Administration Of Acetazolamide Research Articles

Effect of Acetazolamide on Obesity-Induced Glomerular Hyperfiltration: A Randomized Controlled Trial.

AimsObesity is an important risk factor for the development of chronic kidney disease. One of the major factors involved in the pathogenesis of obesity-associated kidney disease is glomerular hyperfiltration. Increasing salt-delivery to the macula densa is expected to decrease glomerular filtration rate (GFR) by activating tubuloglomerular feedback. Acetazolamide, a carbonic anhydrase inhibitor which inhibits salt reabsorption in the proximal tubule, increases distal salt delivery. Its effects on obesity-related glomerular hyperfiltration have not previously been studied. The aim of this investigation was to evaluate whether administration of acetazolamide to obese non diabetic subjects reduces glomerular hyperfiltration.Materials and MethodsThe study was performed using a randomized double-blind crossover design. Obese non-diabetic men with glomerular hyperfiltration were randomized to receive intravenously either acetazolamide or furosemide at equipotent doses. Twelve subjects received the allocated medications. Two weeks later, the same subjects received the drug which they had not received during the first study. Inulin clearance, p-aminohippuric acid clearance and fractional lithium excretion were measured before and after medications administration. The primary end point was a decrease in GFR, measured as inulin clearance.ResultsGFR decreased by 21% following acetazolamide and did not decrease following furosemide. Renal vascular resistance increased by 12% following acetazolamide, while it remained unchanged following furosemide administration. Natriuresis increased similarly following acetazolamide and furosemide administration. Sodium balance was similar in both groups.ConclusionsIntravenous acetazolamide decreased GFR in obese non-diabetic men with glomerular hyperfiltration. Furosemide, administered at equipotent dose, did not affect GFR, suggesting that acetazolamide reduced glomerular hyperfiltration by activating tubuloglomerular feedback.Trial RegistrationClinicalTrials.gov NCT01146288

Acetazolamide protects steatotic liver grafts against cold ischemia reperfusion injury.

Ischemia reperfusion injury (IRI) is a primary concern in liver transplantation, especially when steatosis is present. Acetazolamide (AZ), a specific carbonic anhydrase (CA) inhibitor, has been suggested to protect against hypoxia. Here, we hypothesized that AZ administration could be efficient to protect fatty livers against cold IRI. Obese Zucker rat livers were preserved in Institut Georges Lopez-1 storage solution for 24 hours at 4°C and ex vivo perfused for 2 hours at 37°C. Alternatively, rats were also treated with intravenous injection of AZ (30 mg/kg) before liver recovery. Liver injury, hepatic function, and vascular resistance were determined. CA II protein levels and CA hydratase activity were assessed as well as other parameters involved in IRI (endothelial nitric oxide synthase, mitogen activated protein kinase family, hypoxic inducible factor 1 alpha, and erythropoietin). We demonstrated that AZ administration efficiently protects the steatotic liver against cold IRI. AZ protection was associated with better function, decreased vascular resistance, and activation of endothelial nitric oxide synthase. This was consistent with an effective mitogen activated protein kinase inactivation. Finally, no effect on the hypoxic inductible factor 1 alpha/erythropoietin pathway was observed. The present study demonstrated that AZ administration is a suitable pharmacological strategy for preserving fatty liver grafts against cold IRI.

The pH low insertion peptide pHLIP Variant 3 as a novel marker of acidic malignant lesions

Current strategies for early detection of breast and other cancers are limited in part because some lesions identified as potentially malignant do not develop into aggressive tumors. Acid pH has been suggested as a key characteristic of aggressive tumors that might distinguish aggressive lesions from more indolent pathology. We therefore investigated the novel class of molecules, pH low insertion peptides (pHLIPs), as markers of low pH in tumor allografts and of malignant lesions in a mouse model of spontaneous breast cancer, BALB/neu-T. pHLIP Variant 3 (Var3) conjugated with fluorescent Alexa546 was shown to insert into tumor spheroids in a sequence-specific manner. Its signal reflected pH in murine tumors. It was induced by carbonic anhydrase IX (CAIX) overexpression and inhibited by acetazolamide (AZA) administration. By using (31)P magnetic resonance spectroscopy (MRS), we demonstrated that pHLIP Var3 was retained in tumors of pH equal to or less than 6.7 but not in tissues of higher pH. In BALB/neu-T mice at different stages of the disease, the fluorescent signal from pHLIP Var3 marked cancerous lesions with a very low false-positive rate. However, only ∼60% of the smallest lesions retained a pHLIP Var3 signal, suggesting heterogeneity in pH. Taken together, these results show that pHLIP can identify regions of lower pH, allowing for its development as a theranostic tool for clinical applications.

