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PubMed1991

Terlipressin-induced metabolic acidosis.

Vasopressin and its analogue terlipressin are potent vasoconstrictors which reduce mesenteric blood flow and have been used in the therapy of variceal hemorrhage. This vasoconstrictor effect applies on vascular beds throughout the body. Since in literature vasopressin is rarely described to determine lactic acidosis, we report of a patient in whom a severe metabolic (probably lactic) acidosis appeared, associated with terlipressin administration for bleeding esophageal varices. By exclusion, the temporal sequence with terlipressin therapy, the contemporary increase of arterial blood pressure and autoptic data in the case presented make likely a diagnosis of terlipressin-induced lactic acidosis. Because of the seriousness of metabolic acidosis observed in our patient we suggest a careful monitoring of acid-base parameters in patients under treatment with vasopressin analogues.

Acidosis↗
PubMed1987

The influence of acidosis on the distribution of lidocaine and bupivacaine into the myocardium and brain of the sheep.

To test the hypothesis that acidosis can increase the toxicity of bupivacaine more than that of lidocaine by increasing the distribution into the brain, myocardium, or both, studies were performed to measure the in vivo tissue:blood partition coefficients during continuous steady state intravenous infusions of these agents in anesthetized sheep during normal acid-base status and during combined respiratory-metabolic acidosis. Acidosis decreased the partition coefficient of both agents into the myocardium and that of bupivacaine into the brain but did not systematically change that of either agent into skeletal muscle or fat. Total body and hepatic drug clearances were not affected systematically, but plasma binding of both agents was decreased. Thus predictions based on the pH partition hypothesis about the effects of acidosis on myocardial:blood partition coefficients being a basis for explaining the relative toxicity of these agents were not supported.

Acidosis↗
PubMed1993

Progressive sensorineural hearing loss in association with distal renal tubular acidosis.

The autosomal recessive inherited syndrome of distal renal tubular acidosis and sensorineural hearing loss may present in one of two distinct fashions. The rare adolescent form is characterized by mild renal tubular acidosis, mild to moderate sensorineural hearing loss, and otherwise normal growth and development. The more common infantile type typically presents in the first year of life with failure to thrive, acidosis, and a more severe sensorineural hearing loss. In this report, progression of sensorineural hearing loss is documented for the first time in two siblings with the infantile variant. This association suggests that all children with distal renal tubular acidosis should undergo sequential audiologic evaluations with the institution of appropriate amplification and educational intervention as needed.

Acidosis, Renal Tubular↗
PubMed1982

The role of catecholamines in metabolic acidosis.

Catecholamines (noradrenaline and adrenaline) are catabolic hormones secreted during stress. They initiate many metabolic processes including increased production of both ketoacids and lactic acid. Support for a direct participation of these hormones in the development and/or maintenance of ketoacidosis includes: (1) the high incidence of stress (approx. 70%) as a precipitating factor for ketoacidosis; (2) the elevated plasma levels of noradrenaline (norepinephrine) in patients with ketoacidosis; (3) the rise in plasma concentrations of ketone bodies during catecholamine infusion; and (4) the reduction in the incidence of ketoacidosis with beta-adrenergic pharmacological blockade. Support for a direct participation of catecholamines in the development and/or maintenance of lactic acidosis includes: (1) the common association of stress and lactic acidosis; (2) the rise in plasma lactate concentration during adrenaline (epinephrine) infusion; (3) the precipitation of lactic acidosis by adrenaline intoxication and phaeochromocytoma; and (4) the vasoconstrictor effects of catecholamines leading to tissue anoxia and lactic acid production. Thus, in susceptible patients, catecholamines may be principal determinants of whether ketoacidosis and/or lactic acidosis develops.

Acidosis↗
PubMed1982

The role of altered lactate kinetics in the pathogenesis of type B lactic acidosis.

