Exertional heat stress promotes the presence of bacterial DNA in plasma: A counterbalanced randomised controlled trial.

OBJECTIVES: The primary aim was to explore the impact of exertional-heat stress (EHS) promoted exercise-associated bacteraemia. A secondary aim was to examine if an amino acid beverage (AAB) intervention may mitigate exercise-associated bacteraemia. DESIGN: Counterbalanced randomised control trial. METHODS: Twenty endurance trained male participants completed two randomised EHS trials. On one occasion, participants consumed a 237 mL AAB twice daily for 7 days prior, immediately before and every 20 min during EHS (2 h running at 60 % V̇O2max in 35 °C). On the other occasion, a water volume control (CON) equivalent was consumed. Whole blood samples were collected pre- and immediately post-EHS, and were analysed for plasma DNA concentration by fluorometer quantification after microbial extraction, and bacterial relative abundance by next generation 16s rRNA gene sequencing. RESULTS: Increased concentration of microbial DNA in plasma pre- to post-EHS was observed on CON (pre-EHS 0.014 ng/µL, post-EHS 0.039 ng/µL) (p < 0.001) and AAB (pre-EHS 0.015 ng/µL, post-EHS 0.031 ng/µL) (p < 0.001). The magnitude of change from pre- to post-exercise on AAB was 40 % lower, but no significant difference was observed versus CON (p = 0.455). Predominant bacterial groups identified included: phyla-Proteobacteria (88.0 %), family-Burkholderiaceae (59.1 %), and genus-Curvibacter (58.6 %). No significant variation in absolute and relative change in α-diversity and relative abundance for phyla, family, and genus bacterial groups was observed in AAB versus CON. CONCLUSIONS: The increased presence of microbial-bacterial DNA in systemic circulation in response to EHS appears positive in all participants. An amino acid beverage supplementation period prior to and consumption during EHS did not provide significant attenuation of EHS-associated bacteraemia.

The increase in core body temperature in response to exertional-heat stress can predict exercise-induced gastrointestinal syndrome.

Utilizing metadata from existing exertional and exertional-heat stress studies, the study aimed to determine if the exercise-associated increase in core body temperature can predict the change in exercise-induced gastrointestinal syndrome (EIGS) biomarkers and exercise-associated gastrointestinal symptoms (Ex-GIS). Endurance-trained individuals completed 2 h of running exercise in temperate (21.2-30.0°C) to hot (35.0-37.2°C) ambient conditions (n = 132 trials). Blood samples were collected pre- and post-exercise to determine the change in gastrointestinal integrity biomarkers and systemic inflammatory cytokines. Physiological and thermoregulatory strain variables were assessed every 10-15 min during exercise. The strength of the linear relationship between maximal (M-Tre) and change (Δ Tre) in rectal temperature and EIGS variables was determined via Spearman's rank correlation coefficients. While the strength of prediction was determined via simple and multiple linear regression analyses dependent on screened EIGS and Ex-GIS confounding factors. Significant positive correlations between Tre maximum (M-Tre) and change (Δ Tre) with I-FABP (rs = 0.434, p < 0.001; and rs = 0.305, p < 0.001; respectively), sCD14 (rs = 0.358, p < 0.001; and rs = 0.362, p < 0.001), systemic inflammatory response profile (SIR-Profile) (p < 0.001), and total Ex-GIS (p < 0.05) were observed. M-Tre and Δ Tre significantly predicted (adjusted R2) magnitude of change in I-FABP (R2(2,123)=0.164, p < 0.001; and R2(2,119)=0.058, p = 0.011; respectively), sCD14 (R2(2,81)=0.249, p < 0.001; and R2(2,77)=0.214, p < 0.001), SIR-Profile (p < 0.001), and total Ex-GIS (p < 0.05). Strong to weak correlations were observed between M-Tre and Δ Tre with plasma concentrations of I-FABP, sCD14, SIR-Profile, and Ex-GIS in response to exercise. M-Tre and Δ Tre can predict the magnitude of these EIGS variables and Ex-GIS in response to exercise.