CT perfusion with acetazolamide challenge in C6 gliomas and angiogenesis.

BackgroundThis study was performed to investigate the correlation between CT perfusion with acetazolamide challenge and angiogenesis in C6 gliomas.MethodsThirty-two male Sprague-Dawley rats were evaluated. The rats were divided randomly to four groups: eight rats with orthotopically implanted C6 gliomas at 10-days old (Group A), eight rats with gliomas at 14-days old (Group B), eight rats with gliomas at 18-days old (Group C), eight rats with orthotopically injected normal saline served as controls. CT perfusion was performed before and after administration of acetazolamide. Changes in perfusion parameters due to acetazolamide administration were calculated and analyzed.ResultsElevated carbon dioxide partial pressure and decreased pH were found in all 32 rats post acetazolamide challenge (P<0.01). Cerebral blood flowpre-challenge was increased in group C (95.0±2.5 ml/100g/min), as compared to group B (80.1±11.3 ml/100g/min) and group A (63.1±2.1 ml/100g/min). Cerebral blood flow percentage changes were detected with a reduction in group C (54.2±4.8%) as compared to controls (111.3±22.2%). Cerebral blood volume pre-challenge was increased in group C (50.8±1.7ml/100g), as compared to group B (45.7±1.9 ml/100g) and group A (38.2±0.8 ml/100g). Cerebral blood volume percentage changes were decreased in group C (23.5±4.6%) as compared to controls (113.5±30.4%). Angiogenesis ratio = [(CD105-MVD) / (FVIII-MVD)] ×100%. Positive correlations were observed between CD105-microvessel density, angiogenesis ratio, vascular endothelial growth factor, proliferation marker and cerebral blood flowpre-challenge, cerebral blood volume pre-challenge. Negative correlations were observed between CD105-microvessel density and cerebral blood flow percentage changes (P<0.01, correlation coefficient r=-0.788), cerebral blood volume percentage changes (P<0.01, r=-0.703). Negative correlations were observed between angiogenesis ratio, vascular endothelial growth factor, proliferation marker and cerebral blood flow percentage changes, cerebral blood volume percentage changes.ConclusionOur findings suggest that CT perfusion with challenge can provide new insight into non-invasive assessment of rat C6 glioma angiogenesis.

Comparison of Preoperative Oral Acetazolamide and Intraperitoneal Normal Saline Irrigation for Reduction of Postoperative Pain After Laparoscopic Cholecystectomy

Visceral and shoulder tip pain following laparoscopic cholecystectomy is mainly due to carbon dioxide (CO2) insufflation. Various methods have been adopted to eliminate residual CO2. We compared the postoperative analgesic efficacy of intraperitoneal normal saline (30 mL/kg) irrigation with preoperative oral acetazolamide administration in patients undergoing laparoscopic cholecystectomy. Sixty patients between 20 and 60 years of age were included in this prospective, randomized, double-blind study. Patients in Group I received placebo, Group II patients received preoperative oral acetazolamide (5 mg/kg), and Group III patients received intraperitoneal irrigation with 30 mL/kg of normal saline. Intravenous paracetamol (1 g) was administered every 6 hours for postoperative analgesia. Parietal and visceral pain scores at rest, on movement, and on coughing and shoulder tip pain were recorded using a visual analog scale after arrival in the postanesthesia care unit, at 1, 2, 4, 6, 12, and 24 hours after surgery. Rescue analgesia was provided with an intravenous fentanyl (1 μg/kg) bolus whenever the visual analog scale score was ≥4. Compared with Group I, Group III patients had significantly lower visceral pain scores at all time intervals except at 12 hours. Group III patients also recorded significantly lower visceral pain scores than Group II from 2 to 24 hours. There was no significant difference in shoulder tip pain. The total dose of fentanyl used was significantly less in Group III. Intraperitoneal normal saline irrigation is more effective than acetazolamide in reducing postoperative visceral pain after laparoscopic cholecystectomy and has significant opioid-sparing effect. However, its effect on shoulder pain is comparable to that of acetazolamide.