Of the two types of lactic acidosis, Type B is the most difficult to explain in terms of mechanisms of lactic acid accumulation because the tissue hypoxia that accompanies Type A is not present except as a terminal event. The methods of pharmacokinetics show that for lactate to accumulate to an extent that would disturb acid-base balance, either lactate synthesis or lactate removal would have to be increased or decreased, respectively, by about 7-10-fold. To produce lactic acidosis within a few hours, synthesis would have to increase at the same time as clearance decreased. At normal contribution of the liver to the total lactate clearance (30%-40%), a total cessation of hepatic lactate clearance would not result in lactic acidosis without a concomitant rise in the rate of lactate synthesis. Again, to produce an acidosis this increase would have to be about 8-fold at a normal fractional hepatic clearance. The control of hepatic lactate uptake is discussed in the light of the relatively low hepatic extraction of lactate and in relation to to two main models of hepatic drug (lactate) clearance; the 'well-stirred' and 'parallel-tube' models.

Acidosis↗
PubMed1982

Metabolic acidosis and changes in water and electrolyte balance after maximal exercise.

The purpose of this investigation was to study lactate production and the consequent changes in acid-base status, and in water and electrolyte balance, in response to 1 min of maximal exercise in sprint- and endurance-trained subjects. So far, the results from only two subjects (one sprinter and one marathon runner) have been analysed. The rate of lactate production was higher in the sprinter than in the marathon runner, as shown by peak blood lactate concentrations of 20.8 and 13.3 mM for the two subjects, respectively. Arterial blood pH fell from 7.43 to 7.14 in the sprinter and from 7.44 to 7.23 for the marathon runner. The metabolic acidosis was partly compensated for by a lowering of arterial CO2 tension by 0.0775 kPa per 1 mM drop in base excess. In each subject large changes in water and electrolyte balance occurred. Haematocrit increased dramatically in both subjects, and the calculated decrease in plasma volume was 20% for the marathon runner and 30% for the sprinter. In each subject sodium was removed from the circulation in amounts sufficient to keep the plasma sodium concentration constant. Plasma potassium concentration was unrelated to the state of acidosis, being 2.5 mM above the resting concentration immediately after maximal exercise, and dropping by 3 mM in the subsequent 2-3 min of recovery during prevailing acidosis. The degree of lactic acidosis was large in both subjects, although more severe in the sprinter than in the endurance runner. However, buffer capacity and compensatory mechanisms were largely similar in both subjects.

Acidosis↗
PubMed2001

Rapid astrocyte death induced by transient hypoxia, acidosis, and extracellular ion shifts.

Death of astrocytes requires hours to days in injury models that use hypoxia, acidosis, or calcium paradox protocols. These methods do not incorporate the shifts in extracellular K(+), Na(+), Cl(-), and Ca(2+) that accompany acute brain insults. We studied astrocyte survival after exposure to hypoxic, acidic, ion-shifted Ringer (HAIR), with respective [Ca(2+)], [K(+)], [Na(+)], [Cl(-)], and [HCO(-)(3)] of 0.13, 65, 51, 75, and 13 mM (15% CO(2)/85% N(2), pH 6.6). Intracellular pH (pH(i)) was monitored with the fluorescent dye BCECF. Cell death was indicated by a steep fall in the pH-insensitive, 440-nm-induced fluorescence (F440) and was confirmed by propidium iodide staining. After 15-40-min HAIR exposure, reperfusion with standard Ringer caused death of most cultured (and acutely dissociated) astrocytes within 20 min. Cell death was not prevented if low Ca(2+) was maintained during reperfusion. Survival fell with increased HAIR duration, elevated temperature, or absence of external glucose. Comparable durations of hypoxia, acidosis, or ion shifts alone did not lead to acute cell death, while modest loss was noted when acidosis was paired with either hypoxia or ion shifts. Severe cell loss required the triad of hypoxia, acidosis, and ion shifts. Intracellular pH was significantly higher in HAIR media, compared with solutions of low pH alone or with low pH plus hypoxia. These results indicate that astrocytes can be killed rapidly by changes in the extracellular microenvironment that occur in settings of traumatic and ischemic brain injury.

