Increased cancer risk is associated with select dietary factors. Dietary lifestyles can alter systemic acid-base balance over time. Acidogenic diets, which are typically high in animal protein and salt and low in fruits and vegetables, can lead to a sub-clinical or low-grade state of metabolic acidosis. The relationship between diet and cancer risk prompts questions about the role of acidosis in the initiation and progression of cancer. Cancer is triggered by genetic and epigenetic perturbations in the normal cell, but it has become clear that microenvironmental and systemic factors exert modifying effects on cancer cell development. While there are no studies showing a direct link between diet-induced acidosis and cancer, acid-base disequilibrium has been shown to modulate molecular activity including adrenal glucocorticoid, insulin growth factor (IGF-1), and adipocyte cytokine signaling, dysregulated cellular metabolism, and osteoclast activation, which may serve as intermediary or downstream effectors of carcinogenesis or tumor promotion. In short, diet-induced acidosis may influence molecular activities at the cellular level that promote carcinogenesis or tumor progression. This review defines the relationship between dietary lifestyle and acid-base balance and discusses the potential consequences of diet-induced acidosis and cancer occurrence or progression.

The live export of cattle is an important industry for Australia. Concerns have arisen about animal welfare and in particular heat stress which may cause production losses and death. Cattle shipped live to the Middle East from a southern Australian winter can face continuous and prolonged periods of high heat and humidity as they cross the equator and arrive into a northern hemisphere summer, leading to heat stress and excessive heat load. Some live animal exporters treat heat stressed cattle with electrolyte supplements, but no scientific data exists as to whether this is beneficial to cattle in these unique environmental conditions. In response to industry’s concerns, the experiments described here monitored the physiological responses of Bos taurus and Bos indicus to conditions similar to those experienced by cattle being shipped from southern Australian to the Middle East. Initial experiments were conducted in climate controlled rooms at Murdoch University where intensive monitoring was possible. In the Bos taurus, increases in core body temperature, reductions in feed intake, and increased water intake were measured. There were also changes in blood gas variables consistent with the observed panting causing a compensated respiratory alkalosis. Following the heating period, there were decreases in blood and urinary pH. Bos indicus showed similar responses to the heat, but the changes were less pronounced at the temperatures tested. A pair feeding experiment was conducted to separate the effects of heat from the reductions in feed intake, and this indicated that the major measured effects were due to the responses to heat. On the basis of the measured responses, an electrolyte supplement was formulated and tested on Bos taurus, in the climate controlled rooms, and then on a commercial live export vessel. Results from these experiments indicated improved buffering capacity and a weight advantage for supplemented cattle, even in the absence of extreme heat stress. A final experiment investigated the effects of amount and quality of roughage in a pelleted feed on core and rumen temperature and feed intakes in Bos taurus subjected to hot environmental conditions in climate controlled rooms at Murdoch University. Both pelleted feeds had approximately the same metabolisable energy and crude protein but differed in content and type of roughage. There were no differences in feed intake, core temperature or rumen temperature between diets. This work has led to a greater understanding of the physiological responses of cattle to prolonged and continuous high heat and humidity, the requirements and effects of supplemental electrolytes in these conditions, and the effect of manipulating export diets. The demonstration of advantages in weight and buffering capacity with the electrolyte supplement highlights future areas of research to investigate electrolyte doses, route and types of supplementation, and dietary manipulation.

