Sodium Lactate Infusion Research Articles

Acid-base dysregulation and chemosensory mechanisms in panic disorder: a translational update.

Panic disorder (PD), a complex anxiety disorder characterized by recurrent panic attacks, represents a poorly understood psychiatric condition which is associated with significant morbidity and an increased risk of suicide attempts and completed suicide. Recently however, neuroimaging and panic provocation challenge studies have provided insights into the pathoetiology of panic phenomena and have begun to elucidate potential neural mechanisms that may underlie panic attacks. In this regard, accumulating evidence suggests that acidosis may be a contributing factor in induction of panic. Challenge studies in patients with PD reveal that panic attacks may be reliably provoked by agents that lead to acid–base dysbalance such as CO2 inhalation and sodium lactate infusion. Chemosensory mechanisms that translate pH into panic-relevant fear, autonomic, and respiratory responses are therefore of high relevance to the understanding of panic pathophysiology. Herein, we provide a current update on clinical and preclinical studies supporting how acid–base imbalance and diverse chemosensory mechanisms may be associated with PD and discuss future implications of these findings.

A Selective Orexin-1 Receptor Antagonist Attenuates Stress-Induced Hyperarousal without Hypnotic Effects

Orexins (OXs) are peptides produced by perifornical (PeF) and lateral hypothalamic neurons that exert a prominent role in arousal-related processes, including stress. A critical role for the orexin-1 receptor (OX1R) in complex emotional behavior is emerging, such as overactivation of the OX1R pathway being associated with panic or anxiety states. Here we characterize a brain-penetrant, selective, and high-affinity OX1R antagonist, compound 56 [N-({3-[(3-ethoxy-6-methylpyridin-2-yl)carbonyl]-3-azabicyclo[4.1.0]hept-4-yl}methyl)-5-(trifluoromethyl)pyrimidin-2-amine]. Ex vivo receptor binding studies demonstrated that, after subcutaneous administration, compound 56 crossed the blood-brain barrier and occupied OX1Rs in the rat brain at lower doses than standard OX1R antagonists GSK-1059865 [5-bromo-N-({1-[(3-fluoro-2-methoxyphenyl)carbonyl]-5-methylpiperidin-2-yl}methyl)pyridin-2-amine], SB-334867 [1-(2-methyl-1,3-benzoxazol-6-yl)-3-(1,5-naphthyridin-4-yl)urea], and SB-408124 [1-(6,8-difluoro-2-methylquinolin-4-yl)-3-[4-(dimethylamino)phenyl]urea]. Although compound 56 did not alter spontaneous sleep in rats and in wild-type mice, its administration in orexin-2 receptor knockout mice selectively promoted rapid eye movement sleep, demonstrating target engagement and specific OX1R blockade. In a rat model of psychological stress induced by cage exchange, the OX1R antagonist prevented the prolongation of sleep onset without affecting sleep duration. In a rat model of panic vulnerability (involving disinhibition of the PeF OX region) to threatening internal state changes (i.e., intravenous sodium lactate infusion), compound 56 attenuated sodium lactate-induced panic-like behaviors and cardiovascular responses without altering baseline locomotor or autonomic activity. In conclusion, OX1R antagonism represents a novel therapeutic strategy for the treatment of various psychiatric disorders associated with stress or hyperarousal states.

Hypertonic sodium lactate improves fluid balance and hemodynamics in porcine endotoxic shock.

