The present study determined the independent contributions of temperature, strong ion difference ([SID]), total weak acid concentration ([A_tot]) and PCO₂ to changes in arterial and mixed venous [H⁺] and total carbon dioxide concentration ([TCO₂]) during 37 min of moderate intensity exercise (~50% of heart rate max) and the first 60 min of recovery. Six horses were fitted with indwelling carotid and pulmonary artery (PA) catheters, had PA temperature measured, and had blood samples withdrawn for immediate analysis of plasma ion and gas concentrations. The increase in core temperature during exercise (+4.5 °C; p < 0.001) significantly (p < 0.05) increased PO₂, PCO₂, and [H⁺], but without a significant effect on [TCO₂] (p > 0.01). The physicochemical acid-base approach was used to determine contributions of independent variables (except temperature) to the changes in [H⁺] and [TCO₂]. In both arterial and venous blood, there was no acidosis during exercise and recovery despite significant (p < 0.05) increases in [lactate] and in venous PCO₂. In arterial blood plasma, a mild alkalosis with exercise was due to primarily to a decrease in PCO₂ (p < 0.05) and an increase in [SID] (p < 0.1). In venous blood plasma, a near absence of change in [H⁺] was due to the acidifying effects of increased PCO₂ (p < 0.01) being offset by the alkalizing effects of increased [SID] (p < 0.05). The effect of temperature on PO₂ (p < 0.001) resulted in an increased arterio-venous PO₂ difference (p < 0.001) that would facilitate O₂ transfer to contracting muscle. The simultaneous changes in the PCO₂ and the concentrations of the other independent acid-base variables (contributions from individual strong and weak ions as manifest in [SID] and [A_tot]) show complex, multilevel control of acid-base states in horses performing even moderate intensity exercise. Correction of acid-base variables to core body temperature presents a markedly different physiological response to exercise than that provided by variables measured and presented at an instrument temperature of 37 °C.

Summary: Reasons for performing study: Standardbred and Thoroughbred racehorses around the world are tested for performance enhancing substances. Among these are blood alkalising substances that raise plasma pH and total carbon dioxide (TCO ₂ ) concentration. However, many horses have an elevated TCO ₂ due to dietary, environmental and health concerns without having been administered an alkalising substance. Objectives: The purposes of this study were to determine the acid‐base profile of a cross section of Standardbred horses in racing/race training in Ontario and the main independent variables that contributed to acid‐base state. Materials and methods: On nonracing days, blood from 211 horses at rest, from 9 training facilities, was analysed within 30 min for plasma pH (7.406 ± 0.039; mean ± s.e.), PCO ₂ (50.0 ± 3.4 mmHg), from which [HCO ₃ ^‐ ] (31.2 ± 2.8 mmol/l) and [TCO ₂ ] (33.1 ± 2.9 mmol/l; range 25.66–42.9) were calculated. From these, a subset of 161 horses had full data sets for plasma protein and strong ion concentrations. These data were further analysed by facility and level of TCO ₂ . Data on nutrition, training, racing and medications were also collected. Results: There were significant differences amongst facilities with respect to plasma pH, TCO ₂ , strong ion difference ([SID]), PCO ₂ and total weak acid concentration ([A _tot ]). Horses having the highest TCO ₂ (37.0–42.9 mmol/l, n = 16) had significantly higher [SID] (52.9 ± 0.8 mEq/l) and PCO ₂ (52.5 ± 0.7 mmHg) and relatively low [A _tot ] (14.9 ± 0.7 mEq/l) compared to average TCO ₂ (32.1.0–34.9 mmol/l) horses (n = 75). In horses with the lowest TCO ₂ (n = 11) the greatest contributor was elevated [A _tot ] (21.0 ± 0.7 mEq/l) and unmeasured (acetate, citrate, proprionate, butyrate) weak acids (7.0 ± 0.2 mEq/l) while [SID] (49.6 ± 0.8 mEq/l) and PCO ₂ (47.8 ± 1.0 mmHg) were similar to average TCO ₂ horses. Thirty‐two horses had a TCO ₂ ranging from 35.0–36.9 mmol/l). Conclusions: There is a wide range of acid‐base state and factors contributing to acid‐base state amongst Standardbred race horses in Ontario. Dietary, environmental and handling practices and health concerns, that elevate plasma [SID], lower [A _tot ] and lower the concentration of unmeasured weak acids are the primary contributors to alkalosis and elevated TCO ₂ .