e algumas vias de sinalização envolvidas com a reabsorção de HCO3-, além do efeito do tratamento com florizina e com streptozotocina. Para isso, utilizamos o método de microperfusão estacionária in vivo. Perfusões tubulares com solução de glicose 5mM aumentaram a reabsorção de bicarbonato em comparação com soluções contendo florizina sem glicose. Porém, perfusão de soluções de glicose 20mM ocasionaram efeito intermediário sobre esta reabsorção. A perfusão de solução contendo glicose 5mM com os inibidores PD169316 e LY294002 aboliu o efeito estimulatório promovido pela glicose 5mM. O tratamento com streptozotocina aboliu o efeito inibitório da perfusão de solução de glicose 20mM. Já o tratamento com florizina, não apresentou nenhum efeito adicional à inibição ocasionada pela perfusão de glicose 20mM mas inibiu o efeito estimulatório produzido pela perfusão de glicose 5 mM. / We studied the modulation of bicarbonate reabsorption by the apical Na+/H+ exchanger of renal proximal tubule by luminal glucose, and the signaling path of this relationship. Treatment with phloridzin and streptozotocin diabetes on HCO3- reabsorption was also studied. We used stationary microperfusion in vivo for this purpose. Tubule perfusions with 5 mM glucose increased bicarbonate reabsorption compared to solutions without glucose plus phloridzin. Perfusion with 20 mM glucose caused an intermediate effect on JHCO3- compared to 0/phloridzin and 5 mM glucose. The inhibitors PD169316 and LY294002 with 5 mM glucose blocked the stimulatory effect of the latter, but H89 had no such effect. Streptozotocin diabetes abolished the inhibitory effect of 20 mM glucose perfusion. Chronic phloridzin did not produce any additional effect on JHCO3- during 20 mM glucose perfusion in normal rats., but blocked JHCO3- during perfusion with 5 mM glucose.

Ischemic stroke is the leading cause of disability world-wide and affects over 800,000 people per year in the United States. The majority of these strokes are ischemic due to a blockage of blood flow to the brain. Damage to the brain occurs at the onset of stroke, neuronal cell death is irreversible and therefore, quick treatment to remove blockage is critical factor in the recovery from stroke. Mechanical thrombectomy as a treatment for ischemic stroke provides an ideal opportunity to collect blood distal and proximal to the cerebral thrombus to examine neurochemical changes occurring during stroke. The purpose of this dissertation was to explore the trajectory of neurochemical changes that occur in response to ischemic stroke during the first 72 hours and the physiological response from stroke patients to improve stroke outcomes. The specific aims were to: 1) to determine whether venous blood gases predict infarct volume and/or mortality in acute ischemic stroke in young male rats; 2) determine whether venous blood gases predict infarct and edema volume, and/or mortality in acute ischemic stroke in aged male and female rats; 3) compare the presence and relative concentrations of acid/base and electrolytes in static blood distal to thrombus and in peripheral blood drawn from adults who received thrombectomy for ischemic stroke and identify associations to postreperfusion functional outcomes. Specific Aim One was addressed by evaluation of young (three-month old) Sprague-Dawley rats that underwent permanent or transient middle cerebral artery occlusion (MCAO). Pre- and post-MCAO venous samples from permanent and transient models provided pH, carbon dioxide, oxygen, bicarbonate, glucose, hematocrit, hematocrit, and electrolyte values of ionized calcium, potassium and sodium. The analyses indicated that mean differences in the blood gas and electrolytes between pre- to post-MCAO and pH and iCa2+ were predictors of infarct volume in the permanent MCAO model. The second aim was addressed by evaluation of aged (18 month old) male and female rats pre-MCAO, post-MCAO, and at 72 hours of permanent MCAO venous blood gas samples (pH, carbon dioxide, oxygen, bicarbonate, glucose, hematocrit, hematocrit, and electrolyte concentrations of ionized calcium, potassium and sodium). Changes in pH (from pre-MCAO to post-MACO and post-MCAO to 72 hours) and changes in Na+ and iCa2+ (from post-MCAO to 72 hours) were predictors of infarct volume and edema volume, respectively in both sexes. Cox regression revealed there was a 3.25 times increased risk for mortality based on changes (cut-off range within -2.00 to - 7.00) in bicarbonate levels (pre- to post-MCAO). The third aim was addressed by evaluation of acid/base balance (pH, carbon dioxide, oxygen, bicarbonate, ionized calcium, potassium and sodium) of ischemic stroke patients who underwent mechanical thrombectomy. Our results suggests sex differences matter in ischemic stroke populations. Significant differences occur within proximal blood between the sexes. Additionally, females had approximately 2.5 hour increased time between stroke symptom onset to thrombectomy completion time (described as infarct time). Changes in bicarbonate and base deficit were predictors of infarct time, but only in our female population.