IntroductionBased on the potential interest in sodium lactate as an energy substrate and resuscitative fluid, we investigated the effects of hypertonic sodium lactate in a porcine endotoxic shock.MethodsFifteen anesthetized, mechanically ventilated pigs were challenged with intravenous infusion of E. coli endotoxin. Three groups of five animals were randomly assigned to receive 5 mL/kg/h of different fluids: a treatment group received hypertonic sodium lactate 11.2% (HSL group); an isotonic control group receiving 0.9% NaCl (NC group); a hypertonic control group with the same amount of osmoles and sodium than HSL group receiving hypertonic sodium bicarbonate 8.4% (HSB group). Hemodynamic and oxygenation variables, urine output and fluid balance were measured at baseline and at 30, 60, 120, 210 and 300 min. Skin microvascular blood flow at rest and during reactive hyperemia was obtained using a laser Doppler flowmetry technique. Results were given as median with interquartile ranges.ResultsEndotoxin infusion resulted in hypodynamic shock. At 300 min, hemodynamics and oxygenation were significantly enhanced in HSL group: mean arterial pressure (103 [81–120] mmHg vs. 49 [41–62] in NC group vs. 71 [60–78] in HSB group), cardiac index (1.6 [1.2–1.8] L/min/m2 vs. 0.9 [0.5–1.1] in NC group vs. 1.3 [0.9–1.6] in HSB group) and partial pressure of oxygen (366 [308–392] mmHg vs. 166 [130–206] in NC group vs. 277 [189–303] in HSB group). At the same time, microvascular reactivity was significantly better in HSL group with a lower venoarterial CO2 tension difference (5.5 [4–10] mmHg vs. 17 [14–25] in NC group vs. 14 [12–15] in HSB group). The cumulative fluid balance was lower in HSL group (-325 [-655; -150] mL) compared to NC (+560 [+230; +900] mL, p = 0.008) and HSB (+185 [-110; +645] mL, p = 0.03) groups.ConclusionsIn our hypodynamic model of endotoxic shock, infusion of hypertonic sodium lactate improves hemodynamic and microvascular reactivity with a negative fluid balance and a better oxygenation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-014-0467-3) contains supplementary material, which is available to authorized users.

Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain

Experimental evidence suggests that lactate is neuroprotective after acute brain injury; however, data in humans are lacking. We examined whether exogenous lactate supplementation improves cerebral energy metabolism in humans with traumatic brain injury (TBI). We prospectively studied 15 consecutive patients with severe TBI monitored with cerebral microdialysis (CMD), brain tissue PO2 (PbtO2), and intracranial pressure (ICP). Intervention consisted of a 3-h intravenous infusion of hypertonic sodium lactate (aiming to increase systemic lactate to ca. 5 mmol/L), administered in the early phase following TBI. We examined the effect of sodium lactate on neurochemistry (CMD lactate, pyruvate, glucose, and glutamate), PbtO2, and ICP. Treatment was started on average 33 ± 16 h after TBI. A mixed-effects multilevel regression model revealed that sodium lactate therapy was associated with a significant increase in CMD concentrations of lactate [coefficient 0.47 mmol/L, 95% confidence interval (CI) 0.31-0.63 mmol/L], pyruvate [13.1 (8.78-17.4) μmol/L], and glucose [0.1 (0.04-0.16) mmol/L; all p < 0.01]. A concomitant reduction of CMD glutamate [-0.95 (-1.94 to 0.06) mmol/L, p = 0.06] and ICP [-0.86 (-1.47 to -0.24) mmHg, p < 0.01] was also observed. Exogenous supplemental lactate can be utilized aerobically as a preferential energy substrate by the injured human brain, with sparing of cerebral glucose. Increased availability of cerebral extracellular pyruvate and glucose, coupled with a reduction of brain glutamate and ICP, suggests that hypertonic lactate therapy has beneficial cerebral metabolic and hemodynamic effects after TBI.

Half-molar sodium lactate infusion improves cardiac performance in acute heart failure: a pilot randomised controlled clinical trial

