Reduction In Renal Blood Flow Research Articles

Cardiovascular effects of Roflumilast during sepsis: Risks or benefits?

BackgroundPhosphodiesterase-4 (PDE4) is responsible for terminating cyclic adenosine monophosphate (cAMP) signalling. PDE4 inhibitors, such as roflumilast (RFM), have anti-inflammatory activity and have been studied in inflammation-induced tissue damage in sepsis. However, the role of RFM on cardiovascular derangements induced by sepsis is still unknown. Thus, we aimed to evaluate the potential effects of RFM on cardiovascular collapse and multiorgan damage caused by sepsis. MethodsSepsis was induced by cecal ligation and puncture (CLP) in male rats. Six hours after the CLP or sham procedure, animals were randomly assigned to receive either RFM (0.3 mg/kg) or vehicle subcutaneously, and cardiovascular parameters were assessed 24 h after the surgery and organ/plasma samples were collected for further analyses. ResultsSepsis induced hypotension, tachycardia, reduced renal blood flow (RBF) and hyporeactivity to vasoconstrictors both in vivo and ex vivo. RFM treatment increased systemic cAMP levels and RBF. RFM also attenuated hypoperfusion and liver damage induced by CLP. Furthermore, RFM reduced systemic nitric oxide (NO) levels in septic rats, while there were no changes in hepatic NOS-2 expression. Nevertheless, RFM exacerbated sepsis-induced hypotension and tachycardia without ameliorating vascular hyporeactivity. ConclusionOur data show that PDE-4 inhibition protects septic rats from hepatic injury and improves renal perfusion. However, RFM worsened hemodynamic parameters and showed no protection against sepsis-induced cardiovascular dysfunction and mortality. Thus, despite the anti-inflammatory benefits of RFM, its application in sepsis should be approached cautiously.

OXGR1-Dependent (Pro)Renin Receptor Upregulation in Collecting Ducts of the Clipped Kidney Contributes to Na+ Balance in Goldblatt Hypertensive Mice.

The two-kidney, one-clip (2K1C) Goldblatt rodent model elicits a reduction in renal blood flow (RBF) in the clipped kidney (CK). The reduced RBF and oxygen bio-ability causes the accumulation of the tricarboxylic cycle intermediary, α-ketoglutarate, which activates the oxoglutarate receptor-1 (OXGR1). In the kidney, OXGR1 is abundantly expressed in intercalated cells (ICs) of the collecting duct (CD), thus contributing to sodium transport and electrolyte balance. The (pro)renin receptor (PRR), a member of the renin-angiotensin system (RAS), is a key regulator of sodium reabsorption and blood pressure (BP) that is expressed in ICs. The PRR is upregulated in 2K1C rats. Here, we tested the hypothesis that chronic reduction in RBF in the CK leads to OXGR1-dependent PRR upregulation in the CD and alters sodium balance and BP in 2K1C mice. To determine the role of OXGR1 in regulating the PRR in the CDs during renovascular hypertension, we performed 2K1C Goldblatt surgery (clip = 0.13 mm internal gap, 14 days) in two groups of male mice: (1) mice treated with Montelukast (OXGR1 antagonist; 5 mg/Kg/day); (2) OXGR1-/- knockout mice. Wild-type and sham-operated mice were used as controls. After 14 days, 2K1C mice showed increased systolic BP (SBP) (108 ± 11 vs. control 82 ± 5 mmHg, p < 0.01) and a lower natriuretic response after the saline challenge test. The CK group showed upregulation of erythropoietin, augmented α-ketoglutarate, and increased PRR expression in the renal medulla. The CK of OXGR1 knockout mice and mice subjected to the OXGR1 antagonist elicited impaired PRR upregulation, attenuated SBP, and better natriuretic responses. In 2K1C mice, the effect of reduced RBF on the OXGR1-dependent PRR upregulation in the CK may contribute to the anti-natriuretic and increased SBP responses.

