Administration Of Salt Research Articles

Abstract 082: Intrarenal Nacl Boli Cause Longlasting Inhibition of Renal Sympathetic Nerve Activity (RSNA)

Afferent renal nerve fibers from the kidney likely counterregulate salt sensitive blood pressure increases by decreasing renal sympathetic nerve activity. We recently reported on a long-lasting tonic sympatho-inhibition due to intrarenal afferent renal nerve stimulation eliciting a TRPV1 dependent neuro-humoral pathway. We wanted to test the hypothesis that sodium influences this afferent sympatho-depressory mechanism. Groups of anesthetized SD rats (n=8) were equipped with femoral catheters (blood pressure (BP) & heart rate (HR) recording, drug application), a renal arterial catheter for intrarenal administration (IRA) of high salt (10 % NaCl, 10 μl) or Capsaicin (CAP 3.3, 6.6, 10, 33*10-7 M, 10 μl) and a bipolar electrode for RSNA recordings; eventually an intravenous (iv) bolus of the NK1-receptor blocker RP67580 (10*10-3M, 15 μl) was given. Cultured dorsal root ganglion neurons (Th11-L2) of rats with renal afferents were investigated in current clamp mode to assess action potential generation or in voltage clamp mode to investigate inward currents during 10 sec superperfusion to 4.5 % NaCl or equiosmotic mannitol. solution Results are given in mean±SEM. IRA high salt and IRA CAP decreased RSNA from baseline 4.1±0.6 μV*sec to 2.2±0.8 μV*sec (10% NaCl, p<0.05) and 3.9±0.5 μV*sec to 0.9±0.2 μV*sec (CAP, p<0.01). Suppressed RSNA in high salt groups and CAP could be unmasked by systemic (i.v.) administration of the NK1-blocker (2.7±1.8 μV*sec to 5.8±2.2 μV*sec; p<0.05 (10% NaCl); 1.0±0.2 μV*sec to 6.1±1.5 μV*sec; p<0.01 (CAP)). Cultured renal neurons exhibited production of action potentials (3.5±0.8*, from baseline, p<0.05) and increased sustained inward currents from baseline during exposure to NaCl 4.5 % (-10708.8±3546.5 pA*, from baseline, p<0.05). No responses to equiosmolar mannitol. Increased intrarenal sodium concentrations might induce long-lasting sympatho-depression via a neuro-humoral TRPV1 dependent and tachykinin mediated afferent nerve pathway from the kidney. Impairment of this sympatho-depressory mechanism could be involved in salt sensitive hypertension.

Intrarenal High Salt Administration Causes Tonic Inhibition of Renal Sympathetic Nerve Activity (RSNA)

Afferent renal nerve fibers from the kidney likely counterregulate salt sensitive blood pressure increases by decreasing renal sympathetic nerve activity. We recently reported on a long‐lasting tonic sympatho‐inhibition due to intrarenal afferent renal nerve stimulation eliciting a TRPV1 dependent neuro‐humoral pathway. We wanted to test the hypothesis that sodium influences this afferent sympatho‐depressory mechanism.Groups of anesthetized SD rats (n=8) were equipped with femoral catheters (blood pressure (BP) & heart rate (HR) recording, drug application), a renal arterial catheter for intrarenal administration (IRA) of high salt (10 % NaCl, 10 μl) or Capsaicin (CAP 3.3, 6.6, 10, 33*10–7 M, 10 μl) and a bipolar electrode for RSNA recordings; eventually an intravenous (iv) bolus of the NK1‐receptor blocker RP67580 (10*10–3M, 15 μl) was given. Cultured dorsal root ganglion neurons (Th11‐L2) of rats with renal afferents were investigated in current clamp mode to assess action potential generation or in voltage clamp mode to investigate inward currents during 10 sec exposure to 4.5 % NaCl or equi‐osmotic 20% mannitol. Results are given in mean±SEM.IRA high salt and IRA CAP decreased RSNA from baseline 4.1±0.6 μV*sec to 2.2±0.8 μV*sec (10% NaCl, p<0.05) and 3.9±0.5 μV*sec to 0.9±0.2 μV*sec (CAP, p<0.01). Suppressed RSNA in high salt groups and CAP could be unmasked by systemic (i.v.) administration of the NK1‐blocker (2.7±1.8 μV*sec to 5.8±2.2 μV*sec; p<0.05 (10% NaCl); 1.0±0.2 μV*sec to 6.1±1.5 μV*sec; p<0.01 (CAP)). Cultured renal neurons exhibited production of action potentials (3.5±0.8*, from baseline, p<0.05) and increased sustained inward currents from baseline during exposure to NaCl 4.5 % (−10708.8±3546.5 pA*, from baseline, p<0.05). No responses to mannitol 20%.Increased intrarenal sodium concentrations might induce long‐lasting sympatho‐depression via a neuro‐humoral TRPV1 dependent and tachykinin mediated afferent nerve pathway from the kidney. Impairment of this sympatho‐depressory mechanism could be involved in salt sensitive hypertension.Support or Funding InformationDFG Deutsche Forschungsgemeinschaft VE 104/4‐1This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Liquid chromatography coupled with hybrid ion trap time-of-flight mass spectrometry method for the determination of caulophine in rat bio-samples and its pharmacokinetic study after intragastric and intraperitoneal administration.

