trauma care have shifted towards balanced blood components for immediate blood replacement, known as remote damage control resuscitation (RDCR). This shift led to the adoption of prehospital transfusion, with packed red blood cells (pRBC) showing increased survival rates upon hospital arrival but no overall increase in survival. Additionally, fresh frozen plasma (FFP) and its timing of administration remain controversial. The development of hemoglobin-based oxygen carriers (HBOCs) aims to rival blood products, offering logistical advantages and potential to replace pRBC and FFP in challenging accessibility scenarios. This study investigates HBOCs' effcacy during hemorrhagic shock, hypothesizing their comparability to crystalloids, pRBC, and FFP in microcirculatory function. Methods:. To study the effcacy of HBOCs during hemorrhagic shock, Golden Syrian hamsters were instrumented with a dorsal window chamber, and catheters in the left common carotid artery, the animals were hemorrhaged for 50% of their blood volume (estimated as 7% of body weight) and resuscitated with 25% of their blood volume with LR, FP, HBOC, or pRBC. Shock was monitored for 30 minutes while resuscitation was monitored for 1 hour. Microvascular perfusion was characterized by vessel diameter, flow, and functional capillary density. Systemic variables were characterized as mean arterial pressure (MAP), heart rate (HR), and blood chemistry. Results: Across all animals, the baseline mean arterial pressure (MAP) and heart rate (HR) averaged 112.69 ± 11.16 mmHg and 404.44 ± 45.78 beats per minute (BPM), respectively. During shock, these values decreased to 50.76±11.57 mmHg and 379.36±60.49 BPM. Post-resuscitation using LR, FP, or HBOC, the MAP showed increases of 12%, 20%, and 44%, respectively. However, there were no significant changes observed in the HR. The HBOC group notably demonstrated the most substantial increase in MAP following shock. Arteriole diameter, both less than and greater than 60 μm, did not reveal any statistically significant differences between the HBOC group, except for the pRBC group, which showed larger diameters than the HBOC group after an hour post-resuscitation in arterioles < 60 μm. The arteriole flow in the HBOC group averaged a flow rate of 2.42 nL/s, compared to LR (0.13 nL/s), FP (1.30 nL/s), and pRBC (3.64 nL/s) in arterioles > 60 after an hour post-resuscitation, showing similar statistically significant differences in the HBOC group after the 60-minute post-resuscitation period. Conclusion: HBOCs exhibit promising potential as a resuscitation fluid for immediate blood replacement, not only due to their logistical advantages over blood component therapy but also for their ability to maintain more stable MAPs and better blood flow through small arterioles compared to component therapies. Project number: R01HL159862 Project number: R01HL162120. 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.

Metformin as an alternative therapeutic intervention in hemorrhagic shock

Hemorrhagic shock (HS) continues to significantly contribute to civilian and military mortality, underscoring the critical need for new resuscitation strategies. Recent discussions have emphasized the pivotal role of impaired oxygen delivery and cellular metabolism in exacerbating HS-related damage. Metformin, a well-established diabetes medication, exhibits promising potential to enhance cellular metabolism and activate pathways linked to improved oxygen uptake, thereby optimizing cellular energy management. Thus, this study aimed to assess metformin's effcacy in ameliorating outcomes in animals subjected to HS. To achieve this, Wistar rats were surgically prepared with femoral artery and vein catheters. HS was induced by controlled blood withdrawal to maintain a mean arterial pressure (MAP) within the range of 35-40 mmHg for 90 minutes. Throughout the protocol, blood pressure (BP) and heart rate (HR) were assessed. The animals were divided into two groups: Lactated Ringer's solution (LR) and LR treated with Metformin (Met). Metformin was administered in three bolus injections: at the start of resuscitation (10mg), 45 minutes into resuscitation (5mg), and 90 minutes into resuscitation (5mg). After 120 minutes, the animals were euthanized, and blood samples were collected for subsequent analysis, including metabolomic profiling of the tricarboxylic acid (TCA) cycle, amino acids, and lipids. Additionally, trypsin-like enzyme activity in the plasma and markers of brain injury were evaluated. Animals treated with Met showed significantly higher systolic blood pressure after resuscitation (LR: 74±5 mmHg vs. LR+Met: 94±3 mmHg) with no significant changes in HR observed. Brain injury markers such as GFAP (Glial fibrillary acidic protein), S100B (astrocytic protein specific to the central nervous system), Tau (microtubule-associated protein), and NFL (axonal protein neurofilament light) were assessed. Animals reperfused with LR and treated with Met displayed a 22% reduction in GFAP levels compared to those reperfused with LR alone, while other markers remained unchanged. Met treatment also led to a reduction in plasmatic metabolites, including Lactate (30%), Succinate (24%), and Fumarate (22%), along with an increase in Citrate (23%) and α-ketoglutarate (24%)—all constituents of the TCA cycle. Additionally, an increase in amino acid metabolites and a decrease in lipid metabolites were observed. Recent research has suggested that HS results in elevated levels of trypsin-like enzymes in the plasma and that inhibiting these enzymes might improve outcomes during resuscitation. Our study revealed that treatment with Met reduced approximately 60% of trypsin-like enzyme activity in the plasma compared to the LR-only group. In conclusion, our study demonstrates that Met, when administered in conjunction with LR as a resuscitation solution, significantly enhances post-resuscitation BP compared to LR alone. This improved outcome may be associated with alterations in the TCA cycle and the inhibition of trypsin-like enzyme activity. However, further investigations are necessary to elucidate the precise role of these changes in the observed enhancements within this experimental model. This work was supported by National Institutes of Health grant R01HL162120. 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.