IntroductionAcute heart failure (AHF) is characterized by inadequate cardiac output (CO), congestive symptoms, poor peripheral perfusion and end-organ dysfunction. Treatment often includes a combination of diuretics, oxygen, positive pressure ventilation, inotropes and vasodilators or vasopressors. Lactate is a marker of illness severity but is also an important metabolic substrate for the myocardium at rest and during stress. We tested the effects of half-molar sodium lactate infusion on cardiac performance in AHF.MethodsWe conducted a prospective, randomised, controlled, open-label, pilot clinical trial in 40 patients fulfilling two of the following three criteria for AHF: (1) left ventricular ejection fraction <40%, (2) acute pulmonary oedema or respiratory failure of predominantly cardiac origin requiring mechanical ventilation and (3) currently receiving vasopressor and/or inotropic support. Patients in the intervention group received a 3 ml/kg bolus of half-molar sodium lactate over the course of 15 minutes followed by 1 ml/kg/h continuous infusion for 24 hours. The control group received only a 3 ml/kg bolus of Hartmann’s solution without continuous infusion. The primary outcome was CO assessed by transthoracic echocardiography 24 hours after randomisation. Secondary outcomes included a measure of right ventricular systolic function (tricuspid annular plane systolic excursion (TAPSE)), acid-base balance, electrolyte and organ function parameters, along with length of stay and mortality.ResultsThe infusion of half-molar sodium lactate increased (mean ± SD) CO from 4.05 ± 1.37 L/min to 5.49 ± 1.9 L/min (P < 0.01) and TAPSE from 14.7 ± 5.5 mm to 18.3 ± 7 mm (P = 0.02). Plasma sodium and pH increased (136 ± 4 to 146 ± 6 and 7.40 ± 0.06 to 7.53 ± 0.03, respectively; both P < 0.01), but potassium, chloride and phosphate levels decreased. There were no significant differences in the need for vasoactive therapy, respiratory support, renal or liver function tests, duration of ICU and hospital stay or 28- and 90-day mortality.ConclusionsInfusion of half-molar sodium lactate improved cardiac performance and led to metabolic alkalosis in AHF patients without any detrimental effects on organ function.Trial registrationClinicaltrials.gov NCT01981655. Registered 13 August 2013.

Sodium lactate for fluid resuscitation: the preferred solution for the coming decades?

In a recent issue of Critical Care, 0.5 M sodium lactate infusion for 24 hours was reported to increase cardiac output in patients with acute heart failure. This effect was associated with a concomitant metabolic alkalosis and a negative water balance. Growing data strongly support the role of lactate as a preferential oxidizable substrate to supply energy metabolism leading to improved organ function (heart and brain especially) in ischemic conditions. Due to its sodium/chloride imbalance, this solution prevents hyperchloremic acidosis and limits fluid overload despite the obligatory high sodium load. Sodium lactate solution therefore shows many advantages and appears a very promising means for resuscitation of critically ill patients. Further studies are needed to establish the most appropriate dose and indications for sodium lactate infusion in order to prevent the occurrence of severe hypernatremia and metabolic alkalosis.

Half-molar sodium lactate infusion to prevent intracranial hypertensive episodes in severe traumatic brain injured patients: a randomized controlled trial

Preventive treatments of traumatic intracranial hypertension are not yet established. We aimed to compare the efficiency of half-molar sodium lactate (SL) versus saline serum solutions in preventing episodes of raised intracranial pressure (ICP) in patients with severe traumatic brain injury (TBI). This was a double-blind, randomized controlled trial including 60 patients with severe TBI requiring ICP monitoring. Patients were randomly allocated to receive a 48-h continuous infusion at 0.5ml/kg/h of either SL (SL group) or isotonic saline solution (control group) within the first 12h post-trauma. Serial measurements of ICP, as well as fluid, sodium, and chloride balance were performed over the 48-h study period. The primary outcome was the number of raised ICP (≥20mmHg) requiring a specific treatment. Raised ICP episodes were reduced in the SL group as compared to the control group within the 48-h study period: 23 versus 53 episodes, respectively (p<0.05). The proportion of patients presenting raised ICP episodes was smaller in the SL group than in the saline group: 11 (36%) versus 20 patients (66%) (p<0.05). Cumulative 48-h fluid and chloride balances were reduced in the SL group compared to the control group (both p<0.01). A 48-h infusion of SL decreased the occurrence of raised ICP episodes in patients with severe TBI, while reducing fluid and chloride balances. These findings suggest that SL solution could be considered as an alternative treatment to prevent raised ICP following severe TBI.

