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Author(s): Toshinori Kasai [sup.1] , Eiji Hashiba [sup.1] , Junichi Saito [sup.1] , Kazuyoshi Hirota [sup.1] Author Affiliations: (1) Department of Anesthesiology, Hirosaki University Postgraduate School of Medicine, 5 Zaifu-cho, [...], The initial distribution volume of glucose (IDVG) has been reported to be a surrogate marker of cardiac preload. However, the relationship between cardiac output and IDVG is not fully understood. We investigated the effects of cardiac output on IDVG in the absence of fluid gain or loss in pigs. Materials and methods Thirteen pigs were anesthetized and allocated to either the modified cardiac output group (m-CO group, n = 10) or the control group (control group, n = 3). In the m-CO group, CO was sequentially modulated from high CO (high CO) to two grades of low CO (low CO-1 and low CO-2) with dobutamine and propranolol with lidocaine, respectively, in the absence of any apparent change in basal fluid volume status. Thermodilutional CO and IDVG were measured at each CO condition. The IDVG was measured according to a one-compartment model with 2 g glucose. The same parameters were measured in the control group using the same time schedule as for the m-CO group but without inotropes and at a stable CO state. Thereafter, 250 ml of 10% dextran were infused over 15 min to compare the effects of a preload-dependent increase in CO on IDVG measurements to the effects of the pharmacological modification of CO. Data were expressed as the mean ± SD. Statistical analysis was performed with repeated measures ANOVA followed by Dunnett's test. Pearson's correlation test was also used. A P value of Results In the m-CO group, where CO increased to 147.2 ± 26.7% of the baseline CO value in the high CO state and decreased to 65.9 ± 11.0 and 37.3 ± 14.4% of the baseline CO value in the low CO-1 state and the low CO-2 state, respectively, the IDVG did not change as CO was modified. IDVG significantly increased in response to volume loading of dextran in the control group. There was no correlation between the IDVG and CO in the m-CO group when there was no fluid gain or loss (r = 0.097, n = 40, P = 0.554), but the IDVG was well correlated with CO in the control group with volume loading (r = 0.764, n = 18, P = 0.0002). Conclusion This study suggests that the IDVG is dependent on the central extracellular fluid volume and not on cardiac output.

Background: We evaluated the correlation between regional oxygen saturation (rSO2) in the frontal and right renal dorsum (cerebral rSO2 and somatic rSO2) measured by near‐infrared spectroscopy (INVOS™ 5100C, Medtronic) and central venous oxygen saturation (ScvO2) measured with a fiber‐optic oximetry catheter (PediaSat™, Edwards Lifesciences) during surgery in order to determine whether noninvasive rSO2 could be used as an alternative to ScvO2 in pediatric cardiac surgery patients. We evaluated the correlation between regional tissue oxygen saturation (cerebral rSO2 and somatic rSO2) measured by near‐infrared spectroscopy and other patient measures with central venous oxygen saturation (ScvO2) measured with a fiber‐optic oximetry catheter to track global oxygen supply demand as a potential alternative or supplement to ScvO2. Patients and Methods: This single‐center prospective observational study enrolled 33 children (weight < 10 kg) who underwent cardiac surgery for congenital heart disease between February 2018 and November 2021. ScvO2, cerebral rSO2, and somatic rSO2 were recorded simultaneously after anesthesia induction and central venous catheter placement. Pearson's correlation coefficient and Bland–Altman analysis were used to determine the relationship between ScvO2 and rSO2. We conducted correlation, Bland Altman, and multiple regression analyses to identify associations between rSO2, patient measures, and ScvO2 values. Results: The patients' median age was 11.0 (quartile 2.0–16.0) months. Their weight was 7.2 (quartile 4.5–9.2) kg. Cerebral rSO2 was significantly positively correlated with ScvO2 (r2 = 0.29, p =.002 in all patients; r2 = 0.61, p =.013 in the patients without mixing at the atrial level), whereas somatic rSO2 was not. The Bland–Altman analysis demonstrated biases [95% confidence interval; 95% CI] (lower and upper limits of agreement [95% CI]) of 0.27% [−4.26 to 4.80] (−24.79 [−32.61 to −16.96] to 25.33 [17.50 to 33.16]) between cerebral rSO2 and ScvO2 and 0.91% [−5.48 to 7.30] (−34.43 [−45.47 to −23.39] to 36.25 [25.21 to 47.29]) between somatic rSO2 and ScvO2. Preoperative brain natriuretic peptide (BNP) and SpO2 were independent variables associated with ScvO2 and cerebral and somatic rSO2. Conclusion: Cerebral rSO2, SpO2, and BNP were significantly correlated with ScvO2, although the cerebral rSO2 correlation was greater for lesions without atrial mixing. rSO2, BNP, and SpO2 might be used to track changes in ScvO2 but cerebral rSO2 is not sufficiently precise to replace it. [ABSTRACT FROM AUTHOR]