Mitochondrial peptides derived from exercising skeletal muscle increase oxidative stress in microvascular endothelial cells

Introduction: Mitochondria-derived peptides are newly discovered small bioactive peptides thought to communicate metabolic status to other cells. Two such peptides, MOTS-c and Humanin, have been shown to have particularly strong local and systemic regulatory effects on metabolism and oxidative stress in tissues, but their effect specifically on vascular endothelial cells remains unclear. Furthermore, it has been proposed that skeletal muscle is a source of MOTS-c and humanin during exercise but this has not been directly shown. Methods: In seven healthy young males, muscle interstitial fluid was collected from microdialysis probes in the thigh muscle, blood was drawn from femoral arterial and venous catheters and thigh muscle biopsies were obtained before and after one acute bout of exercise. In addition, muscle biopsies were obtained before and after 14 days of leg exercise training. Samples were analysed for MOTS-c, Humanin protein and mRNA. To test the effect of MOTS-c on the microvasculature, human endothelial cells derived from the muscle biopsies were incubated for three days with MOTS-c and analysed for mitochondrial respiration and formation of reactive oxygen species (ROS). Furthermore, mice were injected with MOTS-c for 4-weeks to investigate the in-vivo effect of vessels and microvascular endothelial cells. Data was analyzed by linear mixed models performed with R. Results: Acute exercise resulted in an 88% and 55% ( p<0.001) increase in MOTS-c and humanin concentration, respectively, in muscle dialysate, with no effect on the femoral arterial-venous plasma concentration differences. Both MOTS-c and humanin mRNA levels increased (by 20 and 26%; p<0.05) after acute exercise and were 43% and 35% ( p<0.05) higher, respectively, after 14 days of training. A period of MOTS-c treatment of endothelial cells increased mitochondrial respiration and ROS formation by 3-fold and 5-fold, respectively ( p<0.01). Muscle derived endothelial cells from mice injected for 4-weeks presented a similar mitochondrial respiration but a 4-fold ( p<0.05) higher ROS emission. Conclusion: interstitium in response to exercise, muscle is not a likely source of these peptides in plasma. Our data from in vitro and in vivo experiments suggest that treatment with MOTS-c does not influence endothelial metabolism but leads to increased oxidative stress in microvascular endothelial cells. The funding by Novo Nordisk Foundation (application number: 0070369) is gratefully acknowledged. 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 Mitigates HDAC4 Inhibitor-Elicited Protective Effect in Hemorrhage

Introduction: Histone deacetylate inhibition contributes critically to modulating insulin resistance and cardiovascular function. It remains unknown whether inhibition of specific HDAC isoform 4 could improve cardiac function and attenuates inflammatory response and whether HDAC4 inhibition-induced protection is related to irisin. The objective of this study is to investigate whether HDAC4 inhibition induced protective effect against hemorrhage-induced detrimental effects would be diminished by deletion of irisin. Method: Irisin knockout (irisin−/−) 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) Wild type (WT)+Hemorrhage (control) (N=7): WT mice were subjected to hemorrhage for 60 minutes followed by resuscitation; II) NVS-HD-1+Hemorrhage (n=7): The same as the group I except that NVS-HD1, a selective HDAC inhibitor (3mg/kg) was infused during resuscitation; III) Irisin −/− +Hemorrhage (n=6): Irisin −/− mice underwent hemorrhage and resuscitation; IV) NVS-HD-1 + Irisin−/−+Hemorrhage (n=6): The same as the groups III except that NVS-HD-1 was given to Irisin −/− during resuscitation. Myocardial function and hemodynamics were assessed using echocardiography and femoral artery catheterization, respectively. Cytokine releases from serum were measured using Enzyme-linked immunosorbent assay (ELISA). Histological assessment was performed to determine tissue damage in both myocardium and skeletal muscles. TUNEL was carried out to assess apoptotic signal in tissues. Results: As compared to control group, HDAC4 inhibitor significantly improved the cardiac function and recovery of hemodynamics, which was associated with the decreased release of IL6 and TNF-α in hemorrhage. The infiltration of inflammatory cells and TUNEL positive apoptosis in muscles were mitigated by inhibition of HDAC4. However, HDAC4 inhibitor-induced myocardial protection and suppression of inflammation against hemorrhage was lost by genetic deletion of irisin. Conclusion: Selective inhibition of HDAC4 produced protective effects with an improvement in myocardial function and attenuation of inflammation against hemorrhage, which is dependent on irisin. The work is supported by the National Institute of General Medical Sciences (R01GM 141339), United States; the National Heart, Lung, and Blood Institute Grants (R01 HL089405), United States. 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.