<p>Ispitivanja primene vodonika u kliničkim uslovima su prilično nova, međutim efikasnost<br />molekularnog vodonika u dosada&scaron;njim kliničkim ispitivanjima je evidentna. Cilj ovog<br />istraživanja bio je da se ispita uticaj suplementacije sa vodom obogaćenom molekularnim<br />vodonikom (HRW) na bazalne vrednosti parametara oksidativnog stresa kod vrhunskih<br />džudista. Eksperimentalni tretman odvijao se u dve faze. U prvoj fazi ispitanici<br />eksperimentalne grupe (N=6) su bili suplementirani sa HRW (4g) u trajanju od 28 dana,<br />dok je kontrolna grupa (N=6) koristila placebo. Nakon suplementacije ispitanici su imali<br />&bdquo;Washout&ldquo; period u trajanju od 28 dana, a zatim je ponovljen identičan protokol na<br />ispitanicima u trajanju od 28 dana. U drugoj fazi eksperimentalnog tretmana ispitivani su<br />akutni efekti suplementacije molekularnim vodonikom na acido baznu ravnotežu<br />vrhunskih džudiskinja. U ovoj fazi studije ispitanice eksperimentalne grupe (N=4) su<br />suplementirane sa HRW (4g) , dok je kontrolna grupa (N=4) koristila placebo. Nakon<br />suplementacije ispitanice su imale &bdquo;Washout&ldquo; period u trajanju od 4 dana, a zatim je<br />ponovljen identičan protokol na ispitanicama pri čemu su ispitanice eksperimentalne<br />grupe (N=4) koristile placebo, dok je kontrolna grupa (N=4) suplementirana sa HRW.<br />Rezultati ispitivanja aktivnosti antioksidativnih enzima kod Placebo i HRW grupe<br />ukazuju na pojavu statistički značajnih razlika u antioksidativnom statusu kod vrhunskih<br />džudista. Odgovor organizma usled unosa HRW ogleda se u povećanju aktivnosti enzima<br />SOD i sadržaja GSH usled sprovođenja programirane fizičke aktivnosti. Takođe, trend<br />opadanja sadržaja MDA u HRW grupi je bio detektabilan. Primena HRW nije izazvala<br />statistički značajne promene u biohemijsko hematolo&scaron;kim parametrima. Akutni efekti<br />suplementacije sa HRW uticali su statistički značajno na redukciju akumulacije laktata<br />kao i na povećanje pH krvi nakon primene specifičnog džudo fitnes testa (SJFT) kod<br />vrhunskih džudistkinja. Ipak, primena suplementa nije značajno uticala na pobolj&scaron;anje<br />performansi džudistkinja. Dobijeni rezultati ukazuju na ergogenu antioksidantnu moć<br />molekularnog vodonika, pri čemu su dalja istraživanja neophodna kako bi se podesili<br />uslovi u kojima bi molekularni vodonik ispoljio svoje maksimalno delovanje i u sportu.</p> / <p>Research of hydrogen application are quite new in clinical conditions, however the<br />efficiency of molecular hydrogen in previous clinical studies is evident. The aim of this<br />study was to investigate the effect of supplementation with hydrogen rich water (HRW)<br />on baseline oxidative stress parameters in elite male judokas. Experimental treatment was<br />carried out in two phases. In the first phase, experimental group (N=6) were<br />supplemented daily with HRW (4g) for 28 days, while the control group (N=6) was used<br />placebo. After supplementation intake all subjects had &quot;washout&quot; period for 28 days, after<br />which the same protocol was repeated for a period of 28 days. In the second stage of<br />experimental treatment, acute effects of supplementation with molecular hydrogen on<br />acid base balance of elite female judokas were examined. In this phase of the study,<br />subjects from experimental group (N=4) were supplemented daily with HRW (4g), while<br />the control group (N=4) used placebo. After supplementation all subjects had a<br />&quot;washout&quot; period for a 4 days, after which the same protocol was repeated wherein the<br />members of the experimental group (N=4) used placebo, while the control group (N=4)<br />was supplemented daily with HRW. The results of analyzed antioxidant enzymes activity<br />in placebo and HRW group indicated on the occurrence of statistically significant<br />differences in antioxidant status of elite judo athletes. Obtained results indicate that<br />response of the body due to intake HRW is reflected in increasing levels of SOD and<br />GSH due to the implementation of programmed physical activity. Also, trend of MDA<br />decreasing in HRW group was detectable. In addition, application of HRW did not cause<br />negative changes in the biochemical and hematological parameters. Acute effects of<br />supplementation were affected to a statistically significant reduction in lactate<br />accumulation and pH increase after applied special judo fitness test (SJFT) on the top<br />judoka. However, use of supplements had no significant effect on improving performance<br />in elite judokas. Obtained results confirm ergogenic antioxidant power of molecular<br />hydrogen, wherein further studies are necessary in order to adjust the conditions in which<br />molecular hydrogen will exerted its maximum in sport.</p>

