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PubMed1977

On the mechanism of lithium-induced renal tubular acidosis.

The effect of lithium chloride administration on urinary acidification was studied in dogs. Lithium-treated dogs developed hyperchloremic metabolic acidosis with alkaline urine. Bicarbonate loading resulted in a normal increase in urinary Pco2 in normal dogs but failed to produce the same response in lithium-treated dogs. The bicarbonate titration curve of lithium-treated dogs revealed a small leak of bicarbonate at low plasma levels of bicarbonate; at high plasma levels bicarbonate reabsorption was significantly higher in lithium-treated dogs. This pattern of bicarbonate reabsorption is identical to that described in classic distal renal tubular acidosis. Sodium sulfate administration resulted in a normal urinary acidification ilithium-treated dogs. It is possible that lithium administration induces distal renal tubular acidosis by allowing excessive back-diffusion of acid. This excessive back-diffusion of acid would result in a low urinary Pco2 during bicarbonate loading. Sodium sulfate administration, by increasing the negative intratubular potential, would restrict back-diffusion of hydrogen ion and thereby result in a normal acidification in lithium-treated dogs. We previously demonstrated that postureteral obstruction of the kidney fails to increase urinary Pco2 during bicarbonate loading and to lower urinary pH with sodium sulfate. It is possible that a low urinary Pco2 during HCO3 loading can occur as a consequence of either diminished hydrogen ion secretion (postobstructed kidney) or excessive back-diffusion of acid (lithium administration). Further studies are indicated to determine whether both mechanisms may be found in patients with distal renal tubular acidosis.

Absorption↗
PubMed1993

[Renal tubular acidosis in children].

Renal tubular acidosis represents a heterogenous group of disorders with various etiologies and mechanisms. The physiopathologic basis of each type of renal tubular acidosis is reviewed, focusing on the laboratory investigations necessary to define the nature of the hyperchloremic renal tubular acidosis. Clinically, the four types of renal tubular acidosis can be associated with complications such as osteomalacia, urolithiasis and failure to thrive. Very often, the chronic administration of alkali results in normal growth and development, and greatly reduces the risk of stone formation or nephrocalcinosis.

Acid-Base Equilibrium↗
PubMed1993

Extracellular acidosis ameliorates metabolic-inhibitor-induced and potentiates oxidant-induced cell death in renal proximal tubules.

The effect of extracellular acidosis on different types of cell injury and death was examined using suspensions of rabbit renal proximal tubules. Cell death produced by the mitochondrial inhibitors rotenone, antimycin A, carbonyl cyanide p-trifluoromethoxyphenylhydrazone and oligomycin and by the ion exchangers valinomycin, nigericin and monensin was ameliorated by reducing extracellular pH (pHe) from 7.4 to 6.4. The protection lasted for more than 5 hr and was not due to the release of mitochondrial inhibition or to the maintenance of tubular ATP levels. In contrast, extracellular acidosis potentiated the cell injury and death produced by the oxidants t-butyl hydroperoxide, H2O2 and ochratoxin A. Because a decrease in pHe resulted in an increase in lipid peroxidation and in glutathione disulfide formation, and caused a decrease in glutathione peroxidase and glutathione reductase activities, the mechanism of this potentiation is most likely the result of an increase in free-radical production or a decrease in free-radical detoxification. The findings with the oxidants are in marked contrast to those in hepatocytes. These results show that renal cell death as a consequence of mitochondrial inhibition is sensitive to the protective effects of extracellular acidosis and that the effects of extracellular acidosis on cell death are dependent on the mechanism of injury.

Acidosis↗
PubMed1996

Nephrocalcinosis is associated with renal tubular acidosis in children with X-linked hypophosphatemia.