Pulsatile Perfusion Therapy at 0.1 Hz Improves Survival Following Severe Hemorrhage in Rats

Oscillations in arterial pressure and blood flow at 0.1 Hz are associated with protection of tissue oxygenation during conditions of reduced tissue perfusion. Pulsatile Perfusion Therapy (PPT) is a method we have developed to induce these oscillations, and has been associated with increased tolerance to simulated hemorrhage via lower body negative pressure in humans. However, it is unknown how effective this therapy would be in an actual hemorrhage model. The aim for this study was to test the effcacy of PPT in a rat model of severe hemorrhage. We hypothesized that PPT at 0.1 Hz would protect arterial pressure and cerebral blood flow following severe hemorrhage in rats, subsequently improving survival. Eleven adult Sprague-Dawley rats (six female, five male) were anesthetized via isoflurane, then underwent bilateral carotid artery catheterization for assessment of arterial pressure and carotid artery blood flow, while heart rate was assessed via lead II ECG. Following a 15-min baseline period, all animals were hemorrhaged to 50% of their estimated blood volume over 30-min. Rats were then randomly assigned to the PPT group (3 female, 3 male) or the control group (CON; 3 female, 2 male). PPT was administered via inflatable cuffs attached to both hind limbs, oscillating between 0 mmHg and 250 mmHg every 5-s (10-s cycles or 0.1 Hz) for 30-min immediately following hemorrhage. For the CON group, the leg cuffs were also attached but were not inflated for this 30-min period. All animals were then monitored for an additional 150-min recovery period post-hemorrhage, or until death — defined as the absence of ventricular function on the ECG. Survival time and peak mean arterial pressure (MAP), carotid blood flow, and heart rate were assessed to determine the effectiveness of PPT in protecting hemodynamic responses following hemorrhage. PPT increased survival time ( P = 0.02), with 3 of 6 (50%) rats in the PPT group and 0 of 5 (0%) rats in the CON group surviving the entire 180-min recovery period following hemorrhage. During recovery, PPT protected MAP (PPT: −46.5 ± 12.9% vs. CON: −72.6 ± 19.5% from baseline; P = 0.07) and carotid blood flow (PPT: −61.5 ± 17.7% vs. CON: −83.7 ± 6.7% from baseline; P = 0.04), but did not affect heart rate (PPT: 0.11 ± 6.58% vs. CON: −18.70 ± 29.34% from baseline, P = 0.20), although responses were highly variable between subjects. PPT protected arterial pressure and carotid blood flow in rats following severe hemorrhage, subsequently improving survival. These data add further evidence for the use of 0.1 Hz hemodynamic oscillations as a therapeutic intervention for the treatment of hemorrhage. Physiology and Anatomy Department Seed Grant. 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.

Unraveling a Novel Mechanism of Altered Glomerular Hemodynamics in Pre-diabetic Obesity

Background: In pre-diabetic obesity, disrupted glomerular autoregulation leads to increased glomerular capillary pressure and renal blood flow, causing potential barotrauma-induced glomerular damage. A decrease in Afferent arteriole ( Af-Art) resistance causes higher glomerular capillary pressure but the underlying mechanism behind this, specifically in pre-diabetic obesity, remains unclear. Hyperinsulinemia is common in pre-diabetic obesity, but its role in reducing Af-Art resistance in the kidneys is unknown. Kidney blood flow is auto-regulated by vasoconstriction via tubuloglomerular feedback (TGF) and vasodilation through the Distal convoluted tubule-2/connecting tubule (DCT-2/CNT) mechanism. Our earlier studies indicate increased Af-Art dilation in pre-diabetic obese rats through the DCT-2/CNT mechanism without affecting TGF. This DCT-2/CNT induced Af-Art dilation requires initiation from epithelial sodium channels (ENaC) present at this tubular segment and interestingly insulin is a known ENaC activator. Hypothesis: We hypothesize that in the context of pre-diabetic obesity, hyperinsulinemia contributes to an increase in renal cortical blood flow (CBF) by increasing DCT-2/CNT-induced Af-Art dilation, subsequently leading to glomerular injury. Methods: We assessed the effects of insulin on Af-Art dilation by perfusing juxtaposed DCT-2/CNT segments with insulin in normal rabbits. Contribution of DCT-2/CNT induced Af-Art dilation was measured by co-administration of the ENaC blocker benzamil. To study hyperinsulinemia's role in an in-vivo setting without altering blood glucose levels, we used a hyperinsulinemic-euglycemic (HI-EUG) clamp in obese rats with intravenous (IV) glucose and insulin infusions. Renal CBF and blood pressure were monitored using a laser Doppler probe and femoral artery catheter, respectively, both with and without benzamil administration (400 μg/kg, IV). To evaluate insulin's potential role in causation of renal damage, we infused insulin directly into one kidney of lean rats for 6 weeks via a renal sub-capsular catheter, with the contralateral kidney serving as control. Glomerular basement membrane (GBM) thickness, a marker of renal damage, was measured via electron microscopy. Untargeted lipidomic analysis of the renal cortex was performed to identify potential renal damage pathways in insulin infused kidneys. Results: Insulin perfusion in rabbits' DCT-2/CNT potentiated the dilation of adherent Af-Art compared to control infusions with artificial tubular fluid. ENaC inhibition reversed the insulin-induced Af-Art dilation, confirming that insulin increases Af-Art dilation through the ENaC-initiated DCT-2/CNT mechanism. In obese rats, insulin delivery using a HI-EUG clamp resulted in a significant 20.8±4.9% increase in CBF, which was negated by the administration of the ENaC blocker benzamil, indicating the potential involvement of DCT-2/CNT-mediated vasodilation. Neither the HI-EUG clamp nor benzamil infusion affected blood pressure. Additionally, continuous direct insulin infusion into the kidneys of lean rats led to an increase in glomerular basement membrane (GBM) thickness and ceramide accumulation in the renal cortex, both indicative of renal damage. Conclusion: Our study demonstrates that insulin directly augments DCT-2/CNT-mediated Af-Art dilation and increases renal cortical blood flow in obese rats. Chronic renal insulin infusion led to structural changes and damage markers in the kidney, independent of blood glucose and blood pressure levels. Henry Ford Health System Internal Funding. Pilot and Feasibility grant from southeast center for integrated metabolomics. 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.