P100 ALPHA KETOGLUTARATE RECEPTOR 1 REGULATES THE EXPRESSION OF THE (PRO)RENIN RECEPTOR IN MEDULLARY RENAL TISSUES, MODULATES SODIUM EXCRETION AND ATTENUATES TWO-KIDNEY, ONE-CLIP GOLDBLATT HYPERTENSION IN MICE

Background: The two-kidney, one-clip (2K1C) Goldblatt model elicits a reduction of renal blood flow (RBF) in the clipped kidney (CK). The reduced RBF and oxygen bio ability causes the accumulation of the intermediary of the tricarboxylic cycle, α-ketoglutarate, which activates the oxoglutarate receptor-1 (OXGR1). In the kidney, the OXGR1 is abundantly expressed in intercalated cells (IC) of the collecting duct (CD), which may contribute to Na+ transport and electrolyte balance. The (pro)renin receptor (PRR), a member of the renin-angiotensin-aldosterone system is a key regulator of Na+ reabsorption, and blood pressure (BP) and is also expressed in IC. PRR is upregulated in 2K1C. Here, we tested the hypothesis that reduction of RBF in the CK leads to OXGR1-dependent PRR upregulation in the CD and alterations of Na+ balance and BP in 2K1C mice. Methods: To determine the role of OXGR1 in regulating PRR in the CDs during renovascular hypertension, we used 2K1C Goldblatt surgery (clip= 0.13 mm internal gap) in two groups of male mice: 1) Oxgr1-/- knockout (n=6) mice; and 2) mice treated with Montelukast (OXGR1 antagonist; 5 mg/Kg/day, n=6). WT and sham-operated mice were used as controls. Results: 2K1C mice showed increased systolic BP (SBP) (108 ± 11 vs. control 82 ± 5 mmHg, p&lt;0.01) and a lower natriuretic response after the saline challenge test. The CK showed augmented levels of α-ketoglutarate, erythropoietin mRNA levels, PRR (mRNA and protein abundances) in the renal medulla. Non-CK showed PRR upregulation in the CDs. However, the CK of Oxgr1-/- knockout mice, and from those subjected to OXGR1 antagonism, elicited impaired PRR upregulation, attenuated SBP (Oxgr1-/- 2K1C: 90 ± 8 mmHg, p=non-significant vs. control; Montelukast 2K1C: 95 ± 3 mmHg, p&lt;0.05 vs. control) and better natriuretic responses. Conclusion: In 2K1C mice, the effect of reduced RBF on the OXGR1-dependent PRR upregulation in the CK may contribute to the anti-natriuretic and increased SBP responses.

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&lt;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&lt;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.

EARLY FLUID PLUS NOREPINEPHRINE RESUSCITATION DIMINISHES KIDNEY HYPOPERFUSION AND INFLAMMATION IN SEPTIC NEWBORN PIGS.

Sepsis is the most frequent risk factor for acute kidney injury (AKI) in critically ill infants. Sepsis-induced dysregulation of kidney microcirculation in newborns is unresolved. The objective of this study was to use the translational swine model to evaluate changes in kidney function during the early phase of sepsis in newborns and the impact of fluid plus norepinephrine resuscitation. Newborn pigs (3-7-day-old) were allocated randomly to three groups: 1) sham, 2) sepsis (cecal ligation and puncture) without subsequent resuscitation, and 3) sepsis with lactated Ringer plus norepinephrine resuscitation. All animals underwent standard anesthesia and mechanical ventilation. Cardiac output and glomerular filtration rate were measured noninvasively. Mean arterial pressure, total renal blood flow, cortical perfusion, medullary perfusion, and medullary tissue oxygen tension (mtPO 2 ) were determined for 12 h. Cecal ligation and puncture decreased mean arterial pressure and cardiac output by more than 50%, with a proportional increase in renal vascular resistance and a 60-80% reduction in renal blood flow, cortical perfusion, medullary perfusion, and mtPO 2 compared to sham. Cecal ligation and puncture also decreased glomerular filtration rate by ~79% and increased AKI biomarkers. Isolated foci of tubular necrosis were observed in the septic piglets. Except for mtPO 2 , changes in all these parameters were ameliorated in resuscitated piglets. Resuscitation also attenuated sepsis-induced increases in the levels of plasma C-reactive protein, proinflammatory cytokines, lactate dehydrogenase, alanine transaminase, aspartate aminotransferase, and renal NLRP3 inflammasome. These data suggest that newborn pigs subjected to cecal ligation and puncture develop hypodynamic septic AKI. Early implementation of resuscitation lessens the degree of inflammation, AKI, and liver injury.

Renal dysfunction in adults following cardiopulmonary bypass is linked to declines in S-nitroso hemoglobin: a case series.