Author(s): Junichi Saito[sup.1] , Eiji Hashiba[sup.2] , Tetsuya Kushikata[sup.1] , Akio Mikami[sup.3] , Kazuyoshi Hirota[sup.1] Author Affiliations: (1) Department of Anesthesiology, Hirosaki University Graduate School of Medicine, 036-8562, Hirosaki, Japan [...], Presepsin is a useful marker for differentiating sepsis from non-infection-related systemic inflammatory response syndrome. There are data describing elevated presepsin concentrations in patients with kidney dysfunction even in the absence of sepsis, but corresponding data for patients with end-stage kidney disease (ESKD) undergoing living kidney transplantation (LKT) are lacking. We investigated the changes in presepsin concentrations in this patient group in order to elucidate any relationship with renal function. Written informed consent was obtained from patients with ESKD requiring hemodialysis who underwent LKT from June 2014 through March 2015 at Hirosaki University Hospital. Patients with obvious signs of infection were excluded. Perioperative presepsin and procalcitonin concentrations were measured before induction of anesthesia, on admission to the intensive care unit after surgery, and on postoperative day (POD) 1 and POD 2. Preoperative presepsin concentration was markedly higher than the upper limit of normal in patients with ESKD (1252 ± 451 pg/mL). Presepsin concentrations consistently decreased after LKT. Moreover, presepsin concentration was strongly correlated with serum creatinine (r.sup.2 = 0.72, n = 24, p < 0.001). These data suggest that the kidney clearly plays an important role in the metabolism and excretion of presepsin.

Introduction Appropriate adjustment of cardiac preload is essential to maintain cardiac output (CO), especially in patients following cardiac surgery, but the evaluation is not easily performed because either impairment of [...], Purpose Appropriate adjustment of cardiac preload is essential to maintain cardiac output (CO), especially in patients after cardiac surgery. This study was intended to determine whether index of right ventricular end-diastolic volume (RVEDVI), corrected RVEDVI using ejection fraction (cRVEDVI), index of initial distribution volume of glucose (IDVGI), or cardiac filling pressures are correlated with cardiac index (CI) following cardiac surgery in the presence or absence of arrhythmias. Methods Eighty-six consecutive cardiac surgical patients were studied. Patients were divided into two groups: the non-arrhythmia (NA) group (n = 72) and the arrhythmia (A) group (n = 14). Three sets of measurements were performed: on admission to the ICU and daily on the first 2 postoperative days. The relationship between each cardiac preload variable and cardiac index (CI) was evaluated. A p value less than 0.05 indicated statistically significant differences. Results Each studied variable was not different between the two groups immediately after admission to the ICU. cRVEDVI had a linear correlation with CI in both group (NA group: r = 0.67, n = 216, p < 0.001; A group: r = 0.77, n = 42, p < 0.001), but RVEDVI had a poor correlation with CI (NA group: r = 0.27, n = 216, p < 0.001; A group: r = 0.19, n = 42, p = 0.036). IDVGI had a linear correlation with CI (NA group: r = 0.49, n = 216, p < 0.001; A group: r = 0.61, n = 42, p < 0.001), Cardiac filling pressures had no correlation with CI. Conclusion Our results demonstrated that cRVEDVI and IDVGI were correlated with CI in the presence or absence of arrhythmias. cRVEDVI and IDVGI have potential as indirect cardiac preload markers following cardiac surgery. Keywords Cardiac surgery * Cardiac preload * Cardiac output