Functional sympatholysis of Neuropeptide Y-mediated vasoconstriction in humans

Metabolic inhibition of sympathetic vasoconstriction (functional sympatholysis) is essential for adequate perfusion of skeletal muscle during exercise. Functional sympatholysis occurs primarily through post-junctional attenuation of norepinephrine and α-adrenergic-mediated vasoconstriction, though other non-adrenergic neurotransmitters are co-released with norepinephrine. Neuropeptide Y (NPY) is a neurotransmitter that elicits robust vasoconstriction and is co-released with norepinephrine during exercise in an intensity dependent manner. Evidence from animal models indicate that NPY is sensitive to metabolic inhibition, however metabolic inhibition of NPY-mediated vasoconstriction has not been tested in humans. We tested the hypothesis that NPY-mediated vasoconstriction would be attenuated during handgrip exercise in humans. In 10 healthy adults (7M:3F, age: 30±7 years, BMI: 24±5) we measured forearm blood flow (Doppler ultrasound), blood pressure (brachial artery catheter), and calculated changes in forearm vascular conductance (FVC) to local intra-arterial infusions of phenylephrine (PE; α1-agonist) or NPY (Y1R-agonist) during 1) intra-arterial infusion of sodium nitroprusside (SNP; nitric oxide donor) to serve as a non-metabolic vasodilatory control or 2) dynamic rhythmic handgrip exercise (EX; 15% maximal voluntary contraction). The vasoconstrictor responses to PE and NPY were quantified as a percent ΔFVC during each condition (SNP vs. EX) and were compared by two-way RM-ANOVA. The magnitude of sympatholysis (ΔFVC during exercise expressed as a percent of control) for PE and NPY was compared by a paired t-test. As expected, the vasoconstrictor response to PE was attenuated during handgrip exercise compared to SNP (ΔFVC: SNP: -50±24 vs. EX: -17±9 %; p=0.002). Similarly, NPY-mediated vasoconstriction was blunted during handgrip exercise compared to SNP (ΔFVC: SNP: -32±22 vs. EX: -11±7 %; p=0.029). There was no difference in the magnitude of sympatholysis between PE and NPY (PE: 68±18, NPY: 52±34 %; p=0.28). These data indicate that NPY-mediated vasoconstriction is sensitive to metabolic inhibition in humans, and the magnitude of sympatholysis is not different from α1-adrenergic vasoconstriction. Funding: NIH R00HL153777. 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.

Effect of curcumin on inflammatory and oxidative stress markers in Lipopolysaccharide induced animal models of pre-eclampsia