Impaired kidney function is frequently observed in patients following cardiopulmonary bypass (CPB). Our group has previously linked blood transfusion to acute declines in S-nitroso haemoglobin (SNO-Hb; the main regulator of tissue oxygen delivery), reductions in intraoperative renal blood flow, and postoperative kidney dysfunction. While not all CPB patients receive blood, kidney injury is still common. We hypothesized that the CPB procedure itself may negatively impact SNO-Hb levels leading to renal dysfunction. After obtaining written informed consent, blood samples were procured immediately before and after CPB, and on postoperative day (POD) 1. SNO-Hb levels, renal function (estimated glomerular filtration rate; eGFR), and plasma erythropoietin (EPO) concentrations were quantified. Additional outcome data were extracted from the patients' medical records. Twenty-seven patients were enroled, three withdrew consent, and one was excluded after developing bacteremia. SNO-Hb levels declined after surgery and were directly correlated with declines in eGFR (R=0.48). Conversely, plasma EPO concentrations were elevated and inversely correlated with SNO-Hb (R=-0.53) and eGFR (R=-0.55). Finally, ICU stay negatively correlated with SNO-Hb concentration (R=-0.32). SNO-Hb levels are reduced following CPB in the absence of allogenic blood transfusion and are predictive of decreased renal function and prolonged ICU stay. Thus, therapies directed at maintaining or increasing SNO-Hb levels may improve outcomes in adult patients undergoing cardiac surgery.

Transmission of high arterial pressure into renal microvessels during venous-clamping augments ischaemia/reperfusion-induced acute kidney injury in anaesthetized rats.

In two recent studies, we observed that a 30-min renal vein clamping caused formation of interstitial haemorrhagic congestion in ischaemic and ischaemic/reperfused kidney along with the development of severer acute kidney injury (AKI) than renal artery or pedicle clamping. It was suggested that the transmission of high arterial pressure into renal microvessels during vein occlusion probably causes the occurrence of interstitial haemorrhagic congestion that augments AKI. The present investigation aimed to evaluate this suggestion by reducing renal perfusion pressure (RPP) during renal venous occlusion. Anaesthetized male Sprague-Dawley rats were divided into three groups (n = 8), which underwent a 2-h reperfusion period following 30-min bilateral renal venous clamping along with reduced RPP (VIR-rRPP group) or without reduced RPP (VIR group) and an equivalent period after sham-operation (Sham group). The VIR-rRPP group compared with VIR group had lower levels of kidney malondialdehyde and tissue damages as epithelial injuries of proximal tubule and thick ascending limb, vascular congestion, intratubular cast and oedema, along with the less reductions in renal blood flow, creatinine clearance, Na+ -reabsorption, K+ and urea excretion, urine osmolality and free-water reabsorption. Importantly, the formation of intensive interstitial haemorrhagic congestion in the VIR group was not observed in the VIR-rRPP group. These results indicate that the transmission of high arterial pressure into renal microvessels during venous occlusion leads to rupturing of their walls and the formation of interstitial haemorrhagic congestion, which has an augmenting impact on ischaemia/reperfusion-induced renal structural damages and haemodynamic, excretory and urine-concentrating dysfunctions.

Changes in renal blood flow after surgically induced weight loss: can bariatric surgery halt the progression of chronic kidney disease?

BackgroundWe previously demonstrated how kidney injury in patients with morbid obesity can be reversed by bariatric surgery (BaS). Objective(s)Based on previous experience, we hypothesize patients’ potentially reversible kidney injury might be secondary to reduction in renal blood flow (RBF), which improves following BaS. SettingAcademic Hospital. MethodsWe conducted a retrospective analysis of patients who underwent BaS at our institution from 2002 to 2019. We identified patients with chronic kidney disease (CKD) using the estimated glomerular filtration rate (eGFR) from the CKD Epidemiology Collaboration Study (CKD-EPI) classification system. We used the BUN/Creatinine (Cr) ratio pre- and postoperatively to determine a prerenal (decreased RBF) versus intrinsic component as the responsible cause of CKD in this patient population. Decreased RBF was defined as BUN/Cr > 20 preoperatively. ResultsOur analysis included n = 2924 patients, of which 11% (n = 325) presented decreased RBF. From our original sample, only n = 228 patients had the complete data necessary to assess both eGFR and RBF (BUN/Cr). Patients with baseline CKD stage 2 demonstrated preoperative BUN/Cr 20.85 ± 10.23 decreasing to 14.99 ± 9.10 at 12-month follow-up (P < .01). Patients with baseline CKD stage 3 presented with preoperative BUN/Cr 23.88 ± 8.75; after 12-month follow-up, BUN/Cr ratio decreased to 16.38 ± 9.27 (P < .01). Patients with CKD stage 4 and ESRD (eGFR < 30) did not demonstrate a difference for pre- and postoperative BUN/Cr 21.71 ± 9.28 and 19.21 ± 14.58, respectively. Conclusion(s)According to our findings, patients with CKD stages 1–3 present improvement of their kidney function after BaS. This amelioration could be secondary to improvement of the RBF, an unstudied reversible mechanism of kidney injury in the bariatric population.