Das Ziel dieser Arbeit war es, den Einfluss unterschiedlich zusammengesetzter Tränken auf den Säuren-Basen-Haushalt bei Kälbern mit experimentell induzierter metabolischer Azidose zu untersuchen. Bei gesunden Kälbern konnte nachgewiesen werden, dass die Fütterung von milchbasierten ORL mit einer [SID3] ≥92 mmol/l eine Erhöhung der Plasma-[SID3] zur Folge hat (BACHMANN et al. 2009b) und damit eine alkalische Wirkung auf den SBS. Zu prüfen galt die Hypothese, ob es bei Kälbern mit experimentell induzierter metabolischer Azidose zu einem stärkeren alkalisierenden Effekt nach Gabe einer Tränke mit einer hohen [SID3] kommt. Bessere alkalisierende Eigenschaften einer Tränke könnten potentiell genutzt werden, um den Genesungsprozess von Kälbern mit metabolischer Azidose zu beschleunigen. Material und Methoden Zur Verfügung standen zwölf Kälber der Rasse Holstein-Friesian im Alter von weniger als vier Lebenswochen. Unter Verwendung von in der Literatur beschriebenen Induktionsprotokollen konnte per Infusion bei jeweils sechs Tieren eine manifeste hyperchlorämische Azidose und bei weiteren sechs Kälbern eine D-/L-Laktatazidose ausgelöst werden. Die Tiere wurden im Anschluss mit Milchaustauscher, wasser- oder milchaustauscher-basierter oraler Rehydratationslösung getränkt bzw. blieben im nüchternen Zustand. Zur Bestimmung von Stewart-Parametern des Säuren-Basen-Haushaltes im Plasma wurden nach einem festgelegten zeitlichen Schema vor und nach Induktion sowie vor und nach der Tränkegabe venöse Blutproben entnommen. Ergebnisse Bedingt durch die Einleitungsprotokolle war die Interpretation der Messergebnisse durch den starken Anstieg des Plasmavolumens bedeutend erschwert. Die eingesetzten Induktionsprotokolle sind nicht für Untersuchungen des Säuren-Basen-Haushaltes bei Kälbern nach unterschiedlicher Fütterung geeignet. Aus diesem Grund kann die aufgestellte Hypothese, dass die Verabreichung von milchaustauscher-basierter ORL zu einer besseren alkalischen Wirkung bei Kälbern mit metabolischer Azidose führt, anhand der vorliegenden Ergebnisse weder abgelehnt noch bestätigt werden. Einige Untersuchungsergebnisse zeigten positive Effekte auf Parameter des SBS bei Kälbern, denen eine Tränke verabreicht wurde, im Vergleich zu nüchternen Tieren. Diese Parameter waren die Plasma-D-Laktatkonzentration, die Strong Ion Difference [SID3] und [SID4] und ionisiertes Calcium [Ca2+]. Die Effekte waren nicht auf eine bestimmte der drei eingesetzten Tränkevarianten zurückzuführen. Weiterhin konnte gezeigt werden, dass ein quadratischer Zusammenhang zwischen der berechneten Variable Strong Ion Gap [SIGAlb/TP] und den gemessenen D-/L-Laktatkonzentrationen im Plasma besteht. Dies könnte zukünftig genutzt werden, um Faktoren zu etablieren, welche die Ableitung der Plasma-D-/L-Laktatkonzentration bei durchfallkranken Kälbern mit ZNS-Symptomatik aus gängigen Parametern ermöglicht, ohne die Laktatkonzentration direkt messen zu müssen. Schlussfolgerungen Für zukünftige Untersuchungen dieser Art wäre ein Induktionsprotokoll wünschenswert, das sowohl eine metabolische Azidose bei gleichzeitiger Dehydratation der Kälber vereint und so die metabolischen Bedingungen durchfallkranker Kälber simuliert. Die Gabe von ORL als direkte Einmischung in Milch bzw. MAT wird kritisch betrachtet. Ein negativer Effekt bei der Gabe von MAT-basierter ORL konnte bei diesen Untersuchungen auf keinen der bestimmten Parameter des SBS im Vergleich zu den anderen Tränkezusammensetzungen festgestellt werden. Klinische Nebenwirkungen Bei dieser Untersuchung traten nach der mehrfachen Infusion von D-/L-Laktat unerwartete Nebenwirkungen auf. Die Verabreichung führte zu starken Irritationen der Vena jugularis externa und zu Ödembildungen. Erhöhte D-Laktatkonzentrationen werden beim Menschen und verschiedenen Tierarten als Marker für traumatische Prozesse, Ischämie, Diabetes, gastrointestinale und neurologische Störungen diskutiert. Die weitere gezielte Untersuchung des Einflusses der wiederholten oder anhaltenden Einwirkung von D-Laktat auf Epithelzellen könnte nach den vorliegenden Untersuchungsergebnissen einen weiteren Anhaltspunkt für die Aufklärung der genauen pathologischen Mechanismen des D-Laktates bieten.