Effect of hyperosmolar sodium lactate infusion on haemodynamic status and fluid balance compared with hydroxyethyl starch 6% during the cardiac surgery

Background and Aim:No solution has been determined ideal for fluid therapy during cardiac surgery. Previous studies have shown that hyperosmolar sodium lactate (HSL) infusion has improved cardiac performance with smaller volume infusion, which resulted in negative fluid balance. This study compared the effects between a patent-protected HSL infusion and hydroxyethyl starch (HES) 6% on haemodynamic status of the patients undergoing cardiac surgery.Methods:In this open-label prospective controlled randomized study, patients were randomly assigned to receive loading dose of either HSL or HES 6%, at 3 mL/kgBW within 15 min, at the beginning of surgery. Haemodynamic parameters and fluid balance were evaluated, while biochemical parameters and any adverse effect were also recorded. Haemodynamic and laboratory parameters were analyzed through repeated measures analysis of variance. Statistical assessment of fluid management was carried out through Student t-test. All statistical analyses were performed using the statistical package for the social sciences® version 15, 2006 (SPSS Inc., Chicago, IL).Results:Out of 100 enrolled patients in this study (50 patients in each arm), 98 patients were included in analysis (50 in HSL group; 48 in HES group). Cardiac index increased higher in HSL group (P = 0.01), whereas systemic vascular resistance index decreased more in HSL than HES group (P = 0.002). Other haemodynamic parameters were comparable between HSL and HES group. Fluid balance was negative in HSL group, but it was positive in HES group (−445.94 ± 815.30 mL vs. +108.479 ± 1219.91 mL, P < 0.009).Conclusion:Administration of HSL solution during the cardiac surgery improved cardiac performance and haemodynamic status better than HES did.

The impact of increased blood lactate on serum S100B and prolactin concentrations in male adult athletes

S100B is an astroglial protein that is increased in the peripheral bloodstream after traumatic brain injury (TBI). Elevated serum levels of S100B have been shown to be predictive of mild TBI. Furthermore, physical activity (PA) can affect S100B levels. Interestingly, increased serum S100B concentrations have been detected in athletes without apparent TBI. Such increases could be attributed to tissue hypoperfusion reflected by blood lactate concentrations [BLa(-)] and/or increased serotonergic activity reflected by prolactin (PRL). The impact of increased blood lactates on peripheral S100B levels per se are yet unknown. The purpose of our study was to investigate if increased blood lactate induced by sodium lactate infusion, without the "side effects" of PA, resulted in changes in serum S100B and PRL. Twelve male adults were given a sodium lactate infusion for a period of 24 min by a perfusor with an infusion rate of 0.01 mL kg(-1) min(-1), increased every 3 min. The main outcome measures showed no increase in serum S100B (p > 0.05). Prolactin increased significantly (p < 0.05) after [BLa(-)] exceeded a concentration of 4 mmol L(-1). Furthermore, the expected values of blood lactate achieved peak values ranging from 11 to 15 mmol L(-1). We conclude that neither increased blood lactate nor serum PRL play an exclusive role in the regulation of S100B. Nevertheless, PA should be surveyed in medical history and critically assessed in determining the severity of TBI, especially in sports. Further studies are needed to clarify the impact of PA on the biomarker S100B.

Group II metabotropic glutamate receptor type 2 allosteric potentiators prevent sodium lactate-induced panic-like response in panic-vulnerable rats

Rats with chronic inhibition of GABA synthesis by infusion of l-allyglycine, a glutamic acid decarboxylase inhibitor, into their dorsomedial/perifornical hypothalamus are anxious and exhibit panic-like cardio-respiratory responses to treatment with intravenous (i.v.) sodium lactate (NaLac) infusions, in a manner similar to what occurs in patients with panic disorder. We previously showed that either NMDA receptor antagonists or metabotropic glutamate receptor type 2/3 receptor agonists can block such a NaLac response, suggesting that a glutamate mechanism is contributing to this panic-like state. Using this animal model of panic, we tested the efficacy of CBiPES and THIIC, which are selective group II metabotropic glutamate type 2 receptor allosteric potentiators (at 10-30 mg/kg i.p.), in preventing NaLac-induced panic-like behavioral and cardiovascular responses. The positive control was alprazolam (3mg/kg i.p.), a clinically effective anti-panic benzodiazepine. As predicted, panic-prone rats given a NaLac challenge displayed NaLac-induced panic-like cardiovascular (i.e. tachycardia and hypertensive) responses and "anxiety" (i.e. decreased social interaction time) and "flight" (i.e. increased locomotion) -associated behaviors; however, systemic injection of the panic-prone rats with CBiPES, THIIC or alprazolam prior to the NaLac dose blocked all NaLac-induced panic-like behaviors and cardiovascular responses. These data suggested that in a rat animal model, selective group II metabotropic glutamate type 2 receptor allosteric potentiators show an anti-panic efficacy similar to alprazolam.