Introduction: A substantial percentage of fetal, maternal, and neonatal morbidity and mortality is traced to Pre-eclampsia, a life threatening disease. Typical symptoms of the disease include de novo hypertension, proteinuria, renal failure, neurological problems, elevated liver enzymes, and uteroplacental dysfunction. It is estimated that almost 8-10% of all pregnancies are affected by preeclampsia in India. Pre-eclampsia incidentally also involves immune system changes on similar lines as a typical pregnancy. Immune cells like CD4+ T-helper 1 (TH1) cells, cytotoxic NK cells, and autoreactive B cells secrete substances that cause an increase in innate immune activation and inflammation in the maternal circulation and uteroplacental unit, instead of immune changes that promote tolerance and inhibit reactivity to the fetus and placenta. Placental and systemic oxidative stress are the key factors in the emergence of preeclampsia. A number of physiological changes, mineral shortages, and increased oxygen use during pregnancy can all be considered potential causes of oxidative stress. There is yet no effective and secure pharmaceutical treatment for preeclampsia. Pregnancy related safety concerns and the complex aetiology are two significant barriers to the development of pre-eclampsia medications. Medicinal plants and derived products have long been recognized as valuable assets in the treatment of a variety of diseases. Curcumin is a naturally occurring substance with significant in vitro therapeutic promise. The objective of this study was to develop LPS (lipopolysaccharide) induced animal model of Pre-eclampsia and to estimate and compare the hemodynamic parameters, inflammatory markers, oxidative stress markers and proteinuria in pregnant control, LPS-induced Pre-eclampsia, and curcumin-treated Pre-eclampsia in experimental rats. Material and methods: Pre-eclampsia was induced by single dose of 0.5μg/kg LPS. Wistar rats were divided into 8 groups of 8 animals. Female wistar rats were placed with male rats overnight and examined the next morning for the presence of sperm in vaginal smears. The day on which sperm was detected was designated as gestational day 0. After confirmation of pregnancy, each rat was weighed and randomized into groups. Pregnant Wistar rats were given 0.5 μg /kg of body weight LPS intraperitoneally on gestational day 5 for developing Pre-eclampsia models. Protein estimation in urine was done after 24 hours. On 19th or 20th gestation day animals were anesthetized and blood pressure was measured through a non-invasive tail-cuff method using the AD instrument and also through invasive method by inserting a arterial catheter in either of the carotid arteries towards the heart. ECG recording was done through surface ECG recording. Blood was collected by cardiac puncture, centrifuged, and stored at -80ºC on 19th or 20th gestation day. Inflammatory markers were estimated through ELISA reader. Oxidative stress markers were estimated. Pregnancy outcome was assessed through placental weight, number of pup’s delivered and pup’s weight. Statistical analysis was done using one way analysis of variance (ANOVA) followed by post hoc Tukey‘s test for intergroup comparisons. Results: In LPS induced model of pre-eclampsia, single-dose treatment with LPS (0.5ug/kg) induced marked pre-eclampsia in rats. Treatment with curcumin significantly decreased the level of proteinuria, hemodynamic parameters, inflammatory markers and oxidative stress markers in pregnant LPS+ curcumin-treated group when compared with the pregnant LPS group. Treatment with curcumin significantly increases pup’s weight and number of pups. Conclusion: On the basis of this experimental study, it is proposed that curcumin appears to be a potential therapeutic agent as measured by effect on hemodynamic changes, proteinuria, inflammatory markers, oxidative stress markers and pregnancy outcomes in LPS-induced pre- eclampsia. 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.

Heparin vs Saline Infusion For Maintaining the Patency of Arterial Catheters in Children

Heparin vs Saline Infusion For Maintaining the Patency of Arterial Catheters in Children

Hemorrhage Magnitude Correlates with Sympathetic Vasomotion in Conscious Rabbits

Each year, over 1.8 million people die from hemorrhagic shock, and the median time from onset to death is only two hours, making early recognition and prompt action the cornerstone of management. The sympathetic nervous system is the most rapid physiological hemodynamic compensatory mechanism, and we have developed a novel measure of sympathetic vascular control called sympathetic vasomotion which could serve as an early marker of hemorrhage. We performed unilateral renal denervation on six rabbits and instrumented these rabbits with bilateral renal flow probes and arterial pressure telemeters to allow for measurement of sympathetic vasomotion. After a two-week recovery period, the rabbits then underwent controlled blood withdrawal via an auricular arterial catheter. The differences in admittance gain and phase shift occurrence between the innervated and denervated kidneys increased significantly before any other hemodynamic changes. Over the first 15 minutes of hemorrhage, the differences in admittance gain and phase shift correlated with hemorrhage magnitude (r = 0.69 and 0.63, respectively), whereas the differences in coherence did not. The sum of the admittance gain and phase shift differences showed a slightly higher correlation with hemorrhage magnitude (r = 0.71). This data suggests that some features of sympathetic vasomotion may be useful as a biomarker for diagnosing early-stage normotensive hemorrhage and assessing treatment response. Further studies are needed to evaluate the utility of sympathetic nervous system monitoring in clinical contexts. Supported by NIH P01 HL62222 and NIH F30 HL118974. 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.

Testosterone enhances adipose tissue-blood pressure axis in obese mice exposed to early life stress