Change in renal blood flow in response to intrarenal pressure alterations induced by ureteroscopy in an in-vivo porcine model.

High irrigation rates are commonly used during ureteroscopy and can increase intrarenal pressure (IRP) substantially. Concerns have been raised that elevated IRP may diminish renal blood flow (RBF) and perfusion of the kidney. Our objective was to investigate the real-time changes in RBF while increasing IRP during Ureteroscopy (URS) in an in-vivo porcine model. Four renal units in two porcine subjects were used in this study, three experimental units and one control. For the experimental units, RBF was measured by placing an ultrasonic flow cuff around the renal artery, while performing ureteroscopy in the same kidney using a prototype ureteroscope with a pressure sensor at its tip. Irrigation was cycled between two rates to achieve targeted IRPs of 30mmHg and 100mmHg. A control data set was obtained by placing the ultrasonic flow cuff on the contralateral renal artery while performing ipsilateral URS. At high IRP, RBF was reduced in all three experimental trials by 10-20% but not in the control trial. The percentage change in RBF due to alteration in IRP was internally consistent in each porcine renal unit and independent of slower systemic variation in RBF encountered in both the experimental and control units. RBF decreased 10-20% when IRP was increased from 30 to 100mmHg during ureteroscopy in an in-vivo porcine model. While this reduction in RBF is unlikely to have an appreciable effect on tissue oxygenation, it may impact heat-sink capacity in vulnerable regions of the kidney.

Implication of age-related changes on anesthesia management.

Elderly patients have a high risk of perioperative morbidity and mortality. Pluri-morbidities, polypharmacy, and functional dependence may have a great impact on intraoperative management and request specific cautions. In addition to surgical stress, several perioperative noxious stimuli such as fasting, blood loss, postoperative pain, nausea and vomiting, drug adverse reactions, and immobility may trigger a derangement leading to perioperative complications. Older patients have a high risk of major hemodynamic derangement due to aging of the cardiovascular system and associated comorbidities. The hemodynamic monitoring as well as fluid therapy should be the most accurate as possible. Aging is accompanied by decreased renal function, which is related to a reduction in renal blood flow, renal mass, and the number and size of functioning nephrons. Drugs eliminated predominantly by the renal route need dosage adjustments based on residual renal function. Liver mass, hepatic blood flow, and intrinsic metabolic activity are decreased in the elderly, and all drugs metabolized by the liver have a variable half-life, thus requiring dose reduction. Decreased neural plasticity contributes to a high risk for postoperative delirium. Monitoring of anesthesia depth should be mandatory to avoid overdosage of hypnotic drugs. Prevention of postoperative pulmonary complications requires both protective ventilation strategies and adequate recovery of neuromuscular function at the end of surgery. Avoidance of hypothermia cannot be missed. The aim of this review is to describe comprehensive strategies for intraoperative management plans tailored to meet the unique needs of elderly surgical patients, thus improving outcomes in this vulnerable population.

Activation of renal vascular smooth muscle TRPV4 channels by 5-hydroxytryptamine impairs kidney function in neonatal pigs.

Control of microvascular reactivity by 5-hydroxytryptamine (5-HT; serotonin) is complex and may depend on vascular bed type and 5-HT receptors. 5-HT receptors consist of seven families (5-HT1-5-HT7), with 5-HT2 predominantly mediating renal vasoconstriction. Cyclooxygenase (COX) and smooth muscle intracellular Ca2+ levels ([Ca2+]i) have been implicated in 5-HT-induced vascular reactivity. Although 5-HT receptor expression and circulating 5-HT levels are known to be dependent on postnatal age, control of neonatal renal microvascular function by 5-HT is unclear. In the present study, we demonstrate that 5-HT stimulated human TRPV4 transiently expressed in Chinese hamster ovary cells. 5-HT2A is the predominant 5-HT2 receptor subtype in freshly isolated neonatal pig renal microvascular smooth muscle cells (SMCs). HC-067047 (HC), a selective TRPV4 blocker, attenuated cation currents induced by 5-HT in the SMCs. HC also inhibited the 5-HT-induced increase in renal microvascular [Ca2+]i and constriction. Intrarenal artery infusion of 5-HT had minimal effects on systemic hemodynamics but reduced renal blood flow (RBF) and increased renal vascular resistance (RVR) in the pigs. Transdermal measurement of glomerular filtration rate (GFR) indicated that kidney infusion of 5-HT reduced GFR. HC and 5-HT2 receptor antagonist ritanserin attenuated 5-HT effects on RBF, RVR, and GFR. Moreover, the serum and urinary COX-1 and COX-2 levels in 5-HT-treated piglets were unchanged compared with the control. These data suggest that activation of renal microvascular SMC TRPV4 channels by 5-HT impairs kidney function in neonatal pigs independently of COX production.