Acidosis↗
PubMed1993

A Ca(2+)- and pH-dependent K+ channel of rat C6 glioma cells and its possible role in acidosis-induced cell swelling.

The aim of the present study was to explore whether a change in membrane K+ conductance contributes to acidosis-induced swelling of cultured rat C6 glioma cells. Electrophysiological studies were performed using whole-cell and single-channel recordings in combination with cell volume measurements in cell suspension by flow cytometry. Whole-cell recordings revealed a voltage-dependent K+ conductance. The predominant K+ channel in single-channel recordings with symmetrical high K+ concentrations was inwardly rectifying and had conductances of 35 and 15 pS, respectively. A raised internal free Ca2+ concentration and membrane depolarization increased the open probability of this channel. Internal acidosis (pH 6.4-5.4), on the other hand, reduced open probability and single-channel conductance. Both whole-cell and single-channel K+ currents were blocked by quinidine (0.1-1 mM), which was therefore used to analyze the functional consequences of an inhibition of this conductance for cell volume. Thereby, quinidine (1 mM) produced a small (5%) and transient cell swelling of C6 glioma cells. In contrast, acidosis (pH 5.6) caused a much larger (about 20%) and maintained swelling. Since quinidine produced only a minor swelling of C6 cells, it is unlikely that inhibition of the K+ conductance caused acidosis-induced cell swelling. Other mechanisms, such as activation of ion transporters, must therefore be responsible.

Acidosis↗
PubMed2005

In support of fatty acid synthase (FAS) as a metabolic oncogene: extracellular acidosis acts in an epigenetic fashion activating FAS gene expression in cancer cells.

Relatively little information exists on the ultimate molecular mechanisms by which the lipogenic enzyme Fatty Acid Synthase (FAS) is differentially overexpressed in a biologically aggressive subset of human malignancies. Since the microenvironment of solid tumors contains regions of poor oxygenation and high acidity, it has recently been suggested that cancer-associated FAS is a novel metabolic oncogene conferring a selective growth advantage upon stresses such as hypoxia and/or low pH. Here, we performed transient transfection studies with a 178-bp FAS promoter fragment harboring a complex Sterol Regulatory Element Binding Proteins (SREBP)-binding site to evaluate whether extracellular low pH and/or hypoxia may act in an epigenetic fashion by inducing changes in the transcriptional activation of FAS gene in cancer cells. First, MCF-7 breast cancer cells cultured in acidosis (pH 6.5), but not under hypoxia or in the presence of hypoxia mimetics, demonstrated a more than two-fold increase in the transcriptional activity of FAS promoter-reporter constructs compared with control cells grown under standard culture conditions (pH 7.4). Second, the up-regulatory effect of extracellular acidosis on the transcriptional activation of FAS gene was not observed when the FAS promoter was truncated at the SREBP-binding site. Third, MCF-7 cells engineered to overexpress the Her-2/neu (erbB-2) oncogene exhibited a SREBP-dependent activation of the FAS promoter-reporter construct up to three-fold higher than that found in wild-type MCF-7 cells, while extracellular acidosis resulted only in a marginal increase of Her-2/neu-promoted activation of FAS gene. This study reveals for the first time that extracellular acidosis can work in an epigenetic fashion by up-regulating the transcriptional expression of FAS gene in breast cancer cells, a stimulatory effect that is equally mimicked by well-characterized oncogenic stimuli such as Her-2/neu. These findings, altogether, support the "metabolic oncogene" theory for FAS overexpression in cancer cells.

Acidosis↗
PubMed1993

The effects of acidosis and alkalosis on long bone vascular resistance.