Carbonic anhydrase XII in valve interstitial cells promotes the regression of calcific aortic valve stenosis

AimsCalcific aortic valve stenosis (CAVS) is the most common heart valve disease. In the present work we sought to determine the reversibility of mineralization in the aortic valve. Methods and resultsBy using in vitro analyses we found that valve interstitial cells (VICs) have the ability to resorb minerals. We documented that agonist of P2Y2 receptor (P2Y2R) promoted the expression of carbonic anhydrase XII (CAXII) at the cell membrane of VICs, whereby minerals are resorbed. P2Y2R-mediated mineral resorption was corroborated by using mouse VICs isolated from wild type and P2Y2R−/− mice. Measurements of extracellular pH (pHe) by using core–shell nanosensors revealed that P2Y2R-mediated CAXII export to the cell membrane led to an acidification of extracellular space, whereby minerals are resorbed. In vivo, we next treated LDLR−/−/ApoB100/100/IGF2 mice, which had developed CAVS under a high-fat/high-sucrose diet for 8months, with 2-thioUTP (a P2Y2R agonist) or saline for the next 2months. The administration of 2-thioUTP (2mg/kg/day i.p.) reduced the mineral volume in the aortic valve measured with serial microCT analyses, which improved hemodynamics and reduced left ventricular hypertrophy (LVH). Examination of leaflets at necropsy confirmed a lower level of mineralization and fibrosis along with higher levels of CAXII in mice under 2-thioUTP. In another series of experiment, the administration of acetazolamide (a CA inhibitor) prevented the acidification of leaflets and the regression of CAVS induced by 2-thioUTP in LDLR−/−/ApoB100/100/IGF2 mice. ConclusionP2Y2R-mediated expression of CAXII by VICs acidifies the extracellular space and promotes the regression of CAVS.

Abstract T P105: Decrease in Noninvasive Fractional Flow on MRA Is a Useful Marker of Misery Perfusion on SPECT

Background: Cerebrovascular reactivity to acetazolamide on 123I-IMP SPECT is used to detect misery perfusion due to intracranial atherosclerosis. Noninvasive fractional flow reserve (FFR) on time-of-flight magnetic resonance angiography (TOF-MRA) can provide a feasible alternative to identify high-risk intracranial atherosclerosis. We here demonstrate the association between FFR on TOF-MRA and cerebral blood flow pattern on 123I-IMP SPECT. Methods: Patients with a unilateral middle cerebral artery (MCA) stenosis who underwent both TOF-MRA and 123I-IMP SPECT with acetazolamide administration were retrospectively recruited from our radiology database. Signal intensity (SI) was measured in the background, proximal and distal to the stenotic lesion in the MCA on TOF-MRA. Adjusted FFR was calculated: FFR = [distal SI - background SI] / [proximal SI - background SI]. Mean cerebral blood flow (CBF) at rest, CBF after acetazolamide administration, and cerebrovascular reactivity (CVR) were measured in the target MCA territory. CBF patterns of MCA were divided into three: Stage II, CBF at rest of &lt; 80% in that of normal subject and CVR below 10%; Stage 0, CVR over 30% regardless of CBF at rest, and Stage I, any other CBF patterns. We sought the optimum cut-off point for FFR to identify MCA territories with Stage II CBF on 123I-IMP SPECT. Results: A total of 41 sets of diagnostic imaging in 23 patients (mean age 57 y; 14 men, 9 women) was assessed. Four (9.8%) MCA territories demonstrated Stage II, 21 (51.2%) stage I, and 16 (39.0%) stage 0. Mean FFR of MCA with Stage II pattern was 0.59 (IQR 0.38 - 0.69), Stage I was 0.78 (IQR 0.70- 0.92), and Stage 0 was 0.90 (IQR 0.81 - 0.93). The optimal cut-off point for FFR to predict Stage II was ≤ 0.7 (sensitivity 100%; specificity 86%). Conclusion: In patients with unilateral MCA lesions, an FFR decrease was correlated with misery perfusion on 123I-IMP SPECT with acetazolamide, which may be a more feasible predictor of high-risk intracranial stenosis.

Is acetazolamide really useful in the management of traumatic cerebrospinal fluid rhinorrhea?