Effect of beta-blockers on multiple haemodynamics in cirrhosis: A cross-over study by MR-imaging and hepatic vein catheterization.

Non-selective beta-blockers (NSBB) are widely used in the treatment of patients with cirrhosis. Only about 50% respond with a sufficient reduction in their hepatic venous pressure gradient (HVPG) and NSBB may induce detrimental cardiac and renal effects in the presence of severe decompensation. We aimed to assess the effects of NSBB on haemodynamics using magnetic resonance imaging (MRI) and to assess if these haemodynamic changes were related to the disease severity and HVPG response. A prospective cross-over study of 39 patients with cirrhosis. Patients underwent hepatic vein catheterization and MRI with assessments of HVPG, cardiac function, systemic and splanchnic haemodynamics before and after propranolol infusion. Propranolol induced significant decreases in cardiac output (-12%) and blood flow of all vascular compartments, with the largest reductions seen in the azygos venous (-28%), portal venous (-21%), splenic (-19%) and superior mesenteric artery (-16%) blood flow. Renal artery blood flow fell by -5% in the total cohort, with a more pronounced reduction in patients without ascites than in those with ascites (-8% vs. -3%, p = .01). Twenty-four patients were NSBB responders. Their changes in HVPG after NSBB were not significantly associated with other haemodynamic changes. The changes in cardiac, systemic and splanchnic haemodynamics did not differ between NSBB responders and non-responders. The effects of acute NSBB blockade on renal flow seem to depend on the severity of the hyperdynamic state, with the largest reduction in renal blood flow in compensated patients compared to decompensated patients with cirrhosis. However, future studies are needed to assess the effects of NSBB on haemodynamics and renal blood flow in patients with diuretic-resistant ascites.

Post-injury Inhibition of Endothelin-1 Dependent Renal Vasoregulation Mitigates Rhabdomyolysis-Induced Acute Kidney Injury.

In patients with rhabdomyolysis, the overwhelming release of myoglobin into the circulation is the primary cause of kidney injury. Myoglobin causes direct kidney injury as well as severe renal vasoconstriction. An increase in renal vascular resistance (RVR) results in renal blood flow (RBF) and glomerular filtration rate (GFR) reduction, tubular injury, and acute kidney injury (AKI). The mechanisms that underlie rhabdomyolysis-induced AKI are not fully understood but may involve the local production of vasoactive mediators in the kidney. Studies have shown that myoglobin stimulates endothelin-1 (ET-1) production in glomerular mesangial cells. Circulating ET-1 is also increased in rats subjected to glycerol-induced rhabdomyolysis. However, the upstream mechanisms of ET-1 production and downstream effectors of ET-1 actions in rhabdomyolysis-induced AKI remain unclear. Vasoactive ET-1 is generated by ET converting enzyme 1 (ECE-1)-induced proteolytic processing of inactive big ET to biologically active peptides. The downstream ion channel effectors of ET-1-induced vasoregulation include the transient receptor potential cation channel, subfamily C member 3 (TRPC3). This study demonstrates that glycerol-induced rhabdomyolysis in Wistar rats promotes ECE-1-dependent ET-1 production, RVR increase, GFR decrease, and AKI. Rhabdomyolysis-induced increases in RVR and AKI in the rats were attenuated by post-injury pharmacological inhibition of ECE-1, ET receptors, and TRPC3 channels. CRISPR/Cas9-mediated knockout of TRPC3 channels attenuated ET-1-induced renal vascular reactivity and rhabdomyolysis-induced AKI. These findings suggest that ECE-1-driven ET-1 production and downstream activation of TRPC3-dependent renal vasoconstriction contribute to rhabdomyolysis-induced AKI. Hence, post-injury inhibition of ET-1-mediated renal vasoregulation may provide therapeutic targets for rhabdomyolysis-induced AKI.