Key points: Exercise results in rapid and large extracellular to intracellular fluid shifts, as well as significant sweating losses of water and ions. It is unknown whether ions within oral electrolyte supplements are taken up by muscle (and other soft tissues) and whether oral supplementation can effectively offset sweating losses. Pre‐loading with 8 L of a balanced hypotonic electrolyte supplement attenuated extracellular fluid losses, increased exercise duration and increased sweating fluid and ion losses during submaximal exercise. Supplemented electrolytes appear in skeletal muscle within 1 h after administration. Electrolyte supplementation increased exercise performance, improved maintenance of extracellular fluid volumes, and attenuated body fluid losses while maintaining sweating rates. This study used radioactive sodium (²⁴Na) and potassium (⁴²K) in a balanced, hypotonic electrolyte supplement to trace their appearance in skeletal muscle, and also quantified extracellular and whole‐body fluid and ion changes during electrolyte supplementation, exercise and recovery. In a randomized crossover design, 1 h after administration of 1 to 3 L of water or electrolyte supplement with²⁴Na, horses were exercised at 35% VO_2maxto voluntary fatigue or, after administration of 8 L of water or electrolyte supplement with⁴²K were exercised at 50% peak VO₂for 45 min (n= 4 in each trial). Pre‐exercise electrolyte supplementation was associated with decreased loss of fluid and electrolytes from the extracellular fluid compartments during exercise and recovery compared with water alone. The improved fluid and ion balance during prolonged exercise was associated with increased exercise duration, despite continuing sweating losses of fluid and ions. Nasogastric administration of radiotracer²⁴Na⁺and⁴²K⁺showed rapid absorption into the blood with plasma levels peaking 45 min after administration, followed by distribution into the extracellular space and intracellular fluid of muscle within 1 h. Following exercise, virtually all Na⁺remained within the extracellular compartment, while the majority of K⁺underwent intracellular uptake by 2 h of recovery. It is concluded that pre‐loading with a large volume, balanced electrolyte supplement helps maintain whole‐body fluid and ion balance and support muscle function during periods of prolonged sweat ion losses.

Oral electrolyte supplementation may influence acid-base state during exercise due to the intestinal absorption of administered water and electrolytes used to mitigating sweat losses. This study examined the effect of pre-exercise electrolyte supplementation (3 and 8 L) on plasma acid-base variables at rest, during moderate intensity exercise and during recovery. It was hypothesized that electrolyte supplementation will result in improved acid-base state compared to the alkalosis typical of prolonged exercise. In randomized crossover fashion, four horses were administered 3 L or 8 L of a hypotonic electrolyte solution (PNW) intended to replace sweat losses, or water alone (CON), 1 h before treadmill exercise to fatigue (at 35% of peak VO₂) or for 45 min at 50% peak VO₂. Blood was sampled at 10-min intervals before, during and after exercise, and analyzed for dependent and independent acid-base variables. Effects of 3 L of supplementation at low exercise intensities were minimal. In the 8 L trials, plasma [H⁺] decreased (p < 0.05) during exercise and early recovery in CON but not PNW. Plasma TCO₂ decreased (p < 0.05) by 30 min after PNW reaching a nadir of 28.0 ± 1.5 mmol/L during the early exercise period (p = 0.018). Plasma pCO₂ and strong ion difference [SID] were the primary contributors to changes in [H⁺] and [TCO₂], respectively. Pre-exercise PNW of 8 L intended to fully replenish sweat loses maintained [H⁺], decreased [TCO₂] and mitigated the mild alkalosis during moderate intensity exercise.