Traumatic cerebrospinal fluid (CSF) rhinorrhea is a serious and potentially fatal condition as it may lead to meningitis. As acetazolamide decreases CSF production and hence CSF pressure, it has been proposed that the medication may help in curing CSF rhinorrhea. There is no definitive evidence, however, that acetazolamide is actually beneficial in treating traumatic CSF rhinorrhea. The aim of this study was to determine if the administration of acetazolamide in patients of head trauma with CSF rhinorrhea was beneficial in decreasing the duration of CSF rhinorrhea. The acid-base and electrolyte changes caused by the drug were also studied. We conducted a single center randomized prospective study. Forty-four patients of head trauma with CSF rhinorrhea were divided into two groups, the experimental group (21 patients) was given acetazolamide; and, the control group (23 patients) did not receive the medication. The median duration of CSF leak in days, and the electrolyte changes observed on administration of the medication were recorded in both the groups. Both the experimental and control groups were well matched in terms of age, sex, mechanism of injury, Glasgow Coma Scale (GCS) and the type of skull fracture. The median duration of CSF leak in the control group was of 4 days and in the study group, of 5 days. Acetazolamide caused significant metabolic acidosis and hypokalemia (as shown by decreased serum pH, serum bicarbonate and serum potassium levels) in the experimental group when compared to the control group. Acetazolamide did not influence the resolution of traumatic CSF rhinorrhea and instead lead to significant metabolic and electrolyte disturbances.

Hypoxia, not pulmonary vascular pressure, induces blood flow through intrapulmonary arteriovenous anastomoses.

Blood flow through intrapulmonary arteriovenous anastomoses (IPAVA) is increased by acute hypoxia during rest by unknown mechanisms. Oral administration of acetazolamide blunts the pulmonary vascular pressure response to acute hypoxia, thus permitting the observation of IPAVA blood flow with minimal pulmonary pressure change. Hypoxic pulmonary vasoconstriction was attenuated in humans following acetazolamide administration and partially restored with bicarbonate infusion, indicating that the effects of acetazolamide on hypoxic pulmonary vasoconstriction may involve an interaction between arterial pH and PCO2. We observed that IPAVA blood flow during hypoxia was similar before and after acetazolamide administration, even after acid-base status correction, indicating that pulmonary pressure, pH and PCO2 are unlikely regulators of IPAVA blood flow. Blood flow through intrapulmonary arteriovenous anastomoses (IPAVA) is increased with exposure to acute hypoxia and has been associated with pulmonary artery systolic pressure (PASP). We aimed to determine the direct relationship between blood flow through IPAVA and PASP in 10 participants with no detectable intracardiac shunt by comparing: (1) isocapnic hypoxia (control); (2) isocapnic hypoxia with oral administration of acetazolamide (AZ; 250 mg, three times a day for 48 h) to prevent increases in PASP; and (3) isocapnic hypoxia with AZ and 8.4% NaHCO3 infusion (AZ + HCO3 (-) ) to control for AZ-induced acidosis. Isocapnic hypoxia (20 min) was maintained by end-tidal forcing, blood flow through IPAVA was determined by agitated saline contrast echocardiography and PASP was estimated by Doppler ultrasound. Arterial blood samples were collected at rest before each isocapnic-hypoxia condition to determine pH, [HCO3(-)] and Pa,CO2. AZ decreased pH (-0.08 ± 0.01), [HCO3(-)] (-7.1 ± 0.7 mmol l(-1)) and Pa,CO2 (-4.5 ± 1.4 mmHg; P < 0.01), while intravenous NaHCO3 restored arterial blood gas parameters to control levels. Although PASP increased from baseline in all three hypoxic conditions (P < 0.05), a main effect of condition expressed an 11 ± 2% reduction in PASP from control (P < 0.001) following AZ administration while intravenous NaHCO3 partially restored the PASP response to isocapnic hypoxia. Blood flow through IPAVA increased during exposure to isocapnic hypoxia (P < 0.01) and was unrelated to PASP, cardiac output and pulmonary vascular resistance for all conditions. In conclusion, isocapnic hypoxia induces blood flow through IPAVA independent of changes in PASP and the influence of AZ on the PASP response to isocapnic hypoxia is dependent upon the H(+) concentration or Pa,CO2.

Paradoxical normoxia-dependent selective actions of inorganic nitrite in human muscular conduit arteries and related selective actions on central blood pressures.