Impact of intravenous propofol and volatile sevoflurane anesthesia on renal function in an experimental pig model of hemorrhage-induced acute kidney injury

Volatile anesthesia has recently been associated with an independent stimulatory effect on the renal sympathetic nervous system, which causes a reduction in renal blood flow (RBF) and renal excretory function. This anesthetic modality could therefore be a significant contributor to renal injury in the surgical setting. We therefore aimed to investigate the role of anesthetic modality on renal function in an experimental pig model and hypothesized that volatile anesthesia aggravates renal recovery after hemorrhage and resuscitation.Pigs (30±2 kg, 1:1 male-female) were anesthetized with either propofol-fentanyl (P) or sevoflurane-fentanyl (S) and surgically prepared. Renal function and hemodynamics were monitored during a baseline period, a 30-min hemorrhage period, and after 1h recovery after fluid resuscitation with the lost volume (1:1 blood-Ringers Acetate).During baseline, RBF and oxygen delivery (DO 2 ) was significantly lower in the pigs with sevoflurane than propofol anesthesia (RBF P: 191±40 vs S: 130±30 ml min -1 , p&lt;0.001; DO 2 P: 31±5 vs S: 15±3 ml min -1 , p&lt;0.001). Renal vascular resistance (RVR) was also higher in the sevoflurane anesthetized pigs during baseline (P: 0.2±0.05 vs S: 0.5±0.1, p=0.002). There was no statistically different effect of hemorrhage on renal function or hemodynamics between the two anesthetic modalities. Moreover, hemorrhage did not significantly reduce diuresis (P: decreased by 0.7±0.4 ml min -1 , p=0.08; S: decreased by 0.4±0.4 ml min -1 , p=0.38). After resuscitation, both groups recovered similarly regarding hemodynamics and renal function however, creatinine clearance was still significantly decreased in the sevoflurane group compared with baseline (decreased by 37±31 ml min -1 , p=0.02) but recovered in the propofol group. Regarding renal excretory function, no significant differences between the anesthetic modalities were revealed during the experimental protocol.Sevoflurane anesthesia reduced RBF and DO 2 and increased RVR. After hemorrhage and resuscitation, creatinine clearance was significantly lower than before the hemorrhage in the sevoflurane group. Even though this reduction in renal perfusion is in alignment with an increase in renal sympathetic nerve activity, no significant impact of anesthetic modality was seen on renal excretory function. However, sevoflurane anesthesia still has an effect on RBF and creatinine clearance. The choice of anesthesia could therefore effect the incidence of acute kidney injury in patients with higher susceptibility for acute kidney injury. Funding sources: Magnus Bergvall Foundation (2017-02295) and Swedish Research Council (2014-02569 and 2014-07606). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Redistribution of blood flow during exercise is impaired in heart failure with preserved ejection fraction

Exercise intolerance is a cardinal symptom in heart failure with preserved ejection fraction (HFpEF). The underlying pathophysiological mechanisms of HFpEF and their influence on exercise intolerance remains poorly understood. This study investigated the role of re-distribution of blood flow in modulating the increase in hindlimb muscle blood flow during HFpEF.We proposed that exercise intolerance is partially contributed by an impaired ability to divert blood flow from peripheral organs such as the kidney during exercise. We utilised an ovine model of HFpEF in which hypertension was established in aged female sheep. We then examined the mean arterial pressure, heart rate, cardiac output, renal blood flow and hindlimb blood flow response to treadmill exercise in both groups of conscious animals.Animals with HFpEF had elevated left ventricular end diastolic pressures (13 ± 6 vs. 0 ± 1 mmHg, p&lt;0.05) as well as enlarged cardiomyocytes compared to normotensive controls. Exercise in the control animals led to increases in cardiac output and heart rate. These responses were significantly attenuated in HFpEF (increase of 4.5 ± 1 vs. 8 ± 1 L/min, p&lt;0.05) and heart rate (increase of 32 ± 3 vs. 41 ± 4 bpm, p&lt;0.05). In a separate group of instrumented animals, the increase in blood flow to the hindlimb vasculature was attenuated in the HFpEF animals compared to control animals (increase of 2 ± 1 vs. 4 ± 2 L/min, p&lt;0.05). There was a reduction in renal blood flow in the control animals (-150 ± 50 ml/min) and this change was reversed to an increase in the HFpEF animals (+50 ± 20 ml/min).Our results suggest that the exercise intolerance observed in our ovine model of HFpEF may in part be due to an impaired ability to regulate blood flow to the kidney and hindlimb muscles during exercise. RR gratefully acknowledges granting support from the Health Research Council of New Zealand, the University of Auckland Faculty Research Development Fund and the National Heart Foundation of New Zealand. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