Introduction Lung injury following pulmonary resection with no identifiable cause, especially after pneumonectomy, has been termed postpneumonectomy pulmonary edema, and has alarmed both anesthesiologists and thoracic surgeons because of its [...], We report a case in which a 2-year-old girl who underwent a right middle and lower lung lobectomy for congenital cystic adenomatoid malformation suffered massive bleeding and developed acute respiratory distress syndrome (ARDS) during the operation. She was ventilated with a high level of [F.sub.I][O.sub.2] (0.75-1.0), PEEP (10-20 cm[H.sub.2]O), and PIP (33-55 cm[H.sub.2]O) to maintain SP[O.sub.2] (>90%). Following transfer to the ICU, continuous hemodialysis was introduced to reduce excessive blood volume. However, pulmonary oxygenation did not improve, and marked subcutaneous emphysema occurred on postoperative day 3 (POD 3). We introduced venovenous (V-V) extracorporeal membrane oxygenation (ECMO) to rest the lung, and V-V ECMO was changed to right and left atrial ECMO because of unsatisfactory oxygen support on POD 23. A CT scan showed almost the entire lung had collapsed, even though we had administered diuretics, steroids, nitric oxide, sivelestat, and surfactant for ARDS. We applied high-frequency oscillatory ventilation (HFOV) with a mean airway pressure of 20 cm[H.sub.2]O, frequency of 9.2 Hz, and amplitude of 38 cm[H.sub.2]O on POD 45. The collapsed lung was then gradually recruited, and pulmonary oxygenation improved (P/F ratio = 434). ECMO was successfully weaned on POD 88. The patient required a tracheostomy, but she was able to function without a ventilator on POD 142. Although HFOV has failed to show a mortality benefit in ARDS patients, the unique lung recruitment by HFOV can be a useful therapeutic option for severe ARDS patients in combination with sufficient lung rest produced by ECMO. Keywords Extracorporeal membrane oxygenation * High-frequency oscillatory ventilation * ARDS * Postpneumonectomy pulmonary edema

Background: Peripherally inserted central catheters (PICCs) are typically placed under fluoroscopy. We used a magnetic tracking and electrocardiogram-based tip confirmation system for insertion of a PICC insertion in a morbidly obese patient at the bedside. Case presentation: A 53-year-old female with severe obesity (height, 160 cm; weight, 217 kg; BMI, 84.8 kg/m2) was admitted to the intensive care unit. Both bilateral, inguinal, and cervical regions were covered with an excess of adipose tissue, making it difficult to place a central venous line. Since transferring her to fluoroscopy seemed dangerous, a PICC was inserted using Sherlock 3CG® TCS at the bedside. Magnetic sensor guidance failed due to the thick subcutaneous tissue her precordium, but intracavity electrocardiography could direct the tip to an appropriate position. Conclusion: We experienced bedside insertion of a PICC into a patient with BMI of 84.8 kg/m2 patient using a Sherlock 3CG® TCS. Since the interaction between Sherlock 3CG® TCS and body habitus has not been investigated, further reports are needed. [ABSTRACT FROM AUTHOR]

Prolonged ICU stays are associated with high costs and increased mortality. Thus, early prediction of such stays would help clinicians to plan initial interventions, which could lead to efficient utilization of ICU resources. The aim of this study was to develop models for predicting prolonged stays in Japanese ICUs using APACHE II, APACHE III and SAPS II scores. In this multicenter retrospective cohort study, we analyzed the cases of 85,558 patients registered in the Japanese Intensive care Patient Database between 2015 and 2019. Prolonged ICU stay was defined as an ICU stay of >14 days. Multivariable logistic regression analyses were performed to develop three predictive models for prolonged ICU stay using APACHE II, APACHE III and SAPS II scores, respectively. After exclusions, 79,620 patients were analyzed, 2,364 of whom (2.97%) experienced prolonged ICU stays. Multivariable logistic regression analyses showed that severity scores, BMI, MET/RRT, postresuscitation, readmission, length of stay before ICU admission, and diagnosis at ICU admission were significantly associated with higher risk of prolonged ICU stay in all models. The present study developed predictive models for prolonged ICU stay using severity scores. These models may be helpful for efficient utilization of ICU resources. [ABSTRACT FROM AUTHOR]