Evidence of a suffocation alarm system within the periaqueductal gray matter of the rat

Dyspnea, hunger for air, and urge to flee are the cardinal symptoms of panic attacks. Patients also show baseline respiratory abnormalities and a higher rate of comorbid and antecedent respiratory diseases. Panic attacks are also precipitated by infusion of sodium lactate and inhalation of 5% CO₂ in predisposed patients but not in healthy volunteers or patients without panic disorder. Accordingly, Klein [Klein (1993) Arch Gen Psychiatry 50:306-317] suggested that clinical panic is the misfiring of an as-yet-unidentified suffocation alarm system. In rats, selective anoxia of chemoreceptor cells by potassium cyanide (KCN) and electrical and chemical stimulations of periaqueductal gray matter (PAG) produce defensive behaviors, which resemble panic attacks. Thus, here we examined the effects of single or combined administrations of CO₂ (8% and 13%) and KCN (10-80 μg, i.v.) on spontaneous and PAG-evoked behaviors of rats either intact or bearing electrolytic lesions of PAG. Exposure to CO₂ alone reduced grooming while increased exophthalmus, suggesting an arousal response to non-visual cues of environment. Unexpectedly, however, CO₂ attenuated PAG-evoked immobility, trotting, and galloping while facilitated defecation and micturition. Conversely, KCN produced all defensive behaviors of the rat and facilitated PAG-evoked trotting, galloping, and defecation. There were also facilitatory trends in PAG-evoked exophthalmus, immobility, and jumping. Moreover, whereas the KCN-evoked defensive behaviors were attenuated or even suppressed by discrete lesions of PAG, they were markedly facilitated by CO₂. Authors suggest that the PAG harbors an anoxia-sensitive suffocation alarm system which activation precipitates panic attacks and potentiates the subject responses to hypercapnia.

Renal lactate elimination is maintained during moderate exercise in humans

Reduced hepatic lactate elimination initiates blood lactate accumulation during incremental exercise. In this study, we wished to determine whether renal lactate elimination contributes to the initiation of blood lactate accumulation. The renal arterial-to-venous (a-v) lactate difference was determined in nine men during sodium lactate infusion to enhance the evaluation (0.5 mol · L−1 at 16 ± 1 mL · min−1; mean ± s) both at rest and during cycling exercise (heart rate 139 ± 5 beats · min−1). The renal release of erythropoietin was used to detect kidney tissue ischaemia. At rest, the a-v O2 (CaO2-CvO2) and lactate concentration differences were 0.8 ± 0.2 and 0.02 ± 0.02 mmol · L−1, respectively. During exercise, arterial lactate and CaO2-CvO2 increased to 7.1 ± 1.1 and 2.6 ± 0.8 mmol · L−1, respectively (P < 0.05), indicating a ∼70% reduction of renal blood flow with no significant change in the renal venous erythropoietin concentration (0.8 ± 1.4 U · L−1). The a-v lactate concentration difference increased to 0.5 ± 0.8 mmol · L−1, indicating similar lactate elimination as at rest. In conclusion, a ∼70% reduction in renal blood flow does not provoke critical renal ischaemia, and renal lactate elimination is maintained. Thus, kidney lactate elimination is unlikely to contribute to the initial blood lactate accumulation during progressive exercise.

Adaptation of the Secretion of Aldosterone and Angiotensin II to Exercise in Rats.