Previously, we have shown that male and female mice exposed to maternal separation and early weaning (MSEW), a model of early life stress, display exacerbated obesity-induced hypertension in response to chronic high fat diet. However, only male mice showed higher sympathetic tone at baseline, along with increased neuronal activation in PVN and pressor response to the acute stimulation of TRVP1 channels with capsaicin, a mechanism known as adipose afferent reflex (AAR). The aim of this study was to investigate whether obese male MSEW mice show 1) increased intracellular calcium in response to capsaicin in neuronal cultures of dorsal ganglia root (DRG), and 2) a role for sex hormones in AAR reactivity in vivo. Six-months-old control and MSEW fed a high fat diet (HFD, 60% kcal fat) were injected with pAAV-CAG-tdTomato (59462-PHP.S, 1012 viral particles); 8 sites; 4 ul/site; bilateral). After 6 weeks, mice were decapitated and DRGs (L5-T12) were collected and placed in ice-cold HBSS solution, dissociated and mixed with Collagenase P (1 mg/ml in HBSS, 15 min, 37 oC). After 0.25% Trypsin-EDTA incubation, neurons were mechanically dissociated, collected by centrifugation and resuspended in DMEM-10% FBS, plated onto the Matrigel Basement Membrane Matrix covered coverslips and maintained at 37 oC for 15-16 hours. Neuronal cultures were incubated in Ca2+ imaging solution with 2 μM Fura-2 AM, 30 min in dark conditions. After de-estirification, intracellular Ca2+ transients were visualized by exciting Fura-2 at 340 ± 20 nm and 380 ± 20 nm using a high-speed filter changer to obtain a ratiometric value independent of indicator concentration. Emitted light was passed through a dichroic filter (400-nm high pass) and an emitter filter (520 ± 30 nm) and was digitized onto the sensor of an EMCCD camera. Background subtraction and normalization to baseline were used to quantify changes in fluorescence. Despite similar resting uncalibrated ratios of calcium levels between groups (~0.6 ratio units, n=3), sensory neurons from MSEW mice tended to display larger responses to capsaicin (50 uM), showing elevated calcium kinetics vs. controls (0.56±0.09 vs. 0.31±0.12 delta ratio, respectively, p=0.063) as well as longer transients, perhaps indicative of reduced clearance or buffering. A separate set of age-matched mice were gonadectomized. After 4 weeks, anesthetized mice were fitted with carotid artery catheter for direct blood pressure measurement in response to the infusion of perigonadal fat with capsaicin (1.5 pmol/μL during 2 minutes in 4 sites, bilaterally). Capsaicin-induced pressor response was exacerbated in intact MSEW male mice compared to intact controls (9.0±0.2 vs. 1.3±0.2 delta mmHg, respectively, n=6, p<0.05). Orchidectomy attenuated delta blood pressure in MSEW mice to 7.0±0.2 mmHg (p<0.05 vs. intact MSEW), while enhanced delta blood pressure in control mice to 7.5±0.2 mmHg (p<0.05 vs. intact control). MSEW did not influence the pressor response to perigonadal fat stimulation with capsaicin either in intact or ovariectomized obese female mice (n=4-6 per group, p>0.05), suggesting that estradiol may not to play a protective role in obese females AAR reactivity. This data indicates that testosterone could buffer the AAR reactivity of obese control mice, while MSEW exerts an opposite effect. Thus, investigating testosterone signaling on calcium handling mechanisms (i.e., buffers, pumps, ER-mediated calcium release) in sensory neurons innervating visceral fat will provide insights on the sex-specific contribution of afferent sympathoexitatory signals to obesity-hypertension in male MSEW mice. This study was supported by NIH R01 HL135158, and SALT pilot - University of Kentucky to ASL. 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.

Physiologic Validation of the Compensatory Reserve Metric Obtained From Pulse Oximetry Waveforms

Background: The compensatory reserve metric (CRM) provides a novel marker of hemodynamic status in prediction of sudden cardiovascular decompensation during central hypovolemia. The CRM has previously been calculated using arterial waveforms obtained from a photoplethysmographic volume-clamp technique. However, the in-field use of pulse oximetry is becoming more prominent in research and medicine. To improve in-field applicability of the CRM, this project aimed to validate pulse-oximetry derived CRM values relative to physiologic data during simulated hemorrhage through application of lower body negative pressure (LBNP). Methods: Forty-nine healthy adults (25 females) underwent a graded LBNP protocol with the following 5-minute stages: -0, -15, -30, -45, -60, -70, -80, -90, and 100 mmHg, or until the onset of pre-syncopal symptoms (tolerance) was reached. Arterial waveforms were sampled using pulse oximetry (Massimo Radical 7). The CRM was calculated using a validated one-dimensional convolutional neural network. A brachial artery catheter was used to measure intraarterial pressure. A 3-lead ECG was used to measure heart rate. SpO2 was measured using pulse oximetry. Cardiac output and stroke volume were estimated using the photoplethysmographic volume-clamp. Data were binned for the last thirty seconds of each completed stage, and at tolerance. Fixed-effect linear mixed models with repeated measures were used to examine the association between CRM values and physiologic variables. A priori significance was set at P<0.05. Results: The median LBNP stage reached was 70 mmHg (Range: 45-100 mmHg). Relative to baseline, at tolerance there was a 50±12% ( P<0.001) mean reduction in stroke volume, 65±27% ( P<0.001) increase in heart rate, 18±8% ( P<0.001) reduction in mean arterial pressure, 21±7% ( P<0.001) systolic blood pressure, 8±9% ( P<0.001) diastolic blood pressure, and 39±12% ( P<0.001) pulse pressure. The CRM obtained using pulse oximetry was significantly associated with a reduction in stroke volume ( P<0.001), increase in heart rate ( P<0.001), and reductions in systolic ( P=0.033), diastolic ( P=0.036), and pulse pressure ( P=0.002). There was no statistically significant association between CRM and cardiac output ( P=0.421), SpO2 ( P=0.408), or mean arterial pressure ( P=0.214). Conclusion: The CRM obtained using pulse oximetry may be a valid, reliable marker of hemodynamic status with promising in-field applications. Future studies warrant investigation of feasibility and applicability within various contexts ranging from the operating room to the battlefield. The presented work was funded in part by the Congressionally Directed Medical Research Program (Award No. DM180240) and Offce of Naval Research (Awards No. N00014-18-D-7001 and N00014-19-C-2017). 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.