Summary: Background: The tissue dielectric constant (TDC) method uses an open‐ended coaxial probe to achieve non‐invasive measurement of water content in skin. The aim of our study was to test the hypothesis that the changes in circulating blood volume would be associated with the changes in TDC values in patients undergoing haemodialysis. Methods: In this prospective descriptive study, TDC measurements were performed for three parts of the body (the face, shin and hand) before and after patients underwent haemodialysis (N = 83). The primary outcome measure was the correlation between the amount of water removal and ΔTDC at each body site measured (ΔTDC = posthaemodialysis TDC–prehaemodialysis TDC). The secondary outcome measure was the mean difference in TDC value before and after haemodialysis. Results: The TDC values measured at each part of the body were significantly reduced after haemodialysis, but the percentage difference between pre‐ haemodialysis and posthaemodialysis was small for the face, shin and hand, with %mean ± SE values of −4.4 ± 0.70, −3.2 ± 0.98 and −6.0 ± 1.6; 95 per cent confidence intervals (lower bound to upper bound) of 3.0–5.8, 1.3–5.2 and 2.7–9.2; and P values of P = 0.000, P = 0.000 and P = 0.000, respectively. The inverse correlation between ΔTDC and the amount of water removal was also weak (correlation at the face, r = −0.25, P = 0.028; at the shin, r = −0.26, P = 0.018; and at the hand, no significant correlation). Conclusion: Our results indicate that TDC measurement can be used to assess the changes in local oedema, but may be unlikely to evaluate real‐time changes in the circulating blood volume in a clinical setting. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to identify risk factors associated with postoperative delirium in patients undergoing urological surgery. Methods: We prospectively evaluated pre- and postoperative risk factors for postoperative delirium in consecutive 215 patients who received urological surgery between August 2013 and November 2014. Preoperative factors included patient demographics, comorbidities, and frailty assessment. Frailty was measured by handgrip strength, fatigue scale of depression, fall risk assessment, and gait speed (the timed Get-up and Go test). Postoperative factors included types of anesthesia, surgical procedure, renal function and serum albumin decline, blood loss, surgery time, highest body temperature, and complications. Uni- and multivariate logistic regression analyses were performed to assess pre- and postoperative predictors for the development of postoperative delirium. Results: Median age of this cohort was 67 years. Ten patients (4.7%) experienced postoperative delirium. These patients were significantly older, had weak handgrip strength, a higher fall risk assessment score, slow gait speed, and greater renal function decline compared with patients without delirium. Multivariate analysis revealed slow gait speed (>13.0 s) and rapid renal function decline (>30%) were independent risk factors for postoperative delirium. Conclusions: Slow gait speed and rapid renal function decline after urological surgery are significant factors for postoperative delirium. These data will be helpful for perioperative patient management. This study was registered as a clinical trial: UMIN: R000018809. [ABSTRACT FROM AUTHOR]

Phe4 in the nociceptin (NC) sequence has been identified as the most critical residue for receptor interaction. In the present study, we investigated the pharmacological activity of a series of NC(1-13)NH2 analogues, in which the hydrogen atom in the para position of Phe4 was substituted with F, NO2, CN, Cl, Br, I, CH3, OH or NH2. In receptor binding studies, performed using CHO cells expressing the recombinant human NC receptor (CHOhOP4) and in rat cerebral cortex membranes, [(pF)Phe4]NC (1-13)NH2, [(pNO2)Phe4]NC(1-13)NH2, and [(pCN)Phe4NC(1-13)NH2 displayed higher affinity than NC(1-13)NH2. The affinity of [(pCl)Phe4]NC(1-13)NH2 was essentially identical to that of NC(1-13)NH2, while the remaining compounds displayed reduced affinity. In a series of functional assays (stimulation of GTPγS binding in CHOhOP4 cells and rat cerebral cortex membranes and inhibition of cAMP accumulation in CHOhOP4 cells), the para substituted analogues behaved as full agonists (with the exception of [(pOH)Phe4]NC(1-13)NH2 which acted as a partial agonist in the GTPγS binding assays) with the following rank order potency: pF = pNO2 ≥ pCN ≥ NC = NC(1 - 13)NH2 = pCl ≥ pBr > pI = pCH3 > pOH > pNH2 [(pF)Phe4]NC(1-13)NH2 and [(pNO2)Phe4NC(1-13)NH2 were either inactive or displayed micromolar potencies in cAMP accumulation experiments performed on cells expressing classical opioid receptors. All compounds were full agonists in isolated tissues from various species (guinea pig ileum, mouse colon and mouse/rat vas deferens) with the exception of [(pOH)Phe4]NC(1-13)NH2 which displayed partial agonist/weak antagonist activities. The rank order of potency was similar to that found in the other assays. The effects of all analogues were not modified by naloxone. The selective OP4 receptor antagonist [Nphe¹]NC(1-13)NH2, tested in all preparations against one or both of the highly potent derivatives [(pF)Phe4]NC(1-13)NH2 and [(pNO2)Phe4]NC( 1-13)NH2, showed pA2 values similar to those found against NC, the pA2 in the GTPγS binding/rat cerebral cortex assay being much higher (ca. 7.5) than in the other functional assays (ca. 6). This study further supports the notion that Phe4 of NC is the critical residue for receptor occupation and activation. Moreover, as part of this study, we have identified two novel, highly potent and selective agonists for the OP4 receptor, [(pF)Phe4]NC(1-13)NH2 and [(pNO2)Phe4]NC(1-13)NH2. [ABSTRACT FROM AUTHOR]