This study used an ex vivo perfusion model to investigate the direct effects of acidosis and alkalosis on the vascular resistance of the canine tibia. Baseline vascular resistance (BVR) and the vascular smooth muscle response to bolus doses of norepinephrine (NE) (0.025-3.2 nmol) and periarterial sympathetic nerve stimulation (NS) (10-25 Hz: 9 V, 2 ms pulses, 10 s) were studied. In Group I, these parameters were measured at normal pH (duration 7.34-7.44) and then during acidosis (pH 7.2-7.33). In Group II, they were measured at normal pH and then during alkalosis (pH 7.47-7.58). In Group III (control), they were measured serially at a normal pH. Alkalosis increased BVR by 56% (p < 0.0001). Acidosis attenuated (18% reduction) and alkalosis enhanced (66% increase) the vasoconstrictor action of NE (p < 0.0001). Acidosis also attenuated (11% reduction) the effect of sympathetic NS (p = 0.012). It is concluded that perfusion pH influences the sensitivity of long bone resistance vessels to circulating NE and sympathetic NS. Thus, local concentration of hydrogen ions may provide bone with a mechanism to autoregulate blood flow.

Acidosis↗
PubMed1995

Plasmodium berghei infection: dichloroacetate improves survival in rats with lactic acidosis.

The kinetics of Plasmodium berghei infection and the development of lactic acidosis, hypoglycemia, and anemia were defined in young Wistar rats. This model of metabolic dysfunction, which is similar to that of severe human malaria, was used to test the hypothesis that dichloroacetate, a treatment for lactic acidosis, prolonged survival in rats receiving a single antimalarial dose of quinine (20 mg/kg). Rats with hyperlactatemia (lactate > 5 mmol/liter, N = 183) were randomized to receive either dichloroacetate (100 mg/kg, N = 99) or saline (N = 84) and were monitored for outcome (survival or death) for 50 hr. Logistic regression modeling adjusting for baseline venous lactate concentration demonstrated that dichloroacetate increases survival rates in rats with venous lactate concentrations between 5 and 8.9 mmol/liter (odds ratio > 2.2, P < 0.021). This is the first demonstration that specific intervention to treat lactic acidosis can prolong survival and suggests that dichloroacetate may be useful as adjunctive therapy in the management of lactic acidosis complicating severe falciparum malaria.

Acidosis, Lactic↗
PubMed2001

Role of cellular acidosis in production of nitric oxide in canine ischemic myocardium.

We tested the hypothesis that cellular acidosis modulates the production of nitric oxide (NO) in ischemic hearts. In canine hearts, we decreased coronary blood flow (CBF) to one third of the control by reduction of coronary perfusion pressure (105+/-3 to 41+/-5 mmHg), and thereafter we maintained CBF constant (89.8+/-1.6 to 30.0+/-0.5 ml/100 g/min) with an intracoronary administration of either saline, atropine, rauwolscine, HOE140, 8-sulfophenyltheophylline (8SPT), NaHCO3, or HOE642 (the inhibitor of Na+/H+ exchange). The cardiac NO levels defined as the differences of the nitrate and nitrite levels between coronary venous and arterial blood increased in the saline administration (2.9+/-0.2 to 12.7+/-1.7 micromol/l), and the extents of increases were identical in the condition of either saline, atropine, rauwolscine, HOE140 or 8SPT administration. In the condition with either NaHCO3 or HOE642, the increases in the cardiac NO levels were blunted (4.5+/-0.7 and 4.8+/-0.4 micromol/l, respectively). Cyclic GMP content of epicardial coronary artery in the ischemic area increased, which was also attenuated by either NaHCO3 or HOE642. We confirmed the acidosis-induced NO production in a more severe ischemic myocardium, and also showed that cellular acidosis produced by infusion of HCl increased NO production in non-ischemic myocardium. We conclude that cellular acidosis and subsequent activation of Na+/H+ exchanges modulate production of endogenous NO in canine ischemic myocardium.

Acidosis↗
PubMed2003

Cerebrovascular response to acute metabolic acidosis in humans.