The impact of 48 h high carbohydrate diets with high and low FODMAP content on gastrointestinal status and symptoms in response to endurance exercise, and subsequent endurance performance.

This study investigated the effects of a high carbohydrate diet, with varied fermentable oligo-, di-, and mono-saccharide and polyol (FODMAP) content, before endurance exercise on gastrointestinal integrity, motility, and symptoms; and subsequent exercise performance. Twelve endurance athletes were provided with a 48 h high carbohydrate (mean ± SD: 12.1 ± 1.8 g kg day-1) diet on two separate occasions, composed of high (54.8 ± 10.5 g day-1) and low FODMAP (3.0 ± 0.2 g day-1) content. Thereafter, participants completed a 2 h steady-state running exercise at 60% of V ˙ O 2 max (22.9 ± 1.2 °C, 46.4 ± 7.9% RH), followed by a 1 h distance performance test. Pre-exercise and every 20 min during steady-state exercise, 100 mL maltodextrin (10% w/v) solution was consumed. A 150 mL lactulose (20 g) solution was consumed 30 min into the distance performance test to determine orocecal transit time (OCTT) during exercise. Blood was collected pre- and post exercise to determine gastrointestinal integrity biomarkers (i.e., I-FABP, sCD14, and CRP). Breath hydrogen (H2) and gastrointestinal symptoms (GIS) were determined pre-exercise, every 15 min, during and throughout recovery. No differences in gastrointestinal integrity biomarkers, OCTT, or distance completed were observed between trials. Pre-exercise total-GIS (1.3 ± 2.9 vs. 4.3 ± 4.4), gut discomfort (9.9 ± 8.1 vs. 15.8 ± 9.0), and upper-GIS (2.8 ± 2.6 vs. 5.7 ± 4.8) during exercise were less severe on high carbohydrate low FODMAP (HC-LFOD) versus high carbohydrate high FODMAP (HC-HFOD) (p < 0.05). Gut discomfort (3.4 ± 4.4 vs. 0.2 ± 0.6) and total-GIS (4.9 ± 6.8 vs. 0.2 ± 0.6) were higher during recovery on HC-LFOD versus HC-HFOD (p < 0.05). The FODMAP content of a 48 h high carbohydrate diet does not impact gastrointestinal integrity or motility in response to endurance exercise. However, a high FODMAP content exacerbates GIS before and during exercise, but this does not impact performance outcomes.

Does Age Influence Gastrointestinal Status Responses to Exertional-heat Stress?

This meta-data exploration aimed to determine the impact of exertional-heat stress (EHS) on gastrointestinal status of masters age and young adult endurance athletes. Sixteen MASTERS (mean: 44y) and twenty-one YOUNG (26y) recreational endurance athletes completed 2 h of running at 60% ˙V O2max in 35˚C ambient conditions. Blood samples were collected pre-, immediately and 1 h post-EHS, and analyzed for markers of exercise-induced gastrointestinal syndrome (EIGS). Thermo-physiological measures and gastrointestinal symptoms (GIS) were recorded every 10-20 min during EHS. Peak Δ pre- to post-EHS did not substantially differ (p>0.05) between MASTERS and YOUNG for intestinal epithelial injury [I-FABP: 1652pg/ml vs. 1524pg/ml, respectively], bacterial endotoxic translocation [sCD14: -0.09µg/mL vs. 0.84µg/mL, respectively], lipopolysaccharide-binding protein [LBP: 0.26µg/mL vs. 1.76µg/mL, respectively], and systemic inflammatory response profile (SIR-Profile: 92.0arb.unit vs. 154arb.unit, respectively). A significantly higher peak Δ pre- to post-EHS in endogenous endotoxin anti-body IgM (p=0.042), and pro-inflammatory cytokine IL-1ß (p=0.038), was observed in YOUNG compared to MASTERS. No difference was observed between incidence (81% and 80%, respectively) and severity (summative accumulation: 21 and 30, respectively) of reported GIS during EHS between MASTERS and YOUNG. Pathophysiology of EIGS in response to EHS does not substantially differ with age progression, since masters and younger adult endurance athletes responded comparably.