Central α2-adrenergic mechanisms differentially affect baroreflex control of sympathetic and cardiovagal outflow

This study aimed to investigate the impact of central α2-adrenergic mechanisms on arterial baroreflex control of sympathetic and cardiovagal outflow in healthy humans. R-R interval (ECG), blood pressure (brachial arterial catheter), and muscle sympathetic nerve activity (MSNA; peroneal microneurography) were measured in eight healthy participants (5 females; 28±7 years). Sympathetic action potentials (AP) were extracted from the filtered MSNA neurogram (continuous wavelet transform) during a 5-minute baseline (BSL) and an intravenous dexmedetomidine infusion consisting of a loading dose (LD; 10 minutes at 0.225 μg/kg/hr) and a maintenance dose (MD; ~0.15 μg/kg/hr). Sympathetic AP baroreflex threshold gain was measured as the slope of the linear relationship between AP discharge probability and diastolic blood pressure. The linear relationship between R-R interval and systolic blood pressure (sequence technique) quantified cardiovagal baroreflex gain. Mixed-effects analyses and post-hoc t-tests were performed. Data are reported as mean ± SD. Dexmedetomidine reset the baroreflex threshold operating points for all sympathetic AP clusters downwards to lower firing probabilities (cluster 4; BSL: 20±6, LD: 13±8, MD: 6±5%, both p<0.01 vs. BSL) and leftwards to lower diastolic pressures (BSL: 72±9, LD: 69±8, MD: 65±10 mmHg, both p<0.01 vs. BSL). Dexmedetomidine reduced baroreflex threshold gain for the subpopulation of medium-sized sympathetic APs (cluster 4; BSL: -6.5±2.0, LD: -2.6±1.6, MD: -2.0±0.7 %/mmHg, both p<0.01 vs. BSL). Dexmedetomidine did not affect baroreflex threshold gain of small (cluster 1; BSL: -1.9±1.1, LD: -1.3±1.6, MD: -1.1±0.8 %/mmHg, both P>0.88 vs. BSL) or large AP clusters (cluster 9; BSL: -0.8±0.4, LD: -0.8±1.0, MD: -0.2±0.7 %/mmHg, both P>0.98 vs. BSL). Dexmedetomidine reset the cardiovagal baroreflex to lower systolic pressures but did not affect R-R interval (BSL: 1035±261, LD: 1025±308, MD: 1005±292ms, Main effect P=0.45) or gain (BSL: 24±11, LD: 30±20, MD: 26±25 ms/mmHg, Main effect P=0.63). These findings suggest that central α2-adrenergic mechanisms differentially affect arterial baroreflex control of sympathetic and cardiovagal outflow in humans by minimally affecting cardiovagal baroreflex gain but strongly affecting the baroreflex gain for the subpopulation of medium-sized sympathetic APs. This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the National Institutes of Health (NIH). 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.

NADPH Oxidase 4 Knockout in Dahl Salt-Sensitive Rats Impacts Kidney O2 Consumption and UCP2 Responses to a High Salt Diet