BACKGROUND: X-linked hypophosphatemia is characterized clinically by rickets and growth retardation. Therapy of this disorder with phosphate and vitamin D often produces nephrocalcinosis. The long-term effects of nephrocalcinosis on renal function in patients with X-linked hypophosphatemia are unknown. The purpose of this study was to evaluate the prevalence of glomerular and tubular disorders in patients with X-linked hypophosphatemia who developed nephrocalcinosis. METHODS: The creatinine clearance and the prevalence of renal tubular acidosis were compared in 19 patients with X-linked hypophosphatemia and nephrocalcinosis with 15 patients with X-linked hypophosphatemia without nephrocalcinosis. RESULTS: Sixteen of the 19 patients (84%) with nephrocalcinosis had a hyperchloremic metabolic acidosis compared with one of the 13 patients without nephrocalcinosis (P < .01). The serum bicarbonate of patients with nephrocalcinosis was 20.0 +/- 0.7 as compared to 24.5 +/- 0.6 mmol/L in patients without nephrocalcinosis (P < .01). The urinary anion gap was positive in all patients with acidosis (+62.1 +/- 13.3 mmol/L). The creatinine clearance was 125 +/- 6 mL/min/1.73 m2 in patients with nephrocalcinosis and 124 +/- 7 mL/min/1.73 m2 in those without nephrocalcinosis. CONCLUSION: Therapy of X-linked hypophosphatemia is often associated with nephrocalcinosis. Nephrocalcinosis is associated with renal tubular acidosis in patients with X-linked hypophosphatemia.

Acidosis, Renal Tubular↗
PubMed1996

The acute impact of NaHCO3 in treatment of metabolic acidosis on back-titration of non-bicarbonate buffers: a quantitative analysis.

OBJECTIVE: The major non-bicarbonate buffers are intracellular proteins, a detrimental effect of severe acidosis could be their titration with H+. This in turn would lead to their net charge becoming more positive, and possibly, to changes in their shape and function. Since NaHCO3 is a treatment option in patients with severe metabolic acidosis, the purpose of this study was to examine the acute effect of the administration of NaHCO3 on back-titration of non-bicarbonate buffers in metabolic acidosis. DESIGN: Prospective, controlled, non-randomized laboratory study. SETTING: Research laboratory. SUBJECTS: 21 male Wistar rats. INTERVENTION: Rats were anesthetized, intubated and ventilated. Ventilation was adjusted at the beginning of the experiment to a PCO2 of approximately 30 mmHg, no further adjustments were made thereafter. Acute metabolic acidosis was induced by the infusion of 3.5 mmol of hydrochloric acid over 1 hour. After an equilibration period, 3 groups of seven rats were studied; group I received 0.75 mmol NaHCO3, group II received equimolar NaCl, and group III served as time control. MEASUREMENTS AND MAIN RESULTS: Measurements were made to enable quantitation of how much HCO3 was retained in the ECF and how much was titrated with H+ and was excreted as "acid-base" CO2. Since there are so few H+ present in the ECF in a free or a bound form, and in the absence of an increase in endogenous acid-production, the source of this H+ is from proteins in the ICF. As compared to the NaCl and the time control groups, the administration of NaHCO3 led to significant alkalinization of the ECF, pH rose from 7.22 +/- 0.03 to 7.34 +/- 0.02. Of the 0.75 mmol of NaHCO3 that was administered, 67% or 0.52 +/- 0.08 mmol was retained in ECF. Only a small amount (0.07 +/- 0.09 mmol) of acid-base CO2 was excreted. CONCLUSIONS: The administration of NaHCO3 does not acutely lead to a significant back-titration of non-bicarbonate buffers, especially under conditions of fixed ventilation.

Acidosis↗
PubMed1977

Organic acidosis in infants.

Any child or adult who has persistent acidosis after apparently adequate treatment should be suspected of having an organic aciduria, as should any person with a large anion gap and acidosis. The possibility that some can presently be treated, makes early diagnosis urgent. Acidosis occurs in hypoperfused states, and treatment of the hypoperfusion with half- to two-thirds-strength of physiological saline with 40 mEq/1 of potassium may correct the acidosis without there being any need to use bicarbonate.

Acidosis↗
PubMed1998

Anion gap acidosis.