Amino Acid-Based Beverage Interventions Ameliorate Exercise-Induced Gastrointestinal Syndrome in Response to Exertional-Heat Stress: The Heat Exertion Amino Acid Technology (HEAAT) Study.

The study aimed to determine the effects of two differing amino acid beverage interventions on biomarkers of intestinal epithelial integrity and systemic inflammation in response to an exertional-heat stress challenge. One week after the initial assessment, participants (n = 20) were randomly allocated to complete two exertional-heat stress trials, with at least 1 week washout. Trials included a water control trial (CON), and one of two possible amino acid beverage intervention trials (VS001 or VS006). On VS001 (4.5 g/L) and VS006 (6.4 g/L), participants were asked to consume two 237-ml prefabricated doses daily for 7 days before the exertional-heat stress, and one 237-ml dose immediately before, and every 20 min during 2-hr running at 60% maximal oxygen uptake in 35 °C ambient conditions. A water volume equivalent was provided on CON. Whole blood samples were collected pre-, immediately post-, 1 and 2 hr postexercise, and analyzed for plasma concentrations of cortisol, intestinal fatty acid protein, soluble CD14, and immunoglobulin M (IgM) by ELISA, and systemic inflammatory cytokines by multiplex. Preexercise resting biomarker concentrations for all variables did not significantly differ between trials (p > .05). A lower response magnitude for intestinal fatty acid protein (mean [95% CI]: 249 [60, 437] pg/ml, 900 [464, 1,336] pg/ml), soluble CD14 (-93 [-458, 272] ng/ml, 12 [-174, 197] ng/ml), and IgM (-6.5 [-23.0, 9.9] MMU/ml, -10.4 [-16.2, 4.7] MMU/ml) were observed on VS001 and V006 compared with CON (p < .05), respectively. Systemic inflammatory response profile was lower on VS001, but not VS006, versus CON (p < .05). Total gastrointestinal symptoms did not significantly differ between trials. Amino acid beverages' consumption (i.e., 4.5-6.4 g/L), twice daily for 7 days, immediately before, and during exertional-heat stress ameliorated intestinal epithelial integrity and systemic inflammatory perturbations associated with exercising in the heat, but without exacerbating gastrointestinal symptoms.

The Effect of Gut-Training and Feeding-Challenge on Markers of Gastrointestinal Status in Response to Endurance Exercise: A Systematic Literature Review.

BACKGROUND: Nutrition during exercise is vital in sustaining prolonged activity and enhancing athletic performance; however, exercise-induced gastrointestinal syndrome (EIGS) and exercise-associated gastrointestinal symptoms (Ex-GIS) are common issues among endurance athletes. Despite this, there has been no systematic assessment of existing trials that examine the impact of repetitive exposure of the gastrointestinal tract to nutrients before and/or during exercise on gastrointestinal integrity, function, and/or symptoms. OBJECTIVE: This systematic literature review aimed to identify and synthesize research that has investigated the impact of 'gut-training' or 'feeding-challenge' before and/or during exercise on markers of gastrointestinal integrity, function, and symptoms. METHODS: Five databases (Ovid MEDLINE, EMBASE, CINAHL Plus, Web of Science Core Collection, and SPORTDiscus) were searched for literature that focused on gut-training or feeding-challenge before and/or during exercise that included EIGS and Ex-GIS variables. Quality assessment was conducted in duplicate and independently using the Cochrane Collaboration's risk-of-bias (RoB 2) tool. RESULTS: Overall, 304 studies were identified, and eight studies were included after screening. Gut-training or feeding-challenge interventions included provision of carbohydrates only (n = 7) in various forms (e.g., gels or liquid solutions) during cycling or running, or carbohydrate with protein (n = 1) during intermittent exercise, over a varied duration (4-28 days). Gut discomfort decreased by an average of 47% and 26% with a 2-week repetitive carbohydrate feeding protocol (n = 2) and through repeated fluid ingestion over five trials (n = 1), respectively. Repetitive carbohydrate feeding during exercise for 2 weeks resulted in the reduction of carbohydrate malabsorption by 45-54% (n = 2), but also led to no significant change (n = 1). The effect of gut-training and feeding-challenges on the incidence and severity of Ex-GIS were assessed using different tools (n = 6). Significant improvements in total, upper, and lower gastrointestinal symptoms were observed (n = 2), as well as unclear results (n = 4). No significant changes in gastric emptying rate (n = 2), or markers of intestinal injury and permeability were found (n = 3). Inconclusive results were found in studies that investigated plasma inflammatory cytokine concentration in response to exercise with increased carbohydrate feeding (n = 2). CONCLUSIONS: Overall, gut-training or feeding-challenge around exercise may provide advantages in reducing gut discomfort, and potentially improve carbohydrate malabsorption and Ex-GIS, which may have exercise performance implications.