Aldosterone is a mineralocorticoid produced by the zona glomerulosa (ZG) cells of the adrenal cortex. Previous studies have demonstrated that exercise is one of the stresses known to increase aldosterone production. Both potassium and angiotensin II levels in the plasma were correlated with aldosterone secretion during exercise, but the action mechanism is still unclear. In our in vivo study, male rats were catheterized via right jugular vein (RJV), and divided into four groups including water immersion, swim, lactate infusion (13 mg/kg/min) and pyruvate infusion (13 mg/kg/min) groups. Each group was treated for 10 min. Blood samples were collected at 0, 10, 15, 30, 60 and 120 min from RJV after administration. In an in vitro study, ZG cells from experimental rats were challenged by lactate (1-10 mM) with or without angiotensin II (10 nM) for 60 min. The levels of plasma angiotensin II and those of aldosterone in plasma and medium were measured by radioimmunoassay. Protein expressions in cell lysates were measured by immunoblotting assay. Ten min after exercise and lactate infusion, plasma levels of aldosterone and lactate were significantly higher than those in the control group. The level of angiotensin II was increased by swimming but not by lactate infusion. The levels of plasma sodium were increased whereas those of plasma potassium were decreased by swimming and infusion of sodium lactate or sodium pyruvate. The responses of plasma osmolality were synchronized with those of plasma sodium in the experimental animals. Administration of angiotensin II (10 nM) in vitro significantly increased aldosterone production. Sodium lactate (1-10 mM) alone did not alter the release of aldosterone. Co-incubation of angiotensin II (10 nM) with sodium lactate (10 mM) resulted in an increased production of aldosterone as compared with the group treated with angiotensin II alone. Administration of sodium lactate did not alter the protein expression of P450scc, but enhanced steroidogenic acute regulatory protein (StAR) expression in the presence of angiotensin II (10 nM) in ZG cells. These results demonstrated that short-time exercise led to the increase of aldosterone secretion, which is associated with the increased secretion of angiotensin II and the direct stimulatory effect of lactate on the action of angiotensin II in ZG cells. (poster)

Vigorous exercise increases brain lactate and Glx (glutamate+glutamine): A dynamic 1H-MRS study

Vigorous exercise increases lactate and glucose uptake by the brain in excess of the increase in brain oxygen uptake. The metabolic fate of this non-oxidized carbohydrate entering the brain is poorly understood, but accumulation of lactate in the brain and/or increased net synthesis of amino acid neurotransmitters are possible explanations. Previous proton magnetic resonance spectroscopy (1H-MRS) studies using conventional pulse sequences have not detected changes in brain lactate following exercise. This contrasts with 1H-MRS studies showing increased brain lactate when blood lactate levels are raised by an intravenous infusion of sodium lactate. Using a J-editing 1H-MRS technique for measuring lactate, we demonstrated a significant 19% increase in lactate in the visual cortex following graded exercise to approximately 85% of predicted maximum heart rate. However, the magnitude of the increase was insufficient to account for more than a small fraction of the non-oxidized carbohydrate entering the brain with exercise. We also report a significant 18% increase in Glx (combined signal from glutamate and glutamine) in visual cortex following exercise, which may represent an activity-dependent increase in glutamate. Future studies will be necessary to test the hypothesis that non-oxidized carbohydrate entering the brain during vigorous exercise is directed, in part, toward increased net synthesis of amino acid neurotransmitters. The possible relevance of these findings to panic disorder and major depression is discussed.