A rapid and precise liquid chromatography coupled with hybrid ion trap/time-of-flight mass spectrometry method to detect and quantify caulophine and its possible active metabolites in rat plasma and urine was developed. Samples were prepared by plasma protein precipitation combined with a liquid-liquid extraction method. The separation was carried out on an InertSustain® C18 column with a mobile phase comprising methanol and 0.1% aqueous formic acid solution. The analysis was complete in 20min with a flow rate of 0.4mL/min. Taspine was used as the internal standard. Mass spectrometric detection was conducted with hybrid ion trap/time-of-flight equipped with electrospray ionization in the positive ion mode. The calibration curves of caulophine were linear over the concentration ranges of 0.002-0.20μg/mL for plasma and 0.005-0.50μg/mL for urine with the correlation coefficients greater than 0.998 in both cases. The method was successfully used to investigate the pharmacokinetics and bioavailability in rat plasma and urine samples after intragastric and intraperitoneal administration of caulophine sodium salt.

Lithium increases ammonium excretion leading to altered urinary acid-base buffer composition.

Previous reports identify a voltage dependent distal renal tubular acidosis (dRTA) secondary to lithium (Li+) salt administration. This was based on the inability of Li+-treated patients to increase the urine-blood (U-B) pCO2 when challenged with NaHCO3 and, the ability of sodium neutral phosphate or Na2SO4 administration to restore U-B pCO2 in experimental animal models. The underlying mechanisms for the Li+-induced dRTA are still unknown. To address this point, a 7days time course of the urinary acid-base parameters was investigated in rats challenged with LiCl, LiCitrate, NaCl, or NaCitrate. LiCl induced the largest polyuria and a mild metabolic acidosis. Li+-treatment induced a biphasic response. In the first 2days, proper urine volume and acidification occurred, while from the 3rd day of treatment, polyuria developed progressively. In this latter phase, the LiCl-treated group progressively excreted more NH4+ and less pCO2, suggesting that NH3/NH4+ became the main urinary buffer. This physiological parameter was corroborated by the upregulation of NBCn1 (a marker of increased ammonium recycling) in the inner stripe of outer medulla of LiCl treated rats. Finally, by investigating NH4+ excretion in ENaC-cKO mice, a model resistant to Li+-induced polyuria, a primary role of the CD was confirmed. By definition, dRTA is characterized by deficient urinary ammonium excretion. Our data question the presence of a voltage-dependent Li+-induced dRTA in rats treated with LiCl for 7 days and the data suggest that the alkaline urine pH induced by NH3/NH4+ as the main buffer has lead to the interpretation dRTA in previous studies.

Do Pharmaceuticals Improve Driving in Individuals with ADHD? A Review of the Literature and Evidence for Clinical Practice.