Human pregnancy is characterized by significant increases in central ventilatory drive and perceived respiratory discomfort (breathlessness). The physiological mechanisms of hyperventilation and breathlessness in pregnancy remain largely unknown and understudied. Objective: The main purpose of this research was to elucidate the mechanisms of maternal hyperventilation, and to systematically examine the contribution of alterations in central ventilatory drive, static/dynamic respiratory mechanics and their interaction with respect to the intensity of perceived breathlessness during exercise in pregnancy. General Methods: Experiments were conducted between 34-38 wks gestation and again 4-5 months post-partum in a total of 35 healthy, young women. A comprehensive mathematical model of ventilatory control was used to examine the role of alterations in wakefulness and central chemoreflex drives to breathe, acid-base balance and female sex hormones in maternal hyperventilation. The effects of pregnancy on detailed ventilatory (breathing pattern, airway function, operating lung volumes, esophageal pressure-derived indices of respiratory mechanics) and perceptual (breathing and leg discomfort) responses to incremental cycle exercise to the limits of tolerance were also examined. Results: Maternal hyperventilation resulted from a complex interaction between alterations in arterial and central acid-base balance and other factors that directly affect ventilation, including increased wakefulness and central chemoreflex drives to breathe, increased metabolism and decreased cerebral blood flow. Mechanical adaptations of the respiratory system, including recruitment of resting inspiratory capacity and reduced airway resistance, accommodated the increased demand for tidal volume expansion during exercise in pregnancy, while preserving effort-displacement and breathlessness-ventilation relationships. Variation in the severity of gestational breathlessness could not be explained by respiratory mechanical/muscular factors, but ultimately reflected variation in the amplitude of maternal hyperventilation and temporal desensitization to the sensory consequences of increased ventilation. Conclusion: Our results indicated that 1) the hyperventilation and attendant hypocapnia/alkalosis of pregnancy can be explained by alterations in wakefulness and central chemoreflex drives to breathe, acid-base balance, metabolic rate and cerebral blood flow; 2) mechanical adaptations of the respiratory system obviated the anticipated rise in perceived breathlessness for a given ventilation during exercise in pregnancy, and helped to ensure that peak aerobic working capacity was admirably preserved, even in late gestation; and 3) gestational breathlessness ultimately reflected the normal awareness of increased ventilation and contractile respiratory muscle effort. / Thesis (Ph.D, Kinesiology & Health Studies) -- Queen's University, 2008-08-28 16:01:40.78

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No. of bitstreams: 1 milioni_f_dr_bauru.pdf: 5480525 bytes, checksum: 6ac2fa2e539201d14af3503b4de493a1 (MD5) Previous issue date: 2018-08-20 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O objetivo da presente tese foi verificar a influência da suplementação de β-Alanina associado ao treinamento intervalado de alta intensidade (HIIT) na performance de sprints repetidos. Participaram do estudo conduzido em caráter randomizado e duplo-cego, 20 jovens saudáveis alocados em dois grupos (Gβ [n = 10] – 6,4 g.dia-1 de β-Alanina; GP [n = 10] – 6,4 g.dia-1 de dextrose - placebo). Os participantes foram avaliados em três momentos