OBJECTIVES: Evaluation of the cerebrovascular response (delta CBV/delta PaCO2) during baseline metabolic conditions and acute metabolic acidosis. METHODS: 15 healthy subjects, 5 m, 10 f, 56 +/- 10 yrs were investigated. For acidification, NH4Cl was given orally. CBV was measured using Near Infrared Spectroscopy (OXYMON) during normo-, hyper- and hypocapnia. RESULTS: Acute metabolic acidosis was realised: mean delta BE -2.7 mEq.L-1 (p < 0.001) with mean delta PaCO2 -0.2 kPa (p < 0.01). During normo-, hyper- and hypocapnia, CBV values of 3.51, 4.82 and 2.55 mL.100 g-1 were calculated during baseline metabolic conditions and 3.70, 4.86 and 2.63 mL.100 g-1 during acute metabolic acidosis. The CBV/PaCO2 response showed a hockeystick configuration with the point of infliction around normocapnia. delta CBV/delta PaCO2 reactivity from normo- to hypercapnia and from normo- to hypocapnia was calculated; no significant differences in delta CBV/delta PaCO2 were found in both metabolic conditions. CONCLUSION: Cerebrovascular reactivity to CO2 does not alter during acute metabolic acidosis.

Acidosis↗
PubMed1995

The role of intracellular acidosis in muscle fatigue.

Muscle fatigue is often accompanied by an intracellular acidosis of variable size. The variability reflects the involvement of different metabolic pathways, the presence or absence of blood flow and the effectiveness of pH-regulating pathways. Intracellular acidosis affects many aspects of muscle cell function; for instance it reduces maximal Ca(2+)-activated force and Ca2+ sensitivity, slows the maximal shortening velocity and prolongs relaxation. However, acidosis is not the only metabolic change in fatigue which causes each of the above, and there are important aspects of muscle fatigue (e.g., the failure of Ca2+ release) which do not appear to be caused by acidosis.

Acidosis↗
PubMed1995

Graded intracellular acidosis produces extensive and reversible reductions in the effective free energy change of ATP hydrolysis in a molluscan muscle.

Phosphorus nuclear magnetic resonance spectroscopy was used to evaluate the impact of experimental reductions of intracellular pH on in vitro preparations of the radula protractor muscle of the marine gastropod, Busycon canaliculatum. The intracellular pH of radula refractor muscle bundles superfused with buffered artificial sea water (pH = 7.8) was 7.29. It was possible to clamp muscle intracellular pH at various acidotic states by changing the superfusate to 5, 10, and 15 mmol.l-1 5,5-dimethyl-oxazolidine-2,4-dione in buffered artificial sea water (pH = 6.5). Consistent and temporally stable reductions of intracellular pH were achieved (intracellular pH = 6.98, 6.79, and 6.62, respectively). During the acidotic transitions, arginine phosphate concentrations decreased and inorganic phosphate concentrations increased in a reciprocal manner and remained essentially constant after the intracellular pH stabilized. The extent of changes in arginine phosphate and inorganic phosphate was directly proportional to the magnitude of the imposed acidosis. Total adenosine triphosphate concentrations remained unchanged in all treatments. However, the magnesium adenosine triphosphate to total adenosine triphosphate ratio declined in direct relation to the extent of the acidosis. Intracellular free Mg2+ fell incrementally with reduced intracellular pH. All of the above effects were rapidly reversed when the 5,5-dimethyl-oxazolidine-2,4-dione was washed out by changing the superfusate to buffered artificial sea water (pH = 7.8). Mg-adenosine diphosphate concentrations were calculated in all treatments using equilibrium constants for the arginine kinase reaction corrected for pH and intracellular free [Mg2+]. The metabolite, intracellular pH, and [Mg2+] data were used to estimate the effective free energy of hydrolysis of adenosine triphosphate (dG/d xi ATP) under most experimental conditions. Experimental acidosis resulted in dramatic reductions in dG/d xi ATP which were fully reversible upon wash-out of 5,5-dimethyl-dioxazolidine-2,4-dione and recovery to normal intracellular pH conditions. Acidosis resulted in net hydrolysis of arginine phosphate, likely via a complex mechanism involving enhancement of rate of adenosine triphosphate hydrolysis and/or inhibition of adenosine triphosphate synthesis.