Although an anion gap at less than 20 mEq/L rarely has a defined etiology, significant elevations in the anion gap almost always signify presence of an acidosis that can be easily identified. Anion gap acidoses can be divided into those caused by lactate accumulation, ketoacid production, toxin/drugs, and uremia. Lactic acidoses caused by decreased oxygen delivery or defective oxygen utilization are associated with high mortality. The treatment of lactic acidosis is controversial. The use of bicarbonate to increase pH is rarely successful and, by generating PCO2, may worsen outcome. Ketoacidosis is usually secondary to diabetes or alcohol. Treatment is aimed at turning off ketogenesis and repairing fluid and electrolyte abnormalities. Methanol, ethylene glycol, and salicylates are responsible for the majority of toxin-induced anion gap acidoses. Both methanol and ethylene glycol are associated with severe acidoses and elevated osmolar gaps. Treatment of both is alcohol infusion to decrease formation of toxic metabolites and dialyses to remove toxins. Salicylate toxicity usually is associated with a mild metabolic acidosis and a respiratory alkalosis. Uremia is associated with a mild acidosis secondary to decreased ammonia secretion and an anion gap caused by the retention of unmeasured anions. A decrease in anion gap is caused by numerous mechanisms and thus has little clinical utility.

Acid-Base Equilibrium↗
PubMed1998

Transient 5-oxoprolinuria (pyroglutamic aciduria) with systemic acidosis in an adult receiving antibiotic therapy.

5-Oxoprolinuria is a recognized condition with increased urinary excretion of 5-oxoproline and is associated with a variety of inborn metabolic defects involving the series of enzyme-linked reactions known as the gamma-glutamyl cycle. We report the unusual case of a 35-year-old woman who initially presented with staphylococcal pneumonia but went on to develop a transient high anion gap metabolic acidosis. The development and subsequent complete recovery from this acidosis were subsequently shown to be related in time to the intravenous administration of the antibiotics flucloxacillin and netilmicin. Analysis of the patient's urine for organic acids revealed massively increased excretions of 5-oxoproline at the peak of her acidosis. We suggest that this patient developed a transient disturbance in the gamma-glutamyl cycle involving the 5-oxoprolinase step, which resulted in accumulation of 5-oxoproline that caused a severe high anion gap metabolic acidosis. The administered antibiotics remain as possible causative agents.

Acidosis↗
PubMed1998

Acidosis-induced metallothionein (MT) mRNA expression in neonatal rat primary astrocyte cultures.

Metallothionein (MT) mRNA levels were determined following exposure of neonatal rat primary astrocyte cultures to acidosis. Astrocyte total RNA was probed on northern blots with [alpha 32 P]dCTP-labeled synthetic cDNA probes specific for rat MT isoform mRNAs. The probe for MT-I mRNA hybridized to a single mRNA with a size appropriate for MT, approximately 550 nucleotides. MT-I mRNA levels in astrocyte monolayers exposed to pH 6.5 and 6.0 for 3 or 6 hours were unchanged compared with MT-I mRNA levels in control cultures exposed to pH 7.4. In contrast, 9 hour exposure of astrocytes to pH 6.5 and 6.0 led to a significant increase in MT-I mRNA transcripts compared with controls maintained at pH 7.4 (p < 0.001 and p < 0.02, respectively). A probe for MT-II mRNA that hybridizes to a single mRNA (450 nucleotides) was also used to determine the effect of acidosis on astrocyte MT-II mRNA transcripts. Although statistical significance was not attained, a similar trend was noted, with a 9 hour exposure to pH of 6.5 and 6.0 resulting in increased astrocytic expression MT-II mRNA compared with control cells maintained at pH 7.4. Acidosis was also associated with a pH-dependent increase in astrocytic volume. Accordingly, acidosis is invoked as an added stimulus to stress factors associated with the induction of astrocytic MT mRNA transcripts.

Acidosis↗
PubMedDate not supplied

[Acidosis inhibits oxidative phosphorylation in intrasynaptosomal mitochondria by releasing calcium from cytoplasmic store].

The origin of calcium responsible for earlier observed acidosis-induced decrease in ATP content and inhibition of respiration in rat brain synaptosomes was studied. Acidosis (pH 6.0) inhibits both basal and potassium-stimulated 45Ca2+ uptake (60 mM KCl). Calcium channel blockers verapamil (100 microM) and 45Ca2+ (100 microM) have no effect on the level of ATP and respiration rate at pH 6.0. Theophylline (10 mM) releasing calcium from intracellular stores lowered ATP and O2 consumption rate at pH 7.4 but not at pH 6.0 being effective only in calcium-containing medium. Inhibitor of calcium transport in mitochondria ruthenium red (10 microM) prevented acidosis-induced ATP decrease. It is suggested that acidosis inhibits oxidative phosphorylation by releasing calcium from cytoplasmic stores with its subsequent transport into intrasynaptosomal mitochondria.