S-12-5: IMPAIRMENT OF RENAL BLOOD FLOW AUTOREGULATION AND PRESSURE-NATRIURESIS: ROLE IN THE DEVELOPMENT OF HEART FAILURE IN REN-2 TRANSGENIC HYPERTENSIVE RATS

Objective: The prognosis of patients with heart failure (HF), particularly those who were hypertensive before the onset of HF, remains poor and new therapeutic strategies are needed, based on understanding the pathophysiology of the progression of HF. We hypothesized that the kidney is here not simply a victim but also a culprit of the progression. Specifically, we hypothesized that the impairment of renal blood flow (RBF) autoregulation and pressure-natriuresis relationship is present in the very early HF phase, and precedes HF decompensation. Design and method: In Ren-2 transgenic rats (TGR), a model of hypertension with increased endogenous activity of the renin-angiotensin system (RAS), HF was induced by volume overload achieved by creation of the aorto-caval fistula (ACF). One week after ACF creation or sham-operation animals were prepared for studies evaluating in vivo RBF autoregulatory capacity and pressure-natriuresis relationship after stepwise changes in renal arterial pressure (RAP) that were induced by aortic clamps. Sham-operated TGR were evaluated at physiological level of RAP, then at RAP reduced to 125, 100, 90 and 80 mmHg. In ACF TGR RAP was reduced to 100, 90 and 80 mmHg, followed by period of RAP increased to 125 mmHg. Results: In sham-operated TGR as compared with ACF TGR the basal mean arterial pressure (156 ± 3 vs. 98 ± 3 mmHg), RBF (11.45 ± 0.6 vs. 8.13 ± 0.3 ml.min-1.g-1), urine flow (UF) (38.3 ± 3.1 vs. 8.7 ± 1.0 μl.min-1.g-1) and absolute sodium excretion (UNaV) (4.77 ± 0.54 vs. 0.46 ± 0.11 μmol.min-1.g-1) were all significantly lower. In sham-operated TGR reductions in RAP resulted in significant decreases in RBF whereas in ACF TGR it did not change in response to RAP alterations. Stepwise reductions in RAP resulted in marked decreases in UF and UNaV in sham-operated as well as in ACF TGR, however, these decreases were significantly greater in the former. Conclusions: Our data show that at the physiological RAP level ACF TGR displayed marked reduction in RBF, UF and UNaV as compared with sham-operated TGR. However, in contrast to sham-operated TGR, ACF TGR displayed well-maintained RBF autoregulatory capacity and better slope of pressure-natriuresis relationship. Thus, even in the very early HF stage the renal dysfunction is demonstrable but such dysfunction and the subsequent onset of HF decompensation cannot be simply ascribed to impaired RBF autoregulation and pressure-natriuresis relationship, at least not in the high-output HF model of originally RAS-dependent hypertensive rat.

Dose and Time-Dependent Effects of Caffeine on Cardiovascular Changes Induced by Adenosine

HIGHLIGHTS • Adenosine induces a reduction in blood pressure, heart rate and renal blood flow. • Caffeine (30 mg/kg) blocked all the cardiovascular changes induced by adenosine. • The effect of caffeine lasts for 4 hours.

Tubular Elabela-APJ axis attenuates ischemia-reperfusion induced acute kidney injury and the following AKI-CKD transition by protecting renal microcirculation.

Rationale: Ischemia-reperfusion injury (I/R) is a common cause of acute kidney injury (AKI). Post-ischemic recovery of renal blood supply plays an important role in attenuating injury. Exogenous application of elabela (ELA) peptides has been demonstrated by us and others to alleviate AKI, partly through its receptor APJ. However, the endogenous role of ELA in renal I/R remains unclear. Methods: Renal tubule specific ELA knockout (ApelaKsp KO) mice challenged with bilateral or unilateral I/R were used to investigate the role of endogenous ELA in renal I/R. RNA-sequencing analysis was performed to unbiasedly investigate altered genes in kidneys of ApelaKsp KO mice. Injured mice were treated with ELA32 peptide, Nω-hydroxy-nor-L-arginine (nor-NOHA), prostaglandin E2 (PGE2), Paricalcitol, ML221 or respective vehicles, individually or in combination. Results: ELA is mostly expressed in renal tubules. Aggravated pathological injury and further reduction of renal microvascular blood flow were observed in ApelaKsp KO mice during AKI and the following transition to chronic kidney disease (AKI-CKD). RNA-seq analysis suggested that two blood flow regulators, arginine metabolizing enzyme arginase 2 (ARG2) and PGE2 metabolizing enzyme carbonyl reductases 1 and 3 (CBR1/3), were altered in injured ApelaKsp KO mice. Notably, combination application of an ARG2 inhibitor nor-NOHA, and Paricalcitol, a clinically used activator for PGE2 synthesis, alleviated injury-induced AKI/AKI-CKD stages and eliminated the worst outcomes observed in ApelaKsp KO mice. Moreover, while the APJ inhibitor ML221 blocked the beneficial effects of ELA32 peptide on AKI, it showed no effect on combination treatment of nor-NOHA and Paricalcitol. Conclusions: An endogenous tubular ELA-APJ axis regulates renal microvascular blood flow that plays a pivotal role in I/R-induced AKI. Furthermore, improving renal blood flow by inhibiting ARG2 and activating PGE2 is an effective treatment for AKI and prevents the subsequent AKI-CKD transition.