Effect of prebiotics, probiotics, and synbiotics on gastrointestinal outcomes in healthy adults and active adults at rest and in response to exercise-A systematic literature review.

Introduction: A systematic literature search was undertaken to assess the impact of pre-, pro-, and syn-biotic supplementation on measures of gastrointestinal status at rest and in response to acute exercise. Methods: Six databases (Ovid MEDLINE, EMBASE, Cinahl, SportsDISCUS, Web of Science, and Scopus) were used. Included were human research studies in healthy sedentary adults, and healthy active adults, involving supplementation and control or placebo groups. Sedentary individuals with non-communicable disease risk or established gastrointestinal inflammatory or functional diseases/disorders were excluded. Results: A total of n = 1,204 participants were included from n = 37 papers reported resting outcomes, and n = 13 reported exercise-induced gastrointestinal syndrome (EIGS) outcomes. No supplement improved gastrointestinal permeability or gastrointestinal symptoms (GIS), and systemic endotoxemia at rest. Only modest positive changes in inflammatory cytokine profiles were observed in n = 3/15 studies at rest. Prebiotic studies (n = 4/5) reported significantly increased resting fecal Bifidobacteria, but no consistent differences in other microbes. Probiotic studies (n = 4/9) increased the supplemented bacterial species-strain. Only arabinoxylan oligosaccharide supplementation increased total fecal short chain fatty acid (SCFA) and butyrate concentrations. In response to exercise, probiotics did not substantially influence epithelial injury and permeability, systemic endotoxin profile, or GIS. Two studies reported reduced systemic inflammatory cytokine responses to exercise. Probiotic supplementation did not substantially influence GIS during exercise. Discussion: Synbiotic outcomes resembled probiotics, likely due to the minimal dose of prebiotic included. Methodological issues and high risk of bias were identified in several studies, using the Cochrane Risk of Bias Assessment Tool. A major limitation in the majority of included studies was the lack of a comprehensive approach of well-validated biomarkers specific to gastrointestinal outcomes and many included studies featured small sample sizes. Prebiotic supplementation can influence gut microbial composition and SCFA concentration; whereas probiotics increase the supplemented species-strain, with minimal effect on SCFA, and no effect on any other gastrointestinal status marker at rest. Probiotic and synbiotic supplementation does not substantially reduce epithelial injury and permeability, systemic endotoxin and inflammatory cytokine profiles, or GIS in response to acute exercise.

The impact of exercise modality on exercise-induced gastrointestinal syndrome and associated gastrointestinal symptoms.