distintos, previamente ao início, após quatro semanas de HIIT sem suplementação e após 6 semanas de suplementação + HIIT. As avaliações foram compostas por teste incremental até exaustão (TINC); séries de 12 sprints repetidos (RSA); e teste de tempo limite até exaustão a 115% da velocidade máxima atingida no TINC (TLIM). Previamente e imediatamente após TINC e RSA foram realizadas avaliações neuromusculares compostas por saltos verticais máximos, contrações isométricas máximas de extensão de joelho e estimulação elétrica periférica. O HIIT foi composto de dez corridas de 1 min a 90% da velocidade máxima atingida no TINC, com 1 min de recuperação passiva entre as corridas e frequência de 3 sessões semanais. Previamente ao início da suplementação + HIIT e ao final da intervenção, os participantes foram submetidos a biópsias musculares para determinação do conteúdo de carnosina intramuscular, capacidade de tamponamento in vitro e conteúdo de proteínas/enzimas chaves. Após a intervenção, ambos os grupos melhoraram o metabolismo oxidativo (i.e., consumo máximo de oxigênio), entretanto, somente o Gβ melhorou significativamente o conteúdo de carnosina intramuscular e as variáveis do RSA além de apresentar atenuação da fadiga neuromuscular induzida pelo RSA. Não foram verificadas diferenças significativas na capacidade anaeróbia, capacidade de tamponamento in vitro e conteúdo de proteínas/enzimas chaves. Dessa forma, a associação entre suplementação de β-Alanina e HIIT proporcionou melhora significativa do desempenho de sprints repetidos. / The aim of the present thesis was to verify the influence of β-Alanine supplementation associated with high intensity interval training (HIIT) on the performance of repeated sprints. The study was conducted in a randomized, double-blind design and 20 healthy young men were allocated in two groups (Gβ [n = 10] - 6.4 g.day-1 of β-Alanine; GP [n = 10] - 6.4 g.day-1 of dextrose – placebo). The participants were evaluated at three different moments, prior to beginning, after four weeks of HIIT without supplementation and after 6 weeks of supplementation + HIIT. The evaluations were composed by incremental test until exhaustion (TINC); set of 12 repeated sprints (RSA); and time-to-exhaustion test at 115% of the maximum velocity achieved in TINC (TLIM). Previously and immediately after TINC and RSA, neuromuscular evaluations were performed, consisting of maximum vertical jumps, maximal voluntary isometric contractions of knee extension and peripheral electrical stimulation. The HIIT was composed by ten runs of 1-min at 90% of the maximum velocity achieved in TINC, with 1-min of passive recovery between runs and frequency of 3 sessions per week. Prior to the initiation of supplementation + HIIT and at the end of the intervention, the participants underwent muscle biopsies to determine intramuscular carnosine content, muscle buffer capacity in vitro and key protein/enzyme content. After the intervention, both groups improved oxidative metabolism (i.e., maximal oxygen uptake), however, only Gβ significantly improved the intramuscular carnosine content and the RSA variables; in addition to presenting attenuation of the neuromuscular fatigue induced by the RSA. No significant differences were observed in anaerobic capacity, muscle buffer capacity in vitro and key protein/enzyme content. Thus, the association between β-Alanine supplementation and HIIT provided significant improvement in repeated sprints performance. / 2016/02683-6

e algumas vias de sinalização envolvidas com a reabsorção de HCO3-, além do efeito do tratamento com florizina e com streptozotocina. Para isso, utilizamos o método de microperfusão estacionária in vivo. Perfusões tubulares com solução de glicose 5mM aumentaram a reabsorção de bicarbonato em comparação com soluções contendo florizina sem glicose. Porém, perfusão de soluções de glicose 20mM ocasionaram efeito intermediário sobre esta reabsorção. A perfusão de solução contendo glicose 5mM com os inibidores PD169316 e LY294002 aboliu o efeito estimulatório promovido pela glicose 5mM. O tratamento com streptozotocina aboliu o efeito inibitório da perfusão de solução de glicose 20mM. Já o tratamento com florizina, não apresentou nenhum efeito