The lack of availability of a selective, highly potent, competitive antagonist for the nociceptin receptor (OP4) devoid of residual agonistic activity has hampered studies in this area. We report here the in vitro pharmacological properties of the novel non-peptide OP4 antagonist, J-113397, which was recently discovered by Banyu Pharmaceutical investigators. The compound was synthesized as a racemic mixture in our laboratories. J-113397 was shown to antagonize (pA2 7.52) the nociceptin-induced inhibition of cAMP formation in cells expressing the recombinant human OP4 receptor (CHOhOP4) and to displace [125I]Tyr14nociceptin from CHOhOP4 membranes with a pKi of 8.56. It also competitively antagonized the contractile actions of nociceptin in the mouse colon (pA2 8.07) and the inhibitory effect of nociceptin in electrically stimulated preparations such as the mouse vas deferens (pA2 7.85), the guinea pig ileum (7.75), and the rat vas deferens (7.77). At high concentrations (10 µM), the compound was devoid of agonist activity in the mouse vas deferens and CHOhOP4, while it contracted the mouse colon and increased the twitch response of the rat vas deferens, and produced a naloxone-sensitive inhibition of the electrically evoked twitches in the guinea pig ileum. pA2 values for the new antagonist against deltorphin I in the mouse vas deferens (OP1 receptors), or against dermorphin in the guinea pig ileum (OP3 receptors), etorphine in the rat vas deferens (OP receptors), U69593 in the rabbit vas deferens (OP2 receptors) and endomorphin 1 in the mouse colon (OP3 receptors) were lower than 6. Taken together, these data indicate that J-113397 is a high-affinity, selective and competitive antagonist of the OP4 receptor; this novel pharmacological tool will be of great value in studies directed at evaluating the physiological roles of the nociceptin/OP4 system. [ABSTRACT FROM AUTHOR]

Clazosentan, a potent selective endothelin receptor subtype A antagonist, has been demonstrated to be effective in preventing cerebral vasospasms after subarachnoid hemorrhage. We report the successful management of respiratory failure due to pulmonary edema associated with clazosentan, with a hemodynamic monitoring system. A 49-year-old Japanese man underwent emergency clipping for a right internal carotid-posterior communicating artery aneurysm. The surgery and general anesthesia for the rupture proceeded with no complications. Clazosentan was administered from postoperative day 1 to prevent cerebral vasospasm. He presented with respiratory failure six days post surgery and chest X-ray imaging showed pulmonary edema. In our intensive care unit, the patient's N-terminal pro-brain natriuretic peptide was 476 pg/mL although trans-thoracic echography indicated a normal left ventricular ejection fraction (>60%) and normal diastolic function. The hemodynamic monitoring system showed 11 L/minute cardiac output and a cardiac index of 5.6 L/minute/m 2 . We thus diagnosed the cause of the patient's respiratory failure as due to excessive volume, as an adverse event of clazosentan. We changed the cerebral vasospasm-preventive drug to fasudil hydrochloride hydrate and forced urination. His body weight dropped approximately 9 kg as of day 9 in the ICU and he was weaned off the ventilator 23 days post surgery. This case indicates the importance of optimal infusion in patients with clazosentan. Optimal fluid management using a hemodynamic monitoring system could be useful for clazosentan-induced respiratory failure., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Kinoshita et al.)