Inorganic nitrite dilates small resistance arterioles via hypoxia-facilitated reduction to vasodilating nitric oxide. The effects of nitrite in human conduit arteries have not been investigated. In contrast to nitrite, organic nitrates are established selective dilators of conduit arteries. We examined the effects of local and systemic administration of sodium nitrite on the radial artery (a muscular conduit artery), forearm resistance vessels (forearm blood flow), and systemic hemodynamics in healthy male volunteers (n=43). Intrabrachial sodium nitrite (8.7 μmol/min) increased radial artery diameter by a median of 28.0% (25th and 75th percentiles, 25.7% and 40.1%; P<0.001). Nitrite (0.087-87 μmol/min) displayed conduit artery selectivity similar to that of glyceryl trinitrate (0.013-4.4 nmol/min) over resistance arterioles. Nitrite dose-dependently increased local cGMP production at the dose of 2.6 μmol/min by 1.1 pmol·min(-1)·100 mL(-1) tissue (95% confidence interval, 0.5-1.8). Nitrite-induced radial artery dilation was enhanced by administration of acetazolamide (oral or intra-arterial) and oral raloxifene (P=0.0248, P<0.0001, and P=0.0006, respectively) but was inhibited under hypoxia (P<0.0001) and hyperoxia (P=0.0006) compared with normoxia. Systemic intravenous administration of sodium nitrite (8.7 μmol/min) dilated the radial artery by 10.7% (95% confidence interval, 6.8-14.7) and reduced central systolic blood pressure by 11.6 mm Hg (95% confidence interval, 2.4-20.7), augmentation index, and pulse wave velocity without changing peripheral blood pressure. Nitrite selectively dilates conduit arteries at supraphysiological and near-physiological concentrations via a normoxia-dependent mechanism that is associated with cGMP production and is enhanced by acetazolamide and raloxifene. The selective central blood pressure-lowering effects of nitrite have therapeutic potential to reduce cardiovascular events.

Acetazolamide for the Management of Chronic Metabolic Alkalosis in Neonates and Infants

In this study, we evaluated the efficacy and safety of acetazolamide in the management of chronic metabolic alkalosis in neonates and infants with chronic respiratory insufficiency. A retrospective chart review of 90 patients treated with acetazolamide between 2006 and 2007 admitted to the neonatal intensive care unit was performed. Blood gases and electrolytes obtained at baseline and by 24 hours after acetazolamide administration were compared. Compared with baseline and after 24 hours of acetazolamide, mean measured serum bicarbonate (29.5±3.7 vs. 26.9±3.8 mEq/L, P<0.001) and base excess (10.0±3.4 vs. 4.8±4.0 mEq/L, P<0.001) were significantly lower. No significant differences in other electrolytes, blood urea nitrogen, and urine output were noted, except for an increased serum chloride and creatinine. Uncompensated respiratory acidosis developed in 4 (3.1%) treatment courses. Acetazolamide may be effective in decreasing serum bicarbonate in carefully selected patients. Its use and safety as an adjunctive therapy for chronic metabolic alkalosis in neonates and infants with chronic respiratory insufficiency needs further study.

New mucoadhesive polymeric film for ophthalmic administration of acetazolamide.

This article reports the results concerning the design and manufacture of a novel polymeric film for ocular administration of acetazolamide (AZM), and a patent document presented to INPI- National Institute of Industrial/Intelectual Property. The system was designed using mucoadhesive polymers, such as carbomer (CB974P) and sodium carboxymethylcellulose (NaCMC), combined with the poloxamer (POL407) which behaves as a swelling modulator, surfactant and slightly plasticizer. The maximum amount of AZM to be incorporated without loss of homogeneity or precipitation of the drug, was 0.04 mg AZM/mg of the film. The addition of a polymeric coating based on Eudragit RSPO (cationic permeable polymethacrylate polymer) allowed optimizing drug release. The coating in a proportion of 10% (determined as percentage of total weight of the film) seemed to be the most adequate, since 80% of controlled drug release was achieved along 240 minutes. This coating membrane did not affect the mucoadhesive properties of the swellable polymers. Thus, the system obtained, showed good efficiency and the intra ocular pressure (IOP) decreased according to the results derived from in vivo studies performed on normotensive rabbits. Finally, irritation scored studies demonstrated that these systems were not irritant for rabbit´s ocular mucosa.