Collectrin (Tmem27) deficiency in proximal tubules causes hypertension in mice and a TMEM27 variant associates with blood pressure in males in a Latino cohort.

Collectrin (Tmem27), an angiotensin-converting enzyme 2 homologue, is a chaperone of amino acid transporters in the kidney and endothelium. Global collectrin knockout (KO) mice have hypertension, endothelial dysfunction, exaggerated salt sensitivity, and diminished renal blood flow. This phenotype is associated with altered nitric oxide and superoxide balance and increased proximal tubule (PT) Na+/H+ exchanger isoform 3 (NHE3) expression. Collectrin is located on the X chromosome where genome-wide association population studies have largely been excluded. In the present study, we generated PT-specific collectrin KO (PT KO) mice to determine the precise contribution of PT collectrin in blood pressure homeostasis. We also examined the association of human TMEM27 single-nucleotide polymorphisms with blood pressure traits in 11,926 Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Hispanic/Latino participants. PT KO mice exhibited hypertension, and this was associated with increased baseline NHE3 expression and diminished lithium excretion. However, PT KO mice did not display exaggerated salt sensitivity or a reduction in renal blood flow compared with control mice. Furthermore, PT KO mice exhibited enhanced endothelium-mediated dilation, suggesting a compensatory response to systemic hypertension induced by deficiency of collectrin in the PT. In HCHS/SOL participants, we observed sex-specific single-nucleotide polymorphism associations with diastolic blood pressure. In conclusion, loss of collectrin in the PT is sufficient to induce hypertension, at least in part, through activation of NHE3. Importantly, our model supports the notion that altered renal blood flow may be a determining factor for salt sensitivity. Further studies are needed to investigate the role of the TMEM27 locus on blood pressure and salt sensitivity in humans.NEW & NOTEWORTHY The findings of our study are significant in several ways: 1) loss of an amino acid chaperone in the proximal tubule is sufficient to cause hypertension, 2) the results in global and proximal tubule-specific collectrin knockout mice support the notion that vascular dysfunction is required for salt sensitivity or that impaired renal tubule function causes hypertension but is not sufficient to cause salt sensitivity, and 3) our study is the first to implicate a role of collectrin in human hypertension.

Hypertension depresses arterial baroreflex control of both heart rate and cardiac output during rest, exercise, and metaboreflex activation.

Rapid regulation of arterial blood pressure on a beat-by-beat basis occurs primarily via arterial baroreflex control of cardiac output (CO) via rapid changes in heart rate (HR). Previous studies have shown that changes in HR do not always cause changes in CO, because stroke volume may vary. Whether these relationships are altered in hypertension is unknown. Using the spontaneous baroreflex sensitivity (SBRS) approach, we investigated whether baroreflex control of HR and CO were impaired after the induction of hypertension in conscious, chronically instrumented canines at rest, during mild exercise, and during exercise with metaboreflex activation (induced via reductions in hindlimb blood flow) both before and after induction of hypertension (induced via a modified Goldblatt approach-unilateral reduction in renal blood flow to ∼30% of control values until systolic pressure ≥ 140 mmHg and a diastolic pressure ≥ 90 mmHg for >30 days). After induction of hypertension, SBRS control of both HR and CO was reduced in all settings. In control, only about 50% of SBRS changes in HR caused changes in CO. This pattern was sustained in hypertension. Thus, in hypertension, the reduced SBRS in the control of HR caused reduced SBRS control of CO and this likely contributes to the increased incidence of orthostatic hypotension seen in hypertensive patients.