Acidosis↗
PubMed1975

Diagnosis and therapy of renal tubular acidosis in infancy.

While distrubances of the acid-base balance are frequently seen in infancy, renal tubular acidosis is a rather rare disease but should be considered as differential diagnosis if metabolic acidosis persists after adequate treatment. Proximal and distal tubular acidosis with primary and secondary forms can be differentiated. Proximal RTA is characterized by the loss of bicarbonate, distal RTA by a defect to establish a hydrogen ion gradient and thus to accomplish acidification of urine. In addition to these two basic forms a bicarbonate wasting state in distal RTA has been described. A patient with these clinical features is presented. He was admitted to our hospital at the age of 1 month with meningitis, enteritis and marked dystrophy. A persistant hyperchloraemic acidosis with concomitant hypokalaemia was present. The ammonium chloride loading test confirmed the diagnosis of primary distal RTA. Renal biopsy performed with 1 year of age revealed nephrocalcinosis of the inner medullary region of the kidney while the cortex was not affected. The patient first needed alkali doses of 12 mEq/kg/day which could be gradually reduced to 3.5 mEq/kg/day. Under additional potassium substitution of 5 mEq/kg/day he was thriving well. Differential diagnosis and the particular clinical features of this case are discussed.

Acidosis, Renal Tubular↗
PubMed1975

Blood affinity for oxygen in experimental hemorrhagic shock with metabolic acidosis.

This study was designed to evaluate, in vivo, the effect of a severe non-respiratory acidosis on hemoglobin oxygen transport. Oxygen affinity of hemoglobin, Bohr effect, Hill's number and red cell 2,3-DPG were evaluated during experimental hemorrhagic shock in dogs. Three periods were considered: control, hypotension (mean arterial pressure 60 mm Hg for 2 hr 30 min) and blood replacement. There was no significant change in erythrocyte 2,3-DPG following hemorrhagic hypotension but ATP increased significantly. n, the Hill number (2.6), was not changed by in vivo acidosis (pH 7.1). Respiratory Bohr coefficient (BCO2) corresponding to pHe variations was drastically reduced (control BCO2 = 0.55, acidosis BCO2 = 0.31, blood replacement BCO2 = 0.35). P50(7.4) was not modified significantly by hemorrhagic acidosis. It is unlikely that variations of blood affinity for oxygen play a major role in oxygen delivery during early experimental hemorrhagic shock.

Acidosis↗
PubMed1985

Intracellular pH in hibernation and respiratory acidosis in the European hamster.

Intracellular pH was determined (DMO method) in European hamsters, in the spontaneously-occurring respiratory acidosis of hibernation, in hypercapnia due to breathing 12% CO2 in air in euthermy in spring, and in euthermicnormocapnic controls. From euthermy to hibernation, the temperature coefficient of pH was lowest in blood plasma and brain, intermediate in striated muscles (thigh muscles and diaphragm), and highest in heart and liver (Fig. 1). Correspondingly, the estimated dissociation ratio of the protein imidazole buffer groups, alpha Im, decreased markedly in plasma and brain, denoting an acid titration, but varied little in liver and heart. Striated muscles were intermediate (Fig. 2). Like in other mammals, intracellular responses to short-term euthermic respiratory acidosis were characterized by a partial metabolic compensation in the brain and a small metabolic acidification in striated muscles. In hibernation, a powerful metabolic compensation took place in liver and heart, nearly restoring alpha Im, but none occurred in brain (Figs. 3 to 5). The existence of an intracellular acidosis in brain and striated muscles during hibernation is in keeping with an inhibitory role of acidosis, whereas the homeostasis of intracellular alpha Im in liver and heart would subserve the eurythermal functioning of metabolic regulations in these organs, like in most organs of ectotherms.

Acidosis, Respiratory↗