Acidosis↗
PubMed1998

Distal tubular acidosis induced by FK506.

This study was designed to investigate the effect of tacrolimus (FK506) and of cyclosporine (CsA) on tubular function in renal graft recipients. Patients were randomised after renal transplantation to immunosuppressive treatment with FK506 (n = 8) or CsA (n = 8). Patients had a mean age of 45.7 +/- 3.4 yr; there was no difference in age, sex, HLA status or CMV mismatches. Neither was there any difference in the frequency of episodes of acute kidney failure between the groups, nor was there a significant difference in the frequency of episodes of kidney rejection within the first year. The mean FK506 level at the time lay at 14.7 +/- 14.4 ng/mL whole blood, and the mean CsA level at the time of study was 162 +/- 25 ng/mL whole blood. We performed renal function studies 6 months after transplantation: CIn, CPAH, NaHCO3 loading, and Na2SO4 loading. There was no significant impairment of GFR in patients treated with FK506 with 53.6 +/- 2.5 mL/min as compared to 58 +/- 6 mL in group 2. Plasma renin activity (0.6 +/- 0.4 ng/mL vs 2.3 +/- 3; p < 0.01) and aldosterone (69 +/- 17 vs 157 +/- 28.2 pg/mL; p < 0.05) were significantly decreased during treatment with FK506. Fractional HCO3 excretion was low in both groups, indicating that bicarbonate reabsorption in the proximal nephron was unimpaired. Distal renal tubular acidosis was demonstrated in 4 patients of group 1 but in only 1 of group 2. Potassium levels were slightly increased in patients treated with FK506 (5.4 +/- 0.2 mmoL/L) as compared to cyclosporine (4.9 +/- 0.3 mmoL/L; p < 0.05). Distal hydrogen ion secretion, evaluated by the ability to increase urinary pCO2 in a highly alkaline urine, was impaired in patients treated with FK506 (U-B pCO2: 16.1 +/- 4 vs 36 +/- 5.8; p < 0.05) as compared to patients treated with CsA. The maximum acidification capability (NAE) was slightly lowered during therapy with FK506 (67.5 +/- 11.8 versus 86.6 +/- 16.5 mumoL/min, ns). We conclude that FK506 administration results in a decrease in the rate of hydrogen ion secretion by the collecting tubules. This defect was disclosed by the finding of a subnormal pCO2 in a highly alkaline urine. These results show that FK506 is able to induce distal tubular acidosis. Distal tubular acidosis is part of FK506 induced nephrotoxicity, the pathogenesis of this type of hyperkalemic metabolic acidosis found in patients treated with FK506 after renal transplantation has to be further elucidated.

Acidosis, Renal Tubular↗
PubMed2002

Role of the cardiac Na(+)/H(+)exchanger in [Ca(2+)](i)and [Na(+)](i)handling during intracellular acidosis. Effect of cariporide (Hoe 642).