OBJECTIVES: This study aimed to determine the impact of running and cycling exercise modalities on the magnitude of exercise-induced gastrointestinal syndrome (EIGS) and associated gastrointestinal symptoms (GIS). DESIGN: Parallel group trial design. METHODS: Twenty-eight endurance athletes (male n = 14, female n = 14) completed 2 h running at 55 % of maximal oxygen uptake or cycling at 55 % of maximal aerobic power in Tamb 35 °C and 22 % RH. Pre- and post-exercise blood samples were collected and analysed for markers of intestinal epithelial integrity perturbations (i.e., plasma intestinal fatty acid protein (I-FABP), soluble (s)CD14, and lipopolysaccharide binding protein (LBP)) and systemic inflammatory cytokines (i.e., plasma IL-1ß, TNFα, IL-10, and IL-1ra). GIS were assessed pre-exercise and every 10 min during exercise. RESULTS: Exercise-associated Δ for plasma I-FABP (191 and 434 pg‧ml-1) and LBP (-1228 and 315 ng‧ml-1) did not differ between running and cycling, respectively; however for sCD14 was higher (p = 0.030) on cycling (116 ng‧ml-1) vs running (96 ng‧ml-1). There were no differences in absolute pre- and post-exercise systemic inflammatory cytokine concentration, with large individual variation observed. Exercise-associated plasma TNF-α, (p = 0.041) and IL-10 (p = 0.019) responses were greater in running than cycling, but did not lead to a greater systemic inflammatory response profile (p = 0.305) between running (5.0arb.units) and cycling (-2.5arb.units). Although greater GIS incidence occurred in running (44 %) compared with cycling (25 %), there was no difference between groups for GIS severity. CONCLUSIONS: When running and cycling exercise is performed with similar duration, intensity, ambient conditions, and with confounder control, the exercise modality does not substantially impact the magnitude of EIGS or associated GIS severity.

The impact of social enterprise on food insecurity - An Australian case study.

Like many high-income countries, in Australia there are a range of programmes in place, from social security to food banks, to help address food insecurity. So far, they have been unable to adequately alleviate and prevent this growing nutrition challenge. This paper presents an evaluation of a new type of intervention in the food security landscape, the social enterprise. The Community Grocer is a social enterprise that operates weekly fresh fruit and vegetable markets in Melbourne, Australia. The aim of the study was to examine the market's ability to increase access, use and availability of nutritious food in a socially acceptable way, for low socioeconomic status urban-dwelling individuals. The mixed-method evaluation included: comparative price audits (n = 27) at local (<1 km) stores; analysis of operational data from sample markets (n = 3); customer surveys (n = 91) and customer interviews (n = 12), collected in two phases (Autumn 2017, Summer 2018). The results found common (n = 10) fruit and vegetables cost, on average, approximately 40% less at the social enterprise, than local stores. Over twenty per cent of customers were food insecure and 80% of households were low income. Thirty-four different nationalities shopped at the market, and just over half (54%) shopped there weekly. More than 50 types of vegetables and fruit were available to purchase, varying for cultural preferences and seasonality, which supported variety and choice. Overall, this enterprise promotes food security in a localised area through low-cost, convenient, dignified and nutritious offerings.

Soluble guanylate cyclase stimulator BAY 41-8543 and female sex ameliorate uremic aortic remodeling in a rat model of mild uremia.

BACKGROUND: Cardiovascular disease is the leading comorbidity in renal patients and has been related to impaired nitric oxide signaling. Estrogens exert protective effects on the vascular system. This study investigates the effects of biological sex and nitric oxide-independent soluble guanylate cyclase (sGC) stimulator BAY 41-8543 on aortic remodeling in experimental mild uremia. METHOD: Age-matched male and female Wistar rats were assigned for 18 weeks into sham-operated, subtotally nephrectomized (SNX), SNX + BAY 41-8543 and SNX + hydralazine. Analysis involved functional, histological, and molecular kidney and thoracic aorta parameters. RESULTS: SNX significantly increased SBP, which was comparably reduced to control levels by BAY 41-8543 and hydralazine. In SNX males, uremic aortic remodeling was characterized by marked media thickening and increased media-to-lumen ratio (P < 0.01), vascular smooth muscle cell (VSMC) proliferation, macrophage infiltration, extracellular matrix turnover, decreased aortic elastin-to-collagen ratio (P < 0.01) and endothelial nitric oxide-synthase (eNOS) mRNA expression (P < 0.05). No significant alterations of aortic media-to-lumen ratio, VSMC proliferation, macrophage infiltration, matrix metalloproteinase-2, and eNOS mRNA expressions were seen in female uremic animals. BAY 41-8543 significantly ameliorated uremic aortic remodeling and stiffening involving reduced VSMC proliferation, collagen I-deposition, extracellular matrix turnover, and increased elastin content and eNOS mRNA expression. Hydralazine treatment did not substantially alter aortic remodeling. CONCLUSION: Experimental mild uremia leads to pronounced aortic hypertrophic remodeling and stiffening with sex-dependent alternations, and these are more severe in male rats. BAY 41-8543 ameliorates uremic aortic remodeling in a blood pressure-independent manner. The results suggest that sGC-stimulators may offer a novel treatment mode for pathological arterial wall remodeling in patients with impaired renal function.