Background: Initial distribution volume of glucose (IDVG), which is not associated with significant modification of glucose metabolism, has been proposed as an indicator of the central extracellular fluid volume status in adults. However, data on IDVG in children are lacking. This study examined pharmacokinetic data on IDVG in children and compared IDVG with other clinical variables., Methods: In total, 128 daily data sets from 60 consecutive pediatric intensive care patients (body weight ≥8.0 kg), consisting mostly of children undergoing cardiovascular surgery, were studied. Either 1 or 2 g of glucose based on body weight (approximately 0.1 g/kg) was administered. IDVG could not be determined from ten data sets from eight children because of body movement-associated glucose fluctuation during measurement. In the remaining 113 data sets from 55 children, IDVG was determined by applying the one-compartment model. Approximated IDVG based on the incremental plasma glucose level at 3 min postinjection (1-point IDVG), and approximated IDVG based on incremental plasma glucose levels at 3 and 5 min postinjection (2-point IDVG), were also calculated. Postoperative daily IDVG and the relationship between IDVG and cardiac output or circulating blood volume (CBV) were evaluated when data were available., Results: Convergence was assumed in each glucose clearance curve. Mean indexed IDVG (IDVGI) of the first measurement in 55 children was 144 ± 22 (SD) mL/kg, which was associated with a plasma glucose disappearance rate (Ke-glucose) of 0.094 ± 0.033/min. Bias and precision were smaller between 2-point IDVG and standard IDVG than between 1-point IDVG and standard IDVG (-0.02 ± 0.13 L versus 0.07 ± 0.20 L, p <0.001). Postoperative IDVGI in 37 children after cardiovascular surgery increased daily on postoperative days 1-2 (p ≤0.011). Linear correlations were observed between IDVGI and indexed cardiac output (r = 0.588, n = 28, p <0.001) and between IDVGI and indexed CBV (r = 0.547, n = 25, p = 0.0047)., Conclusions: IDVG is a potential marker of fluid volume status in children, even though body movement-associated glucose fluctuation is a major limitation. Two-point IDVG is preferable to 1-point IDVG for approximated IDVG.

Background: Hypotension is common in the early postoperative stages after abdominothoracic esophagectomy for esophageal cancer. We examined the ability of stroke volume variation (SVV), pulse pressure variation (PPV), central venous pressure (CVP), intrathoracic blood volume (ITBV), and initial distribution volume of glucose (IDVG) to predict fluid responsiveness soon after esophagectomy under mechanical ventilation (tidal volume >8 mL/kg) without spontaneous respiratory activity., Methods: Forty-three consecutive non-arrhythmic patients undergoing abdominothoracic esophagectomy were studied. SVV, PPV, cardiac index (CI), and indexed ITBV (ITBVI) were postoperatively measured by single transpulmonary thermodilution (PiCCO system) after patient admission to the intensive care unit (ICU) on the operative day. Indexed IDVG (IDVGI) was then determined using the incremental plasma glucose concentration 3 min after the intravenous administration of 5 g glucose. Fluid responsiveness was defined by an increase in CI >15% compared with pre-loading CI following fluid volume loading with 250 mL of 10% low molecular weight dextran., Results: Twenty-three patients were responsive to fluids while 20 were not. The area under the receiver-operating characteristic (ROC) curve was the highest for CVP (0.690) and the lowest for ITBVI (0.584), but there was no statistical difference between tested variables. Pre-loading IDVGI (r = -0.523, P <0.001), SVV (r = 0.348, P = 0.026) and CVP (r = -0.307, P = 0.046), but not PPV or ITBVI, were correlated with a percentage increase in CI after fluid volume loading., Conclusions: These results suggest that none of the tested variables can accurately predict fluid responsiveness early after abdominothoracic esophagectomy.

Background: Urotensin II (UII) and its receptor (UT) are implicated in mood disorders, such as stress and anxiety, and this may result, at least in part, from increased norepinephrine release from the cerebral cortex. Benzodiazepines have been widely used as hypnotics and anxiolytics, producing a decrease in cerebrocortical norepinephrine release. We hypothesized that there was some interaction between benzodiazepines and the UII system in the cerebral cortex., Methods: In the present study, we have examined the effects of benzodiazepines on UII-increased norepinephrine release from rat cerebrocortical slices and intracellular Ca(2+) concentrations ([Ca(2+)]i) in HEK293 cells expressing rat UT receptor (HEK293-rUT cells)., Results: Midazolam, diazepam and flunitrazepam concentration-dependently inhibited UII-evoked norepinephrine release but did not affect [Ca(2+)]i. The IC(50) of midazolam for inhibition of UII-evoked norepinephrine release (0.32 microM, P < 0.01) was significantly lower than that of diazepam (187 microM) or flunitrazepam (40 microM). The inhibitory effects of midazolam on UII-evoked norepinephrine release were significantly attenuated by flumazenil, a benzodiazepine site antagonist., Conclusion: The present study suggests that midazolam, at clinically relevant concentration, significantly inhibited UII-evoked norepinephrine release. This inhibitory effect may be partially mediated via central benzodiazepine receptors.