Neuronal activation induced BOLD and CBF responses upon acetazolamide administration in patients with steno-occlusive artery disease

Blood-oxygenation-level-dependent (BOLD) MRI is widely used for inferring neuronal activation and is becoming increasingly popular for assessing cerebrovascular reactivity (CVR) when combined with a vasoactive stimulus. The BOLD signal contains changes in cerebral blood flow (CBF) and thus information regarding neurovascular coupling and CVR. The BOLD signal, however, is also modulated by changes in cerebral blood volume (CBV) and cerebral metabolic rate of oxygen (CMRO2), as well as changes in the physiological baseline state. Here, we measured BOLD and CBF responses upon neuronal (visual) activation, before and after a vasodilatory challenge (acetazolamide, ACZ) in patients with vertebrobasilar steno-occlusive disease. After ACZ, the neuronal activation induced BOLD response was reduced or even negative (3 out of 8 subjects), whereas the CBF response remained similar. We show that BOLD alone cannot correctly assess the neuronal activation and underlying neurovascular coupling. The generally assumed positive relationship between BOLD and CBF responses may be severely compromised under changes in the physiological baseline state. Accompanying CBF measurements contain crucial information, and simulations suggest an altered flow–metabolism coupling in these patients.

Paradoxical reduction of cerebral blood flow after acetazolamide loading: a hemodynamic and metabolic study with (15)O PET.

Paradoxical reduction of cerebral blood flow (CBF) after administration of the vasodilator acetazolamide is the most severe stage of cerebrovascular reactivity failure and is often associated with an increased oxygen extraction fraction (OEF). In this study, we aimed to reveal the mechanism underlying this phenomenon by focusing on the ratio of CBF to cerebral blood volume (CBV) as a marker of regional cerebral perfusion pressure (CPP). In 37 patients with unilateral internal carotid or middle cerebral arterial (MCA) steno-occlusive disease and 8 normal controls, the baseline CBF (CBF(b)), CBV, OEF, cerebral oxygen metabolic rate (CMRO2), and CBF after acetazolamide loading in the anterior and posterior MCA territories were measured by (15)O positron emission tomography. Paradoxical CBF reduction was found in 28 of 74 regions (18 of 37 patients) in the ipsilateral hemisphere. High CBF(b) (> 47.6 mL/100 mL/min, n = 7) was associated with normal CBF(b)/CBV, increased CBV, decreased OEF, and normal CMRO2. Low CBF(b) (< 31.8 mL/100 mL/min, n = 9) was associated with decreased CBF(b)/CBV, increased CBV, increased OEF, and decreased CMRO2. These findings demonstrated that paradoxical CBF reduction is not always associated with reduction of CPP, but partly includes high-CBF(b) regions with normal CPP, which has not been described in previous studies.

CrossTalk opposing view: Loop gain is not a consequence of obstructive sleep apnoea.

CrossTalk opposing view: Loop gain is not a consequence of obstructive sleep apnoea.

Illness at high altitudes.

Illness at high altitudes.

Aquaporin‐1 translocation and degradation mediates the water transportation (1062.2)

Acetazolamide (AZA), a prototype of carbonic anhydrase (CA) inhibitor, acts as a diuretic agent with its site of action on renal proximal tubules. These nephron segments also contain aquaporin‐1 (AQP1) water channels, which is required for the formation of concentrated urine. In the present study we examined the role of AQP1 on the diuretic effect of AZA. By using in vivo and in vitro models, we found that the AZA increased the urine volume from 8 hrs to 14 days. However, total CAs activity was decreased within 8 hours and then gradually recovered to the normal level and the CAs protein expression was increased at the beginning of AZA treatment. AQP1 was significantly reduced after AZA administration for 7 days. When combined with NaHCO3, AZA had a more pronounced diuretic effect. But it didn’t induce CA isozymes expression and the CAs activity anymore. However, AQP1 expression was still inhibited from day 7. AZA increased AQP1 ubiquitination in the HK‐2 cell membrane followed by the degradation induced by proteasome. By using the coimmunoprecipitation and the surface plasmon resonance (SPR) methods, we found that AZA facilitated AQP1 translocation onto cell membrane by promoting the interaction of AQP1 and myosin heavy chain (MHC). And this process was mediated by ERK and myosin light chain kinase (MLCK) pathway. These findings indicate that AZA promotes AQP1 translocation and degradation, which may partially mediates the effect of AZA.Grant Funding Source: the National Natural Science Foundation of China (No. 91129727, 81020108031, 30973558)

Assessment of cerebral tissue oxygen saturation in septic patients during acetazolamide provocation — A near infrared spectroscopy study