Attention-deficit/hyperactivity disorder (ADHD) is defined as a disorder of impaired attention and/or behavioral control. Studies suggest that the condition can dispose individuals to a higher risk of automobile accidents. ADHD symptoms respond to pharmacotherapy in a majority of uncomplicated cases. Evidence on how pharmacotherapies for ADHD impact driving behavior or outcomes could allow clinicians to support on-road safety rationally. We therefore undertook a review to identify the evidence base to date indicating positive or negative effects of pharmacotherapies on driving behavior in individuals with ADHD. Further, we evaluated the level of evidence for these effects, their specificity to ADHD, and how they may inform clinical care. We identified studies involving pharmacotherapy for ADHD that evaluated driving-related activities or outcomes. We then categorized these studies by the mode of measurement used and by the ADHD specificity of the driving behaviors measured. Finally, we extracted themes of interest to clinical practice in pharmacologic intervention. In total, 14 studies, involving 2-61 subjects diagnosed with ADHD, looked at computer-measured, observer-measured, or self-reported driving behavior correlates of pharmacotherapy during simulation or on-road driving. Of these studies, 13 involved psychostimulant agents and two used atomoxetine. All but three investigations (one of methylphenidate, one of mixed amphetamine salts, and one of atomoxetine) found favorable changes in measures such as steering and braking behaviors or reaction to unexpected events. One study found adverse effects on driving at hour 17 following mixed amphetamine salt administration. Four studies compared two pharmacotherapies, and each found differences in measured driving behavior between the therapies. One study explored impact on ADHD-specific driving impairments, and the same study was the only one to explore correlation of clinical measures (ADHD symptoms and self-reported driving behavior) with medication-associated changes-finding dissociation between changes in ADHD symptoms and changes in measured driving measures. While data to date are limited on the ADHD-specific effects of pharmacotherapies used for ADHD on driving, it is clear from our review that these agents have effects on driving-relevant behaviors. Further research is urgently needed to develop an evidence base for clinically predictable effects of pharmacotherapy on driving safety in individuals with ADHD. If possible, clinicians should evaluate the positive and negative effects of pharmacotherapy on driving in their clients.

Abstract P153: Mineralocorticoid Receptor Inhibition Abolishes Sex-specific, Renin Angiotensin Aldosterone System-associated Salt Sensitivity in Female Mice

Up to half of essential hypertension cases in women are associated with salt sensitive blood pressure (BP) increases, however, the sex-specific mechanisms of salt sensitivity in women are unknown. Our lab has shown that female mice are more sensitive to the hypertensive effects of aldosterone than male mice but it is unknown if aldosterone plays a role in salt sensitivity in female mice. We hypothesized that increasing dietary sodium via a high salt diet would increase blood pressure in female mice which would be abrogated by mineralocorticoid receptor (MR) antagonism. To determine salt sensitivity male and female Balb/C mice were implanted with radiotelemeters for continuous recording of BP. BP was recorded during baseline (7 days) and throughout the administration of a high salt (4% NaCl, HS) diet for 7 days with or without concurrent eplerenone supplementation (daily 200 mg/kg/day). Plasma and kidneys were then harvested. Systolic (SBP) and diastolic (DBP) BP were increased in female mice, but not in males, on HS (7.8±3.3 SBP and 7.8±4.0 DBP Δ change in mmHg in female (P<0.05) vs -3.7±3.1 SBP and 3.1±2.1 DBP in male, respectively, n=7-8). Plasma aldosterone levels were decreased in HS male mice compared to control (224±57 vs 151±19 pg/ml, n=3-5), however, increased modestly in HS females (254±56 vs 394±158 pg/ml, n=3-6). Preliminary data indicated that MR antagonism with eplerenone ablated increases in SBP and DBP in HS female mice, while having no effect on blood pressure in HS males (-22.8 SBP and -23.9 DBP Δ change in mmHg in female vs 1.0 SBP and -1.5 DBP in male, n=2). In addition, and in association with an absence of aldosterone suppression with HS, renal mRNA expression of renin (1.4±0.1-fold, P<0.05, n=5), angiotensinogen (4.4±0.2-fold, P<0.05, n=5), AT1 receptor (52.9±0.9-fold, P<0.05, n=5), MR (1.6±0.2-fold, P<0.05, n=5) and α-ENAC (1.3±0.0-fold, P<0.05, n=5) were increased in HS female mice compared to control females. These data indicate that BP increases in HS female mice are associated with unexpected increases in plasma aldosterone as well as mRNA expression of proteins associated with renin angiotensin aldosterone system activation, which may be novel mechanisms via which females have increased risk for salt sensitive hypertension.