Incidence and outcome of metabolic disarrangements consistent with citrate accumulation in critically ill patients undergoing continuous venovenous hemodialysis with regional citrate anticoagulation.

BACKGROUND: Systemic citrate accumulation is a complication of regional citrate anticoagulation (RCA) during continuous renal replacement therapy (CRRT). Our objective was to determine the incidence of clinical signs consistent with citrate accumulation in a large and representative cohort of intensive care unit patients undergoing RCA-CRRT. METHODS: Patients treated with RCA-CRRT during 2008-2010 were retrospectively analyzed. Decreased systemic ionized calcium (iCa), increased demand for calcium substitution, elevated total calcium to iCa ratio, and metabolic acidosis were evaluated as indicators for citrate accumulation. RESULTS: In the 3-year period, 1070 patients were treated with RCA-continuous venovenous hemodialysis. Metabolic signs of citrate accumulation occurred in 32 patients (2.99%, 64.5 ± 14.0 years, 65.6% male, Acute Physiology and Chronic Health Evaluation score 34.2 ± 9.7): systemic iCa decreased to 1.01 ± 0.10 mmol/L with a simultaneous increase of the calcium substitution rate to 129% ± 26%, and the mean total calcium to iCa ratio increased to 2.51 ± 0.54. All 32 patients had therapy-resistant shock with severe lactic acidosis (pH 7.20 ± 0.11, lactate 136 ± 61 mg/dL), indicating severe intracellular hypoxia. None of the patients survived. CONCLUSIONS: The incidence of disarrangements consistent with citrate accumulation in patients undergoing RCA-continuous venovenous hemodialysis was low, taking place exclusively in patients with severe lactic acidosis due to multiorgan failure. This suggests that the appearance of citrate accumulation is secondary to a severe failure of cellular respiration.

Tyrosine kinases inhibition by Imatinib slows progression in chronic anti-thy1 glomerulosclerosis of the rat.

BACKGROUND: Chronic progressive mesangioproliferative nephropathy represents a major cause of end-stage renal disease worldwide. Until now, effective approaches to stop or even slow its progression are limited. We tested the effects of an inhibitor of PDGF receptor, abl and c-kit tyrosine kinases, Imatinib, in a chronic progressive model of mesangioproliferative glomerulosclerosis. METHODS: Anti-thy1 glomerulosclerosis was induced by injection of anti-thy1 antibody into uninephrectomized Wistar rats. One week after disease induction, according to the degree of proteinuria, animals were stratified and assigned to chronic glomerulosclerosis (cGS) and cGS plus Imatinib (10 mg/kg body weight/day). In week 20, renoprotective actions of Imatinib were analyzed by a set of functional, histological and molecular biological parameters. RESULTS: Untreated cGS rats showed elevation of systolic blood pressure and marked progression in proteinuria, renal fibrosis, cell infiltration, cell proliferation and function lost. Administration of Imatinib went along significantly with lower systolic blood pressure (-10 mmHg) and proteinuria (-33%). Imatinib administration was paralled by significant reductions in tubulointerstitial accumulation of matrix proteins (-44%), collagen I deposition (-86%), expression of TGF-beta1 (-30%), production of fibronectin (-23%), myofibroblast differentiation (-87%), macrophage infiltration (-36%) and cell proliferation (-45%), respectively. In comparison with untreated cGS animals, Imatinib therapy lowered also blood creatinine (-41%) and blood urea concentrations (-36%) and improved creatinine clearance (+25%). Glomerular fibrotic changes were lowered moderately by Imatinib. CONCLUSIONS: Therapy with Imatinib limits the progressive course of chronic anti-thy1 glomerulosclerosis towards tubulointerstitial fibrosis and renal insufficiency. This was paralleled by direct and indirect sign of TGF-ß1 and PDGF inhibition. The findings suggest that the pharmacological principal of inhibition of tyrosine kinases with drugs such as Imatinib might serve as approach for limiting progression of human mesangioproliferative glomerulosclerosis.