adicional à inibição ocasionada pela perfusão de glicose 20mM mas inibiu o efeito estimulatório produzido pela perfusão de glicose 5 mM. / We studied the modulation of bicarbonate reabsorption by the apical Na+/H+ exchanger of renal proximal tubule by luminal glucose, and the signaling path of this relationship. Treatment with phloridzin and streptozotocin diabetes on HCO3- reabsorption was also studied. We used stationary microperfusion in vivo for this purpose. Tubule perfusions with 5 mM glucose increased bicarbonate reabsorption compared to solutions without glucose plus phloridzin. Perfusion with 20 mM glucose caused an intermediate effect on JHCO3- compared to 0/phloridzin and 5 mM glucose. The inhibitors PD169316 and LY294002 with 5 mM glucose blocked the stimulatory effect of the latter, but H89 had no such effect. Streptozotocin diabetes abolished the inhibitory effect of 20 mM glucose perfusion. Chronic phloridzin did not produce any additional effect on JHCO3- during 20 mM glucose perfusion in normal rats., but blocked JHCO3- during perfusion with 5 mM glucose.

This thesis is missing pages 87, 172 and 255. No other copies of the thesis have these pages. -Digitization Centre / This thesis examined the effects of exhaustive exercise on acid-base and metabolite status in the intracellular and extracellular compartments of two very different fish species: the active, pelagic rainbow trout, and the sluggish, benthic starry flounder. In both species, exhaustive exercise resulted in an acidosis in the extracellular compartment of mixed respiratory and metabolic origin. Despite the reduction in pHe, red blood cell pHi was well regulated, though more precisely in trout than in flounder. Catecholamines were mobilized into the blood after exercise in trout but not in flounder. Circulating catecholamines may play an important role in regulating red blood cell (RBC) pHi in trout after exercise. In trout, lactate appeared in the blood in excess of H+ ; the reverse pattern was observed in flounder. H+ appearance was similar in both species. Differential release of lactate from the muscle mass was apparently responsible for this discrepancy. After exhaustive exercise, both trout and flounder experienced a severe intracellular acidosis in the white muscle, as measured by 14c-DMO (5,5-dimethyl -2,4-oxazolidinenione) distribution. H+ and lactate were not produced in equimolar quantities, with H+ produced in excess of lactate. Muscle lactate and H+ production was about 3-fold lower in flounder than in trout. The muscle intracellular acid-base disturbance was corrected more rapidly in flounder (4-8h) than in trout (8-12h). In flounder, this occurred prior to , but in trout after , correction of the extracellular acidosis. In flounder, a more rapid correction of muscle metabolite status was associated with the more rapid correction of the intracellular acidosis. After exercise there was a reduction in the whole body extracellular fluid volume and expansion of the intracellular fluid volume, largely reflecting changes within the muscle. This fluid shift resulted in a general hemoconcentration. Exercise led to a transient increase in net H+ excretion in both trout and flounder. Negligible amounts of lactate were transferred to the water. In flounder, about 20% of the total H+ load produced passed through the extracellular space and was transiently stored in the water, which appeared to hasten correction of the intracellular acid-base disturbance. In contrast, in trout, a much smaller portion of the acid load (about 6%), though about the same absolute amount as in flounder, was transferred to the water. This appeared to expedite correction of the extracellular acidosis.The results of this thesis argue against a prominent role for the Cori cycle in the final disposition of the lactate burden produced during exercise. Instead, it is suggested that the bulk of the lactate was metabolized in situ, either by oxidation or glyconeogenesis. In flounder, this was almost the sole fate of lactate, as very little appeared in the blood space. In trout, a significant portion of the lactate was exported to the blood, which was taken up and metabolized by aerobic tissues. / Thesis / Doctor of Philosophy (PhD)