Abstract P475: What’s in a Letter: N vs. J Determines Responses to Ang II/DOCA and DPP4 Gene Deletion

Activation of the renin-angiotensin-aldosterone system (RAAS) drives blood pressure (BP) responses and kidney injury in humans and rodent models. Previously, we reported activation of dipeptidyl peptidase 4 (DPP4) by RAAS which may play an important role in BP responses and kidney injury. Classically, either angiotensin II (Ang II) or deoxycorticosterone (DOCA)-salt administration to mice, raises their BP over a period of hours to days. Recently, the two have been combined to elicit more robust kidney injury and proteinuria. Although there are not many head to head comparison studies, it is known through historical association that different strains of mice have different baseline BPs and vary in their response to vasoconstrictor agents for BP peaks as well as associated kidney injury. In this regard, the C57Bl/6J and C57Bl/6N mice are genetically very similar although they differ with respect to their responses to circadian rhythm on salt sensitivity to BP. Therefore, we hypothesized that J versus N strain will have differential BP responses to Ang II/DOCA and kidney injury susceptibility. C57Bl/6 J and N mice ( DPP4 +/+ and DPP4 -/- ) were subjected to Ang II/DOCA salt infusion for 2 weeks (Ang II 1000ng/kg/min via miniosmotic pumps, DOCA 50mg pellet, 0.9% saline in drinking water) and compared to mice receiving saline only (osmotic pumps). BP was measured by Millar catheter. Kidney injury was quantified via albuminuria and histology. While the Ang II/DOCA treated J strain had mean BP (MBP) of 135mmHg, the Ang II/DOCA treated N strain had MBP of 125mmHg. There was no effect of DPP4 gene deletion on BP in either strain. The J strain treated with Ang II/DOCA salt had higher albuminuria when compared to the N strain (180ug/ml vs. 60ug/ml). DPP4 -/- mice on the J strain receiving Ang II/DOCA had a relative improvement in albuminuria (120ug/ml vs. 180ug/ml). Surprisingly, the DPP4 -/- mice on the N strain had higher albuminuria when compared to the DPP4 +/+ mice receiving Ang II/DOCA (143ug/ml vs. 60ug/ml). Taken together, our results suggest that mice strain plays an important role in BP and kidney injury responses to Ang II/DOCA and DPP4 gene deletion. These results highlight the importance of selecting patient populations carefully to maximize the benefit of DPP4 inhibitors.

In vivo analysis of supersaturation/precipitation/absorption behavior after oral administration of pioglitazone hydrochloride salt; determinant site of oral absorption

The purpose of this study was to evaluate in vivo supersaturation/precipitation/absorption behavior in the gastrointestinal (GI) tract based on the luminal concentration-time profiles after oral administration of pioglitazone (PG, a highly permeable lipophilic base) and its hydrochloride salt (PG-HCl) to rats. In the in vitro precipitation experiment in the classic closed system, while the supersaturation was stable in the simulated gastric condition, PG drastically precipitated in the simulated intestinal condition, particularly at a higher initial degree of supersaturation. Nonetheless, a drastic and moderate improvement in absorption was observed in vivo at a low and high dose of PG-HCl, respectively. Analysis based on the luminal concentration of PG after oral administration of PG-HCl at a low dose revealed that most of the dissolved PG emptied from the stomach was rapidly absorbed before its precipitation in the duodenum. At a high dose of PG-HCl, PG partly precipitated in the duodenum but was absorbed to some extent. Therefore, the extent of the absorption was mainly dependent on the duodenal precipitation behavior. Furthermore, a higher-than expected absorption after oral administration of PG-HCl from in vitro precipitation study may be due to the absorption process in the small intestine, which suppresses the precipitation by removal of the drug. This study successfully clarify the impact of the absorption process on the supersaturation/precipitation/absorption behavior and key absorption site for a salt formulation of a highly permeable lipophilic base based on the direct observation of in vivo luminal concentration. Our findings may be beneficial in developing an ideal physiologically based pharmacokinetic model and in vitro predictive dissolution tools and/or translating the in silico and in vitro data to the in vivo outcome.