Involvement of the cystic fibrosis transmembrane conductance regulator in the acidosis‐induced efflux of ATP from rat skeletal muscle

The present study was performed to investigate the effect of acidosis on the efflux of ATP from skeletal muscle. Infusion of lactic acid to the perfused hindlimb muscles of anaesthetised rats produced dose-dependent decreases in pH and increases in the interstitial ATP of extensor digitorum longus (EDL) muscle: 10 mM lactic acid reduced the venous pH from 7.22 ± 0.04 to 6.97 ± 0.02 and increased interstitial ATP from 38 ± 8 to 67 ± 11 nM. The increase in interstitial ATP was well-correlated with the decrease in pH (r(2) = 0.93; P < 0.05). Blockade of cellular uptake of lactic acid using α-cyano-hydroxycinnamic acid abolished the lactic acid-induced ATP release, whilst infusion of sodium lactate failed to depress pH or increase interstitial ATP, suggesting that intracellular pH depression, rather than lactate, stimulated the ATP efflux. Incubation of cultured skeletal myoblasts with 10 mM lactic acid significantly increased the accumulation of ATP in the bathing medium from 0.46 ± 0.06 to 0.76 ± 0.08 μM, confirming the skeletal muscle cells as the source of the released ATP. Acidosis-induced ATP efflux from the perfused muscle was abolished by CFTR(inh)-172, a specific inhibitor of the cystic fibrosis transmembrane conductance regulator (CFTR), or glibenclamide, an inhibitor of both K(ATP) channels and CFTR, but it was not affected by atractyloside, an inhibitor of the mitochondrial ATP transporter. Silencing of the CFTR gene using an siRNA abolished the acidosis-induced increase in ATP release from cultured myoblasts. CFTR expression on skeletal muscle cells was confirmed using immunostaining in the intact muscle and Western blotting in the cultured cells. These data suggest that depression of the intracellular pH of skeletal muscle cells stimulates ATP efflux, and that CFTR plays an important role in the release mechanism.

Renal lactate uptake during exercise in humans

The Cori cycle is critical for lactate metabolism during exercise as attenuated lactate elimination contributes to the arterial lactate accumulation. We evaluated renal lactate elimination by measuring the arterial‐renal venous (a‐v) lactate difference at rest, following infusion of sodium lactate (0.5 mM) and during moderate cycling that elicited a heart rate of 123 ± 9 b·min−1(mean ± SEM) combined with sodium lactate infusion in nine healthy men. At rest, the a‐v oxygen content and the a‐v lactate differences were 0.8 ± 0.2 mM and 0.02 ± 0.02 mM, respectively. Following infusion of sodium lactate the arterial lactate and the a‐v lactate difference were elevated to 6.5 ± 0.4 mM (P &lt; 0.05) and 0.2 ± 0.3 mM (P &lt; 0.05), respectively. During exercise with sodium lactate infusion arterial lactate reached 7.1 ± 1.1 mM (P &lt; 0.05) and the a‐v oxygen content difference increased to 2.6 ± 0.8 mM (P &lt; 0.05), indicating a 70% reduction of renal blood flow. The a‐v lactate difference increased to 0.5 ± 0.8 mM but was not significantly different from the pre‐exercise level and lactate uptake was not different during exercise than at rest with sodium lactate infusion suggesting that renal lactate uptake is driven by the lactate arterial concentration. In conclusion, during moderate exercise renal lactate extraction increases as renal blood flow is reduced by 70% and lactate uptake is maintained.

Improving 1H MRSI measurement of cerebral lactate for clinical applications

Accurate measurement of cerebral lactate is critical to the understanding of brain function for psychiatric disorders such as panic disorder and bipolar disorder as well as mitochondrial dysfunction. Proton magnetic spectroscopic imaging (MRSI) techniques can be used to study lactate in vivo; however, accurate measurement of cerebral lactate, which is normally at low basal abundance, can be challenging. In this study, regional lactate measurements obtained with two different MRSI analytic approaches were evaluated using proton echo-planar spectroscopic imaging (PEPSI) data from 18 healthy adults participating in an in vivo sodium lactate infusion study. The results demonstrate that averaging data within a region of interest (ROI) before spectral fitting with LCModel results in significantly improved lactate measurement as compared to averaging chemical concentrations derived from the fitting of individual voxels in the ROI. Simulation results that confirm this finding are also presented. This study additionally outlines an atlas-based approach for the systematic computation of regional distributions of chemical concentrations in large MRSI data sets.