Sepsis-associated encephalopathy is a multifactorially determined process of the brain parenchyma. Among other factors, vasogenic causes have been shown to play a role in its development. The aim of the present work was to assess whether cerebral tissue oxygen saturation is influenced by administration of acetazolamide in septic patients compared to controls. 15 patients with severe sepsis and 10 healthy controls were studied. Cerebral oxygen saturation was assessed by INVOS 51 OOC Cerebral Oxymeter (NIRS) before and after administration of 15 mg/kg BW acetazolamide in both groups. The maximal rise that has been found in the partial pressure of CO(2) in the arterial blood of septic patients after administration of acetazolamide was from 35 ± 5 mmHg to 41.1 ± 6.3 mmHg. For the partial pressure of O(2) the observed increase was from 123.7 ± 47.1 mmHg to 139.9 ± 49 mmHg. Vasodilatory stimulus resulted in a similar maximal increase in cerebral oxygen saturation in septic patients and in controls (8.9 ± 6.5% for septic patients and 9.2 ± 4.6% for healthy persons, respectively). Cerebral vasoreactivity to acetazolamide is preserved in patients with severe sepsis.

Inhibition of Carbonic Anhydrase Augments GABAA Receptor-Mediated Analgesia via a Spinal Mechanism of Action

Peripheral nerve injury (PNI) negatively influences spinal gamma-aminobutyric acid (GABA)ergic networks via a reduction in the neuron-specific potassium-chloride (K+-Cl–) cotransporter (KCC2). This process has been linked to the emergence of neuropathic allodynia. In vivo pharmacologic and modeling studies show that a loss of KCC2 function results in a decrease in the efficacy of GABAA-mediated spinal inhibition. One potential strategy to mitigate this effect entails inhibition of carbonic anhydrase activity to reduce HCO3–-dependent depolarization via GABAA receptors when KCC2 function is compromised. We have tested this hypothesis here. Our results show that, similarly to when KCC2 is pharmacologically blocked, PNI causes a loss of analgesic effect for neurosteroid GABAA allosteric modulators at maximally effective doses in naïve mice in the tail-flick test. Remarkably, inhibition of carbonic anhydrase activity with intrathecal acetazolamide rapidly restores an analgesic effect for these compounds, suggesting an important role of carbonic anhydrase activity in regulating GABAA-mediated analgesia after PNI. Moreover, spinal acetazolamide administration leads to a profound reduction in the mouse formalin pain test, indicating that spinal carbonic anhydrase inhibition produces analgesia when primary afferent activity is driven by chemical mediators. Finally, we demonstrate that systemic administration of acetazolamide to rats with PNI produces an antiallodynic effect by itself and an enhancement of the peak analgesic effect with a change in the shape of the dose-response curve of the α1-sparing benzodiazepine L-838,417. Thus, carbonic anhydrase inhibition mitigates the negative effects of loss of KCC2 function after nerve injury in multiple species and through multiple administration routes resulting in an enhancement of analgesic effects for several GABAA allosteric modulators. We suggest that carbonic anhydrase inhibitors, many of which are clinically available, might be advantageously employed for the treatment of pathologic pain states. PerspectiveUsing behavioral pharmacology techniques, we show that spinal GABAA-mediated analgesia can be augmented, especially following nerve injury, via inhibition of carbonic anhydrases. Carbonic anhydrase inhibition alone also produces analgesia, suggesting these enzymes might be targeted for the treatment of pain.

A case of Bardet-Biedl syndrome complicated with intracranial hypertension in a Japanese child

Bardet-Biedl syndrome (BBS) is a rare heterogeneous autosomal recessive disorder characterized by rod-cone dystrophy, postaxial polydactyly, truncal obesity, hypogonadism, learning disability, and renal anomaly that are caused by ciliary dysfunction. 16 genes have been associated with the BBS phenotype. Although recent pathophysiological studies using animal models have shown that ciliary dysfunction may induce hydrocephalus, there have been no reports of BBS with intracranial hypertension. We here describe a 9-year-old Japanese girl who was diagnosed as having BBS and later received renal transplantation due to chronic renal failure. She also exhibited intracranial hypertension, including papilledema and increased intrathecal pressure (260–300mmH2O), but her brain magnetic resonance imaging was normal. No genetic abnormalities were detected by DNA chip analysis or exome sequencing. Her papilledema improved following administration of acetazolamide. This is the first report of a case of BBS complicated with intracranial hypertension and its treatment.