Intracellular acidosis is one of the alterations occurring in cardiac ischemia and has been discussed to be important in altering excitation--contraction coupling. The aim of this study was to determine how intracellular acidosis may affect intracellular sodium and calcium handling. Cardiomyocytes were isolated from the hearts of adult male guinea-pigs by standard techniques and superfused with modified Tyrode's solution at room temperature, either HEPES buffered containing 10 mM NaHCO(3)or HEPES buffered without NaHCO(3), in order to examine a possible interaction with the sodium bicarbonate symport. The whole cell voltage clamp technique was used utilizing 3 M Omega pipettes filled with (mM): Cs aspartate 120, CsCl 20, MgCl(2)1, NaCl 5, Mg-ATP 2, HEPES 10 and either 100 microM Fura-2 or 100 microM SBFI. The pH of the pipette solution was either 7.2 or 6.5. Cells were kept at a holding potential of -80 mV and after a pre-pulse to -40 mV the membrane was continuously clamped to potentials from -30 to +80 mV in 10 mV steps. Intracellular Ca(2+)or Na(+)were estimated using the Fura-2 or SBFI technique (impermeable salt), respectively. The cardiac Na(+)/H(+)exchanger was inhibited using the Na(+)/H(+)- exchange inhibitor cariporide (Hoe 642) (1 microM), when indicated. In NaHCO(3)-free experiments we found an increase in intracellular sodium reflected by a rise in the SBFI ratio of 0.326 +/- 0.01 upon intracellular acidification, in contrast to cells perfused at pH = 7.2 (no significant increase in intracellular Na(+)) (P< 0.05). There was no difference in intracellular calcium handling between cells perfused with solutions of pH = 7.2 or 6.5 (Fura-2 Delta ratio: 0.79 +/- 0.10 vs 0.82 +/- 0.07, n.s.). The l -type calcium current also remained unchanged. Blockade of the Na(+)/H(+)exchanger by Hoe 642 had no influence on cells perfused at pH = 7.2 but inhibited the increase in intracellular Na(+)at pH = 6.5 (0.023 +/- 0.026 in the presence of Hoe 642 vs 0.326 +/- 0.01 without Hoe 642, P< 0.05) without affecting [Ca(2+)](i)or the L-type calcium current. In cells superfused with a Tyrode solution containing NaHCO(3), the increase in intracellular sodium concentration was even more pronounced. Under these conditions Hoe 642 also antagonized this increase in intracellular sodium but without reaching the control level. We conclude that under these experimental conditions intracellular acidification causes an increase in [Na(+)](i)without changing intracellular Ca(2+)or the L-type calcium current. In addition in bicarbonate-buffered systems the acidosis-induced increase in sodium is enhanced which may involve the Na(+)/HCO(3)(minus sign)symport. The effect of cariporide (Hoe 642) in intracellular acidosis seems to be based on antagonization of the rise in intracellular sodium rather than calcium in this model.

Animals↗
PubMed1993

Effect of external acidosis on basal and ATP-evoked calcium influx in cultured astrocytes.

The effect of lactic acidosis on calcium influx, accumulation and efflux was studied in primary cultures of neonatal cortical rat astrocytes. Treatment of cultures with 20 mM sodium lactate, pH 6.0, for 10-60 min resulted in a 35% reduction of 45Ca2+ influx. The decrease in calcium influx was pH dependent because a similar reduction was observed in cultures exposed to pH 6.0 without lactate, while no difference was observed in cultures treated with sodium lactate at pH 7.4. Calcium accumulation was also decreased by lactic acidosis (20% reduction), while calcium efflux was unaffected. Studies with lanthanum, an inhibitor of calcium transport, indicated that the effect of lactic acidosis was not due to non-specific leakage of calcium. The reduction in calcium influx was reversible, thereby indicating that the cells were not permanently damaged by lactic acidosis. In addition to basal calcium influx, stimulated influx (mediated by extracellular ATP, 100 microM) was also reduced by 20 mM sodium lactate, pH 6. These findings suggest that protonization of calcium channels or other calcium entry pathways leads to a reduction in calcium influx in astrocytes. This diminished calcium entry, by affecting calcium-dependent mechanisms necessary for such processes as volume regulation, glycogen metabolism, or regulation of ionic permeability, may alter the ability of astrocytes to elicit appropriate responses following CNS injury.

Adenosine Triphosphate↗
PubMed2001

Fetal exposure to magnesium chloride-adenosine triphosphate (MgCl2-ATP) results in alterations in cerebral blood flow and a metabolic acidosis.