A key role for orexin in panic anxiety

Introductory paragraphPanic disorder is a severe anxiety disorder with recurrent, debilitating panic attacks. In subjects with panic disorder there is evidence of decreased central GABAergic activity as well as marked increases in autonomic and respiratory responses following intravenous infusions of 0.5M sodium lactate1–3. In an animal model of panic disorder, chronic inhibition of GABA synthesis in the dorsomedial/perifornical hypothalamus of rats produces anxiety-like states and a similar vulnerability to sodium lactate-induced cardioexcitatory responses4–9. The dorsomedial/perifornical hypothalamus is enriched in orexin (ORX, also known as hypocretin)-containing neurons10 that play a critical role in arousal10,11, vigilance10 and central autonomic mobilization12, all of which are key components of panic. Here, we demonstrate that activation of the ORX neurons is necessary for developing a panic-prone state in the animal model, and either silencing the hypothalamic ORX gene (Hcrt) product with RNA interference or systemic ORX1 antagonists blocks the panic responses. Moreover, we show that subjects with panic anxiety have elevated levels of ORX in the cerebrospinal fluid compared to subjects without panic anxiety. Taken together our results suggest that the ORX system may be involved in the pathophysiology of panic anxiety, and that ORX antagonists constitute a potential novel treatment strategy for panic disorder.

Sodium lactate infusion during a cycling time-trial does not increase lactate concentration or decrease performance

The aim of this study was to determine whether an exogenous sodium lactate infusion increases blood lactate concentration and decreases performance during a 20-km time-trial. Highly trained male cyclists performed a 20-km time-trial with a saline (control) or sodium lactate infusion. Sodium lactate was infused at rates previously observed to raise blood lactate concentration by 2 mmol·l−1 in trained individuals cycling at 65% of maximum oxygen uptake. Blood lactate concentration increased (P≤0.0001) during both the control and sodium lactate trials compared with rest, with peak values of 9.6 and 10.6 mmol·l−1, respectively. The increase in sodium lactate over time was not significantly different from the control (P=0.34). Time to complete the time-trial and average power for the time-trial were not significantly different between the control (25.72±0.80 min; 348.0±32.4 W) and sodium lactate trials (25.58±0.93 min; 352.6±39.3 W). In addition, rating of perceived exertion, heart rate, and respiratory parameters did not differ between trials. In conclusion, when exogenous lactate is infused during a 20-km cycling time-trial, an exercise bout performed above the maximal lactate steady state, blood lactate concentration did not increase. Furthermore, exogenous lactate infusion did not decrease exercise performance, increase perceived exertion, or change respiratory parameters. Because lactate per se did not change performance outcomes or measured perceived exertion, we suggest that alternative objective measures of exercise intensity and performance be explored.

Chronic inhibition of GABA synthesis in the bed nucleus of the stria terminalis elicits anxiety-like behavior.

The current study tested the hypothesis that chronic loss of inhibitory GABAergic tone in the bed nucleus of the stria terminalis (BNST), a region implicated in anxiety behavior, results in generalized anxiety disorder-like behaviors without panic-like responses (i.e., tachycardia, hypertension and tachypnea) following panicogenic stimuli (e.g., sodium lactate infusions). To test this hypothesis, the GABA synthesis inhibitor L-allylglycine (L-AG) or its inactive isomer D-AG was chronically infused into the BNST of male rats via osmotic mini-pumps. L-AG, but not D-AG, treated rats had increased anxiety-like behavior as measured by social interaction (SI) and elevated-plus maze paradigms. Restoring GABAergic tone, with 100pmoles/100nl of muscimol (a GABA(A) receptor agonist), in the BNST of L-AG treated rats attenuated L-AG-induced anxiety-like behavior in the SI test. To assess panic-like states, L-AG treated rats were intravenously infused with 0.5 M sodium lactate, a panicogenic agent, prior to assessing SI and cardiorespiratory responses. L-AG decreased SI duration again; however, sodium lactate did not induce panic-like cardiorespiratory responses. These findings demonstrate that GABA inhibition in the BNST elicits anxiety-like behavior without increasing sensitivity to lactate, thus suggesting a behavioral profile similar to that of generalized anxiety-like behavior rather than that of panic.