Impact of biological gender and soluble guanylate cyclase stimulation on renal recovery after relief of unilateral ureteral obstruction.

PURPOSE: Gender difference and nitric oxide deficiency contribute to the progression of many chronic kidney diseases. In a model of unilateral ureteral obstruction relief we analyzed the impact of biological gender and nitric oxide/cyclic guanosine monophosphate signaling stimulation on renal disease severity and restoration. MATERIALS AND METHODS: Female and male rats underwent sham surgery or unilateral ureteral obstruction. After 5-day unilateral ureteral obstruction female and male rats were assigned to obstruction relief alone or obstruction relief plus 7-day treatment with the soluble guanylate cyclase stimulator BAY 41-8543. RESULTS: Compared to male rats with obstruction relief renal disease was less severe in female rats, which had significantly less tubulointerstitial matrix accumulation and tubular atrophy. In each gender group α1 and ß1-soluble guanylate cyclase was comparably and significantly increased but female rats produced significantly more cyclic guanosine monophosphate after treatment with the soluble guanylate cyclase stimulator. In each group BAY 41-8543 treatment was associated with significant amelioration of renal matrix protein expansion, macrophage infiltration, tubular apoptosis and atrophy. CONCLUSIONS: Female gender is protective for unilateral ureteral obstruction relief. This was linked to higher sensitivity of the soluble guanylate cyclase enzyme and cyclic guanosine monophosphate production in response to BAY 41-8543. In these female and male rats enhancing the signaling of nitric oxide/cyclic guanosine monophosphate with BAY 41-8543 significantly accelerated the restoration of renal architecture after obstruction relief and largely ameliorated the differences in disease severity due to the gender disparity.

Stimulation of soluble guanylate cyclase improves renal recovery after relief of unilateral ureteral obstruction.

PURPOSE: The antifibrotic effects of soluble guanylate cyclase stimulation and cyclic guanosine monophosphate production have been observed in cases of anti-thy1-induced renal disease. We analyzed the action of the specific soluble guanylate cyclase stimulator BAY 41-8543 on the renal recovery phase in rats with unilateral ureteral obstruction after obstruction was relieved. MATERIALS AND METHODS: Sprague-Dawley® rats underwent reversible unilateral ureteral obstruction for 5 days, after which obstruction was relieved. Rats were randomly assigned to unilateral ureteral obstruction and unilateral ureteral obstruction plus BAY 41-8543 (10 mg/kg body weight daily). Seven days after relief of obstruction we determined treatment effects on renal atrophy, apoptosis, fibrosis and nitric oxide/cyclic guanosine monophosphate signaling. RESULTS: Untreated obstructed rats showed mildly increased systolic blood pressure, marked tubular atrophy and apoptosis, tubulointerstitial macrophage infiltration and fibrosis. Plasma cyclic guanosine monophosphate levels were unaltered in untreated rats with obstruction while renal soluble guanylate cyclase mRNA expression was increased. BAY 41-8543 administration significantly increased plasma cyclic guanosine monophosphate, which was paralleled by significant decreases in systolic blood pressure, renal tubular diameter, apoptosis and renal macrophage infiltration. Also, soluble guanylate cyclase stimulation decreased tubulointerstitial fibrosis, as shown by tubulointerstitial volume, matrix protein accumulation, α-smooth muscle actin expression, collagen IV deposition and transforming growth factor-ß1 mRNA expression. CONCLUSIONS: Soluble guanylate cyclase stimulation by BAY 41-8543 increases cyclic guanosine monophosphate production and subsequently enhances renal recovery after unilateral ureteral obstruction relief through an array of pathways. This finding suggests that soluble guanylate cyclase stimulation may serve as a novel treatment approach to restore or preserve renal structure and function in cases of obstructive kidney disease.