OBJECTIVE: Magnesium chloride-adenosine triphosphate (MgCl(2)-ATP), advocated as an adjunct treatment in shock resuscitation, might be useful for pregnant women who develop hypovolemia secondary to conditions such as placental abruption. The effects of this treatment on the fetus, however, have never been investigated. This study determined the direct, acute effects of MgCl(2)-ATP on fetal organ blood flow, hemodynamic measurements, and metabolic parameters before and after maternal hemorrhage. DESIGN: Experimental, randomized, nonblinded, control study. SETTING: Animal laboratory at a university research facility. SUBJECTS: This study was performed on 11 chronically instrumented, 123-day gestational age, pregnant ewes (term = 147 days) and their fetuses. INTERVENTIONS: Ewes were randomly allocated to either experimental (Expt, n = 5) or control (Cntl, n = 6) groups. After a 60-min baseline period, Expt fetuses received a 60-min iv infusion of MgCl(2)-ATP (150 &mgr;mole/hr each of MgCl(2) and ATP; at 3 mL/hr), and Cntl fetuses received an equivalent volume of 0.9% NaCl. After this infusion-only period, the infusion was continued, and ewes were intermittently bled over 1 hr for a total blood loss of 20 mL/kg (hemorrhage-plus-infusion period). After this, the infusions were continued, and ewes and fetuses were monitored for 1 additional hr (posthemorrhage period). Measurements: At the end of all periods, fetal and maternal blood pressures, blood gases, oxygen saturation, hemoglobin, serum electrolytes, and serum glucose concentrations were measured. At the end of the baseline, infusion-only, and hemorrhage-plus-infusion periods, fetal organ blood flows were determined using a fluorescent microsphere technique. Nonparametric statistics were used for comparisons (2-tailed, p </=.05). MAIN RESULTS: Maternal hemorrhage caused maternal hypotension, resulting in a decrease in fetal oxygen content and an increase in fetal hemoglobin and glucose concentrations. The changes were similar in both groups. In both groups, a progressive fetal metabolic acidosis developed during the hemorrhage period and it continued through the posthemorrhage period. This metabolic acidosis was more severe in the Expt fetuses and appeared to have started during the infusion-only period. There were no fetal deaths in either group. In the Cntl fetuses, there were increases from baseline after the hemorrhage-plus-infusion period in fetal adrenal (71%), brain (89%), and thymus (18%) blood flow and a decrease in muscle (-28%) blood flow. In the Expt fetuses, there were increases during the infusion-only period in adrenal (332%), myocardial (142%), and pancreatic (219%) blood flow and decreases in kidney (-25%) and skin (-75%) blood flow. These changes persisted during the hemorrhage-plus-infusion period. Most strikingly, regional cerebral blood flow in the Expt fetuses did not increase from baseline in any of the 10 brain areas sampled during the infusion-only period or following maternal hemorrhage. In Cntl fetuses, however, there was increase in blood flow in all 10 brain areas sampled following maternal hemorrhage. CONCLUSIONS: In healthy fetuses, direct MgCl(2)-ATP exposure caused metabolic acidosis and a redistribution of cardiac output to different organs. When the MgCl(2)-ATP fetuses were then subject to the effects of maternal hemorrhage, the expected increase in cerebral blood flow was not observed. Although an earlier study suggests that ATP may be beneficial to stressed fetuses when administered to mothers in labor, the direct effect of MgCl(2)-ATP appears to be potentially harmful by producing an acidosis and altering the normal fetal cerebral blood flow response to maternal hemorrhage.

Journal Article↗
PubMed1975

Adaptive tolerance of fish myocardium to hypercapnic acidosis.

Isometric, electrically paced strips of cardiac ventricle from two species of fish (plaice, Pleuronectes platessa; cod, Gadus morrhua) with different tolerance to hypoxia were compared with respect to effects of hypercapnic acidosis. Acidosis was induced by altering the equilibrating gas mixture for the muscle strip chamber from 3% CO2 in 97% 02 to 15% CO2 in 85% O2. The pH was varied further by changing the NaHCO3 content of the Cortland-Ringer solution used in the muscle chamber. After onset of acidosis with the highest buffer value of the Cortland-Ringer solution (35.7 mM NaHCO3), the force decay was similar for the initial 10 min of exposure to high Pco2. Subsequently the cod heart continued to lose force at the same rate, whereas the plaice heart regained a cardiac contractile force that after 40 min even exceeded prehypercapnic values. When buffer values were varied by changing the bicarbonate content of the Cortland-Ringer solution in steps from 0.0 to 35.7 mM NaHCO3, the cod heart showed steep force decays at all buffer values during hypercapnic acidosis. The plaice heart showed a similar decline at low buffer values but at a bicarbonate concentration above 23.8 mM NaHCO3, the initial force decline was reversed and prehypercapnic force restored.