Key Points: Thrombin injures podocytes through its cognate receptors in vitro , and thrombin generation increases during proteinuric glomerular disease. In this study, plasma prothrombin levels modulated in vivo podocyte health and function in a rat model of glomerular disease. Thrombin antagonism may simultaneously prevent thrombosis and CKD progression due to glomerular disease. Background: CKD is a leading cause of death; its progression is driven by glomerular podocyte injury and loss, manifesting as proteinuria. Proteinuria includes loss of coagulation zymogens, cofactors, and inhibitors resulting in a hypercoagulable state characterized by enhanced thrombin generation. Both CKD and proteinuria significantly increase the risk of thromboembolic disease. Meanwhile, anticoagulant medications (which antagonize thrombin and thereby prevent thromboembolism) have been shown to reduce proteinuria in rats, and thrombin has been shown to injure cultured human and rat podocytes. We thus aimed to directly determine the influence of circulating prothrombin, the zymogen precursor of thrombin, on glomerular pathobiology. We hypothesized that (pro)thrombin drives podocytopathy, podocytopenia, and proteinuria. Methods: Glomerular proteinuria was induced with puromycin aminonucleoside in rats. Prothrombin was either knocked down using an antisense oligonucleotide–targeting prothrombin mRNA or elevated by serial intravenous prothrombin protein infusions, previously established methods to model hypoprothrombinemia and hyperprothrombinemia, respectively. After 10 days, plasma prothrombin levels were determined and kidneys were examined for (pro)thrombin colocalization to podocytes, histology, and electron microscopy. Podocytopathy, podocytopenia, proteinuria, and plasma albumin were measured. Results: Antisense oligonucleotide–mediated prothrombin knockdown significantly reduced prothrombin colocalization to podocytes, tubular injury, podocyte foot process effacement, podocytopathy, and proteinuria, along with improved plasma albumin in the puromycin aminonucleoside glomerular disease model. By contrast, elevated prothrombin levels significantly increased podocytopathy and proteinuria. Podocytopenia was significantly improved in hypoprothrombinemic versus hyperprothrombinemic rats. Conclusions: Thrombin generation is enhanced by glomerular proteinuria, and thrombin injures conditionally immortalized podocytes in vitro . In this study, prothrombin knockdown ameliorated in vivo podocyte injury and improved podocyte function in the rat puromycin aminonucleoside–induced glomerular disease model, whereas hyperprothrombinemia exacerbated podocyte injury and diminished podocyte function.

Persons with mild hemophilia A (HA) may use intranasal desmopressin prior to sports participation. Desmopressin is expensive and can cause vomiting, headache, palpitation, and occasionally seizures. Our group has previously documented a 2.3-fold increase in factor VIII activity (FVIII:C) in adolescents with mild HA after moderate-intensity aerobic exercise. Herein, we report principal findings of a randomized trial of intranasal desmopressin vs a standardized, moderate-intensity aerobic exercise regimen in adolescents with mild HA. Our primary objective was to compare the change in FVIII:C associated with these 2 interventions. We also examined changes in hemostatic parameters arising from their sequential administration. The study was conducted simultaneously at the Hospital for Sick Children, Canada, and Nationwide Children’s Hospital, USA. Thirty-two eligible male adolescents (mean age ± standard deviation: 16.1 ± 2.6 years) with mild HA (mean baseline FVIII:C: 27.9% ± 18.4%) were randomized to 1 of 4 study arms (desmopressin followed by exercise, desmopressin alone, exercise followed by desmopressin, and exercise alone). Blood work was obtained at baseline and at 3 subsequent time-points. Participants randomized to exercise cycled on an ergometer for approximately 12 minutes, with the final 3 minutes at 85% of their predicted maximum heart rate. Standard weight-based dosing of desmopressin was used. Mean immediate increase in FVIII:C was 1.7-fold with exercise compared with 1.9-fold with desmopressin (noninferiority, P = .04). Exercise-induced improvement in hemostatic parameters including FVIII:C was brief compared with more sustained improvements seen with desmopressin. More than 60% of participants randomized to receive both exercise and desmopressin achieved normal (>50%) FVIII:C, 75 and 135 minutes into the study protocol.