Abstract 481: Pharmacological Inhibition of Calpain Attenuates Mineralocorticoid Receptor Agonist and High Salt-Induced Abdominal Aortic Aneurysm Incidence and Aortic Rupture in Mice

Background and Objective: Recently, we demonstrated that pharmacological and genetic inhibition of calpains, a class of calcium-activated neutral cysteine proteases, attenuated angiotensin II (AngII)-induced abdominal aortic aneurysms (AAAs) in mice. A newly identified non-invasive model of aneurysm has been developed in mice using deoxycorticosterone acetate (DOCA) coated pellets and oral administration of high salt. It is interesting to note that in this model, systemic administration of renin angiotensin inhibitors had no effect on aneurysm formation. The purpose of this study was to test whether pharmacological inhibition of calpain would influence AAA formation induced by mineralocorticoid receptor agonism and high salt in mice. Methods and Results: To determine whether calpain inhibition influenced DOCA and high salt-induced AAAs, 9 month old male C57BL/6 mice were administered calpain inhibitor, BDA-410 (30 mg/kg/day) or vehicle (n=10 per group) by oral gavage 1 week before DOCA pellet implantation and throughout the subsequent 21 days. Mice were implanted with DOCA pellets (50mg/ mouse for 21 days) and maintained on high salt (0.9% NaCl and 0.2% KCl) water. Calpain inhibition significantly suppressed AAA incidence (defined as increase in aortic diameter or AAA rupture; Vehicle = 60% vs BDA = 20%; P<0.05) compared to the vehicle group. Calpain inhibition also significantly protected DOCA + high salt-induced aortic rupture (Vehicle = 6/10 vs BDA = 1/10; P<0.05) in mice. Conclusion: These data demonstrate that calpain activation plays a critical role in not only AngII-induced, but also aldosterone pathways accelerated AAA formation in mice.

A New Mouse Model for Introduction of Aortic Aneurysm by Implantation of Deoxycorticosterone Acetate Pellets or Aldosterone Infusion in the Presence of High Salt.

Dysfunction of the renin-angiotensin-aldosterone system (RAAS) has been implicated in the etiologies of many cardiovascular diseases, including aortic aneurysm. In particular, the infusion of angiotensin II (Ang II) in the apolipoprotein E-deficient mice (apoE-/-) and low density lipoprotein receptor knockout mice (LDLR-/-) to induce aortic aneurysm has been extensively used in the field. In contrast, whether aldosterone (Aldo), an essential component of RAAS and a downstream effector of Ang II, is involved in aortic aneurysm is largely unknown. Here, we describe a new animal model for induction of aortic aneurysm in mice in which administration of deoxycorticosterone acetate (DOCA) and high salt or aldosterone and high salt, but not DOCA or high salt alone, to C57BL/6 male mice can potently induce aortic aneurysm formation and rupture in an age-dependent manner. This new aortic aneurysm mouse model is different from Ang II infusion mouse model and exhibits several unique features that mimic human aortic aneurysm.

Yunnan salt administration reforms under the Republic of China's Beiyang government

Yunnan salt administration reforms under the Republic of China's Beiyang government

Renal tubular angiotensin converting enzyme is responsible for nitro-L-arginine methyl ester (L-NAME)-induced salt sensitivity

Renal parenchymal injury predisposes to salt-sensitive hypertension, but how this occurs is not known. Here we tested whether renal tubular angiotensin converting enzyme (ACE), the main site of kidney ACE expression, iscentral to the development of salt sensitivity in this setting. Two mouse models were used: it-ACE mice in whichACE expression is selectively eliminated from renal tubular epithelial cells; and ACE 3/9 mice, a compound heterozygous mouse model that makes ACE only in renal tubular epithelium from the ACE 9 allele, and in liver hepatocytes from the ACE 3 allele. Salt sensitivity was induced using a post L-NAME salt challenge. While bothwild-type and ACE 3/9 mice developed arterial hypertension following three weeks of high salt administration, it-ACE mice remained normotensive with low levels of renal angiotensin II. These mice displayed increased sodium excretion, lower sodium accumulation, and an exaggerated reduction in distal sodium transporters. Thus, in mice with renal injury induced by L-NAME pretreatment, renal tubular epithelial ACE, and not ACE expression by renal endothelium, lung, brain, or plasma, isessential for renal angiotensin II accumulation and salt-sensitive hypertension.