Rationale: The effects of a high salt (HS) diet upon renal metabolism and O2 utilization have not been extensively studied and there is a significant gap in our understanding of the role of oxidative stress in the effciency of energy production and substrate metabolism. The present study compared the effects of a HS diet (4% NaCl) on changes in O2 consumption and transcriptomic profiles in Dahl salt-sensitive (SS) rats to SS rats with a global knockout of NADPH oxidase 4 (NOX4) gene (SS Nox4−/−). Methods: Male SS (n=9) and SS Nox4−/− (n=10) rats were fed a 0.4% NaCl (LS) diet. At 7-8 weeks of age, the rats were implanted with a renal artery ultrasonic flow probe (Transonic) together with a femoral arterial catheter and a renal venous catheter. Renal blood flow (RBF) and mean arterial pressure (MAP) were measured continuously (24/7) and arterial (A) and renal venous (Vr) blood was sampled intermittently when rats were fed the LS and on days 7, 14, and 21 after switching to the HS diet. A and Vr blood O2 content was immediately measured by radiometer. From separate groups of rats subjected to the same protocol, the renal cortical tissue (Cx) and outer medulla (OM) were removed for mRNAseq analysis (Novogene, Inc). Results: When switching to the HS diet, the average 24-hour MAP of SS rats rose from 122 ± 2 to 140 ± 2 on HS7 to 164 ± 5 mmHg by HS21. In contrast, MAP in SS Nox4−/− rats increased from 121 ± 2 at LS to 132 ± 1 at HS7 to 152 ± 3 mmHg at HS21 (p<0.05, compared to SS). RBF, normalized by changes of kidney weights obtained in another group of SS and SS Nox4−/− rats fed the same HS diet, SS rats exhibited a significant reduction of RBF over the 3 weeks of the HS diet averaging LS 7.2 ± 0.6, HS7 5.1 ± 0.5 and HS21 4.6 ± 0.7 mL/min/g kidney weight (gkw). This reduction of RBF was not observed in SS Nox4−/− rats (LS 6.8 ± 0.8, HS7 6.6 ± 0.6, HS21 6.0 ± 0.6 mL/min/gkw). The kidney O2 extraction ratio at LS tended to be lower in SS Nox4−/− (11.2 ± 1.7%) compared to SS (14.0 ± 1.1%) (p=0.10). When switched to the HS diet, O2 extraction was significantly reduced in the SS Nox4−/− rats reaching 8.3 ± 1.0% at HS21 (p<0.05), while it did not change significantly in SS (12.7 ± 1.4%) at HS21. Notably, as determined by RNAseq analysis, Ucp2 expression in cortical tissue was significantly greater in SS fed HS than in SS Nox4−/−rats at HS21 . A gene enrichment analysis of the mRNAseq cortical tissue data (GSEA-KEGG pathways) focused on metabolic pathways indicated that knockout of Nox4 resulted in reduced expression of linoleic acid, lysine, and histidine metabolism pathways at LS when compared to SS. Those differences were not observed after HS feeding. However, upregulation of oxidative phosphorylation pathway was observed at HS21 in SS Nox4−/− when compared to SS rats. In the OM, a greater expression of genes associated with fatty acid degradation and carbon metabolism was observed in SS Nox4−/− rats when fed LS which was observed also at HS21. Conclusion: The preliminary results of this study suggest that reduced extraction of O2 in the SS Nox4−/− rats compared to SS rats may be partially explained by the differential response of Ucp2 to salt. Further studies are needed to determine whether the effciency of ATP production is enhanced in SS Nox4−/− as consequence of reduction of reactive oxygen species (e.g., H2O2) and the related downstream pathways such as phosphorylation of mTORC1. R01 HL151587, AHA 23POST1008714. 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.

Femoral arterial cannulation for surgical repair of stanford type A aortic dissection.

The benefits and harms associated with femoral artery cannulation over other sites of arterial cannulation for surgical repair of acute Stanford type A aortic dissection (TAAD) are not conclusively established. We evaluated the outcomes after surgery for TAAD using femoral artery cannulation, supra-aortic arterial cannulation (i.e., innominate/subclavian/axillary artery cannulation), and direct aortic cannulation. 3751 (96.1%) patients were eligible for this analysis. In-hospital mortality using supra-aortic arterial cannulation was comparable to femoral artery cannulation (17.8% vs. 18.4%; adjusted OR 0.846, 95% CI 0.799-1.202). This finding was confirmed in 1028 propensity score-matched pairs of patients with supra-aortic arterial cannulation or femoral artery cannulation (17.5% vs. 17.0%, p=0.770). In-hospital mortality after direct aortic cannulation was lower compared to femoral artery cannulation (14.0% vs. 18.4%, adjusted OR 0.703, 95% CI 0.529-0.934). Among 583 propensity score-matched pairs of patients, direct aortic cannulation was associated with lower rates of in-hospital mortality (13.4% vs. 19.6%, p=0.004) compared to femoral artery cannulation. Switching of the primary site of arterial cannulation was associated with increased rate of in-hospital mortality (36.5% vs. 17.0%; adjusted OR 2.730, 95% CI 1.564-4.765). Ten-year mortality was similar in the study cohorts. In this study, the outcomes of surgery for TAAD using femoral arterial cannulation were comparable to those using supra-aortic arterial cannulation. However, femoral arterial cannulation was associated with higher in-hospital mortality than direct aortic cannulation. ClinicalTrials.gov registration code: NCT04831073.

The stochastic characteristics of wideband-wavelength track irregularity on Chinese HSRs and its application to dynamic wheel–rail interaction

Track irregularities are the major excitations which lead to unfavourable wheel–rail dynamic interaction. In this work, the stochastic characteristics of longitudinal level irregularity on Chinese ballastless high-speed railway (HSR) are analysed based on a series of large-scale measurement campaigns on various arterial lines in Chinese HSR network. The power spectrum density (PSD) of longitudinal level irregularities of various track types is obtained, covering short and middle-to-long wavelength range, as well as the periodical irregularities caused by characteristic lengths of track components. An irregularity spectrum is proposed to represent the stochastic characteristics of the longitudinal level irregularities. Unlike existing irregularity spectra which represent the short and middle-to-long wavelength irregularities separately, the proposed spectrum covers a wide range of wavelength from 0.002 m to 100 m. A vehicle–track model which couples flexible wheelsets and the ballastless track is employed to demonstrate the suitability of the spectrum. It is shown that the proposed spectrum is more suitable than the latter to represent Vehicle–Track Interaction (VTI) on Chinese HSRs. The fitted short-wave spectrum and the proposed wideband wavelength spectrum therefore provide more appropriate representatives of track irregularities for accurate modelling of VTI on Chinese HSRs and railway lines which adopt similar technologies.