Acid-Base Equilibrium↗
PubMed1979

Determination of liver intracellular pH in vivo and its homeostasis in acute acidosis and alkalosis.

An in vivo method is presented for the determination of liver intracellular pH (pHi) using [14C]dimethadione (DMO) in dogs. This method differs from those previously published in that hepatic venous and portal venous blood pH were selected as the extracellular reference pH, and liver blood space corrections are applied to whole liver tissue [14C]DMO activity. Using these corrections, a normal liver pHi of 6.99 +/- 0.03 (SE) was obtained. During acute metabolic acidosis and alkalosis, as well as during acute respiratory acidosis and alkalosis, the liver pHi remained normal; metabolic acidosis was 7.04 +/- 0.04; metabolic alkalosis was 6.92 +/- 0.08; respiratory acidosis was 6.98 +/- 0.04; and respiratory alkalosis was 7.00 +/- 0.10. None of these values was significantly different from normal (P greater than 0.05). Changes in intracellular bicarbonate and lactate appeared to account in part for the observed stability of the liver pHi despite acute manipulations resulting in a range of pH values between 7.09 and 7.63 in arterial blood.

Acid-Base Imbalance↗
PubMed1968

Effect of acute hypoxia and hypercapnic acidosis on the development of acetylstrophanthidin-induced arrhythmias.

The effect of acutely induced hypoxia, hypercapnic acidosis, and the combination of the two on the amount of acetylstrophanthidin (AS) required to produce cardiac arrhythmias was determined in anesthetized dogs. Each animal was studied during ventilation with room air and again during ventilation with gas mixtures of appropriate concentrations; 24 hr separated the study periods. AS was infused intravenously at a rate of 5 mug/kg per min. Significantly less AS was required to produce arrhythmias during hypoxia and hypercapnic acidosis together than during the period with normal arterial Po(2), Pco(2), and pH (10 animals). Included in this group were two animals which had undergone previous bilateral adrenalectomy and four animals in which heart rate was maintained at the same frequency during both study periods. A significant reduction in the toxic dose of AS also was demonstrated in eight animals, two with constant heart rate, during hypoxia with normal arterial Pco(2) and pH. Hypercapnic acidosis alone (eight animals) did not significantly alter the toxic dose of AS. After the administration of propranolol (six animals) or hexamethionium (six animals), no significant difference was observed between the toxic dose of AS during hypoxia and that during ventilation with room air. Thus although hypoxia and hypercapnic acidosis together do reduce the amount of AS required to produce arrhythmias, it is the hypoxia which exerts the predominant effect on the development of this increased sensitivity to AS. Furthermore, this effect of hypoxia occurs primarily as a result of reflexly augmented sympathetic stimulation of the heart.

Adrenal Medulla↗
PubMed1996

Effects of stilbene derivatives SITS and DIDS on development of intracellular acidosis during ischemia in isolated guinea pig ventricular papillary muscle in vitro.

Using ion-selective microelectrode techniques, we investigated the effects of 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS) and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), which are known as Cl(-)-HCO3- exchange blockers, on action potentials and intracellular pH (pHi) in guinea pig ventricular papillary muscles subjected to simulated ischemia. Simulated ischemia was produced by stopping the flow of superfusing solution and then covering the preparations with mineral oil. Simulated ischemia induced a progressive decrease in the maximum upstroke rate and resting membrane potentials, shortened action potential duration, and resulted in cessation of action potentials within 10-12 min after the onset of simulated ischemia. The pHi-measurements revealed progressive intracellular acidosis during the period of simulated ischemia. SITS (0.5 mM) or DIDS (0.1 mM) delayed the onset of ischemia-induced deterioration of action potentials and prolonged the time to cessation of action potentials. SITS or DIDS (0.1-0.5 mM) induced an increase in pHi in HCO3(-)-buffered solution and suppressed the development of intracellular acidosis during ischemia. Under the external Cl(-)-free condition, the time to cessation of action potentials caused by ischemia was significantly delayed, and the development of intracellular acidosis during ischemia was attenuated. The present results indicate that activation of the Cl(-)-HCO3- exchange system would be involved, in part, in the development of intracellular acidosis during cardiac ischemia.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