Hypertension Editors' Picks: Hypertension and Sleep.

Hypertension Editors' Picks: Hypertension and Sleep.

PS 10-17 miRNA PROFILES OF RENAL TUBULAR CELLS AND DIAGNOSIS OF KIDNEY INJURY

Objective: MicroRNAs (miRNAs) are small noncoding RNAs of 18–23 nucleotides that regulate gene expression. Recently, plasma miRNAs have been investigated as biomarkers for various physiological and pathological conditions.The present study details the conserved miRNA expression profiles of tubular tissues, and discusses whether they could be used to distinguish between proximal tubule injury, diagnose acute kidney injury (AKI), and the early-stage renal tubular dysfunction. Design and Method: miRNA expression was assessed with miRNA array and real-time reverse transcription polymerase chain reaction using the TaqMan system. In order to assess the usefulness of miRNAsas biomarkers for kidney injury, AKI was induced in mice by contact freezing the kidney surface with dry ice and the Dahl salt-sensitive (DS) rat was used as renal tubular dysfunction model. Results: The expression profiles of miR-200a/b/c, miR-145, miR-192, miR-194, miR-216a/b, miR-217, and miR-449a in human and rat tubular tissues such as the kidneys, lung, small intestine, and various exocrine glands were adequate for discriminating tubular tissues. In the kidney, miR-192 and miR-194 were highly expressed, whereas miR-145 and miR-449a were absent. miR-145 and miR-449a were relatively specifically expressed in small intestine and lung, respectively. Therefore, the combined levels of miR-200a/b/c, miR-192, and miR-194 in plasma were very useful in diagnosing AKI induced by contact freezing in mice. Moreover, urinary miR-200a levels were useful for the diagnosis of renal tubular dysfunction in Dahl salt-sensitive rat with high salt administration. Conclusions: Our results indicate that miRNA expression profiles are useful as biomarkers for identification of various kidney injuries.

Proanthocyanidins block aldosterone-dependent up-regulation of cardiac gamma ENaC and Nedd4-2 inactivation via SGK1

Aldosterone plays a central role in the development of cardiac pathological states involving ion transport imbalances, especially sodium transport. We have previously demonstrated a cardioprotective effect of proanthocyanidins in aldosterone-treated rats. Our objective was to investigate for the first time the effect of proanthocyanidins on serum and glucocorticoid-regulated kinase 1 (SGK1), epithelial Na+ channel (γ-ENaC), neuronal precursor cells expressed developmentally down-regulated 4-2 (Nedd4-2) and phosphoNedd4-2 protein expression in the hearts of aldosterone-treated rats. Male Wistar rats received aldosterone (1mg kg−1day−1)+1% NaCl for 3weeks. Half of the animals in each group were simultaneously treated with the proanthocyanidins-rich extract (80% w/w) (PRO80, 5mg kg−1day−1). Hypertension and diastolic dysfunction induced by aldosterone were abolished by treatment with PRO80. Expression of fibrotic, inflammatory and oxidative mediators were increased by aldosterone–salt administration and blunted by PRO80. Antioxidant capacity was improved by PRO80. The up-regulated aldosterone mediator SGK1, ENaC and p-Nedd4-2/total Nedd4-2 ratio were blocked by PRO80. PRO80 blunted aldosterone–mineralocorticoid-mediated up-regulation of ENaC provides new mechanistic insight of the beneficial effect of proanthocyanidins preventing the cardiac alterations induced by aldosterone excess.

Acute kidney injury following cardiac surgery: current understanding and future directions.

Acute kidney injury (AKI) complicates recovery from cardiac surgery in up to 30 % of patients, injures and impairs the function of the brain, lungs, and gut, and places patients at a 5-fold increased risk of death during hospitalization. Renal ischemia, reperfusion, inflammation, hemolysis, oxidative stress, cholesterol emboli, and toxins contribute to the development and progression of AKI. Preventive strategies are limited, but current evidence supports maintenance of renal perfusion and intravascular volume while avoiding venous congestion, administration of balanced salt as opposed to high-chloride intravenous fluids, and the avoidance or limitation of cardiopulmonary bypass exposure. AKI that requires renal replacement therapy occurs in 2–5 % of patients following cardiac surgery and is associated with 50 % mortality. For those who recover from renal replacement therapy or even mild AKI, progression to chronic kidney disease in the ensuing months and years is more likely than for those who do not develop AKI. Cardiac surgery continues to be a popular clinical model to evaluate novel therapeutics, off-label use of existing medications, and nonpharmacologic treatments for AKI, since cardiac surgery is fairly common, typically elective, provides a relatively standardized insult, and patients remain hospitalized and monitored following surgery. More efficient and time-sensitive methods to diagnose AKI are imperative to reduce this negative outcome. The discovery and validation of renal damage biomarkers should in time supplant creatinine-based criteria for the clinical diagnosis of AKI.

The Effect of Experimental Thyroid Dysfunction on Markers of Oxidative Stress in Rat Pancreas

Preclinical Research The aim of the present study was to evaluate the effects of thyroid dysfunction on markers of oxidative stress in rat pancreas. Hypothyroidism and hyperthyroidism were, respectively, induced in rats via administration of propylthiouracil (PTU) and L-thyroxine sodium salt in drinking water for 45 days. The activities of superoxide dismutase (SOD), catalase (CAT), glutathioen peroxidase (GPx), glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G6PD), xanthine oxidase (XO), and nonenzymatic markers of oxidative stress including malondialdehyde (MDA), protein carbonyl (PC), reduced glutathione (GSH), and total thiols (T-SH) were determined in the rat pancreas. In hyperthyroid rats, pancreatic CAT, SOD, GPx, GR, XO, G6PD activities were increased compared with those in hypothyroid and control groups. There were no differences in activities of antioxidant enzymes between hypothyroid and control rats. Pancreatic MDA and PC in hyperthyroid rats increased compared with hypothyroid and the control animals. Whereas, hyperthyroid rats had decreased levels of tissue GSH and T-SH compared with hypothyroid and the control groups. The findings showed that only GSH level has decreased significantly in the hypothyroid group compared with control groups. In conclusion, our results showed that experimental hyperthyroidism induces oxidative stress in pancreas of rats, but hypothyroidism has no major impact on oxidative stress markers. Drug Dev Res 77 : 199-205, 2016. © 2016 Wiley Periodicals, Inc.

Противовоспалительная активность натриевой соли 4-(O-β-D-глюкопиранозилокси)бензойной кислоты

Изучена противовоспалительная активность натриевой соли 4-(O-β-D-глюкопиранозилокси)бензойной кислоты и проведено ее сопоставление с активностью известных нестероидных противовоспалительных средств. Животные получали натриевую соль 4-(O-β-D-глюкопиранозилокси)бензойной кислоты, 4-гидроксибензойную кислоту, ацетилсалициловую кислоту внутрижелудочно в дозе 20 мг/кг ежедневно в течение 7 дней до моделирования воспаления. Острую воспалительную реакцию (отек) воспроизводили субплантарным введением 0,1 мл 1 % раствора каррагенина. Выраженность воспалительной реакции оценивали через 60, 120, 240 мин после индукции воспаления по изменению объема лапы (онкометрически). Проведенное исследование показывает, что внутрижелудочное введение животным натриевой соли 4-(O-β-D-глюкопиранозилокси)бензойной кислоты в дозе 20 мг/кг в течение 7 дней уменьшало интенсивность экспериментального воспалительного процесса.

Role of Vasopressin in the Regulation of Renal Sodium Excretion: Interaction with Glucagon‐Like Peptide‐1

The present study aimed to investigate the potential physiological role of vasopressin and the incretin hormone of the gastrointestinal tract (glucagon-like peptide-1; GLP-1) in the regulation of the water-salt balance in a hyperosmolar state as a result of sodium loadings. In rats, the administration of hypertonic NaCl solution resulted in a significant increase in natriuresis, which correlated with the vasopressin excretion rate. Natriuresis following an i.p. NaCl load (23.2±1.4μmol/min/kg) was enhanced by inhibition of V2 receptors (51.6±3.7μmol/min/kg, P<0.05) and was reduced by a V1a antagonist injection (6.3±1.1μmol/min/kg, P<0.05). Compared to i.p. salt administration, oral NaCl loading induced a significant increase in the plasma GLP-1 level within 5min and resulted in more prominent natriuresis and a smaller increase in blood sodium concentration. It was hypothesised that the basis for the fast elimination of excess sodium following an oral NaCl load could be the involvement of GLP-1 in osmoregulation combined with vasopressin. It was demonstrated that GLP-1 mimetic exenatide (1.5nmol/kg) produced a significant decrease in proximal reabsorption and an increase in fractional sodium excretion (from 0.15±0.04% to 9±1%). It was also shown that vasopressin at doses of 1-10μg/kg and the selective V1a agonist (1μg/kg) induced an increase in sodium fractional excretion to 10±2% and 8±2%, respectively. Combined administration of exenatide and V1a agonist revealed their cumulative natriuretic effect, and sodium fractional excretion increased by up to 18±2%. These data suggest that GLP-1 combined with vasopressin could be involved in the regulation of sodium balance in the hyperosmolar state as a result of NaCl loading. Vasopressin regulates the reabsorption of a significant portion of filtered sodium in the distal segment of the nephron and modulates the natriuretic effect of GLP-1.

Immunological Memory Exacerbates Responses to Repeated Hypertensive Stimuli

Accumulating evidence supports a role of adaptive immunity and particularly T cells in the pathogenesis of hypertension. Formation of antigen‐specific memory T cells is a cardinal feature of adaptive immunity. We hypothesized that memory T cells contribute to long‐term renal damage in response to repeated hypertensive challenges. To impose repeated episodes of hypertension, we utilized two mouse models of repeated hypertensive challenges (L‐NAME/high salt treatment and repeated ang II stimulation) and show that effector memory T (TEM) cells are formed upon these repeated challenges and contribute to both salt‐sensitive and ang II‐induced hypertension. L‐NAME followed by high salt increased SBP to 147 ± 14 mmHg and caused a two‐fold increase in effector memory T (TEM) cells in the kidney and bone marrow (BM), as identified by the surface marker CD44hiCD62Llo. Intracellular staining showed that memory T cells were predominant sources of the inflammatory cytokines IL‐17A and IFN‐g. Development and reactivation of memory T cells require the interaction of CD27 on T cells with CD70 on antigen presenting cells. Flow cytometry revealed that L‐NAME/High salt increased expression of CD70 on splenic macrophages by 5‐fold and dendritic cells by 3‐fold. Because memory T cells are a major source of IFN‐g, we examined the hypertensive response to the L‐NAME/high salt protocol in IFN‐g−/− mice. The hypertension caused by L‐NAME was identical between WT, CD70−/− and IFN‐g−/− mice. In contrast, the hypertension induced by subsequent salt administration was markedly attenuated in CD70−/− mice (123 ± 1.3mmHg, p&lt;0.02) and IFN‐g−/− (127.6 ± 5.5, p&lt;0.04). Interestingly, CD70−/− and IFN‐g −/− mice failed to develop memory T cell formation in the kidney. The L‐NAME/high salt caused striking albuminuria and increased urinary N‐gal in WT mice, and these were absent in CD70−/− and IFN‐g −/− mice. We also defined a novel role of BM residing TEM cells in hypertension, in that these cells exhibited clonality, proliferated and redistributed to the kidney in response to repeated salt feeding. Adoptively transferred TEM cells from hypertensive mice homed to the BM and spleen, and expanded upon salt feeding of recipient mice in both the BM and kidney. Thus, these studies show that formation of long‐lived hypertension‐specific TEM cells that are major sources of inflammatory cytokines. These cells place the host at risk of developing blood pressure elevation and end‐organ damage upon delayed exposure to mild stimuli such as salt feeding or low doses of ang II. These studies provide further insight into how the adaptive immune system promotes hypertension.Support or Funding InformationNIH F32 HL124972‐01