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PubMed1994

Acidosis and glucocorticoids concomitantly increase ubiquitin and proteasome subunit mRNAs in rat muscle.

In rat muscle metabolic acidosis increases ATP-dependent protein degradation and levels of mRNAs for ubiquitin (Ub) and proteasome subunits. Because adrenalectomy (ADX) abolishes the proteolytic response to acidosis in muscle, we examined whether glucocorticoids (GCs) are necessary for acidosis-induced changes in Ub and proteasome mRNAs in muscles. Total RNA content of the white fiber extensor digitorum longus or mixed fiber gastrocnemius muscles were lowest in muscles of ADX rats given acid plus GCs. In contrast, the abundance of Ub and C2 and C9 proteasome subunits mRNAs were increased in muscles from this group compared with untreated ADX rats or ADX rats given acid or GCs alone. Because total RNA is reduced, the increase in these mRNAs in muscles of ADX rats receiving acid plus GCs provides evidence for a specific activation of the ATP-dependent-Ub-proteasome pathway. Thus, GCs are required but not sufficient to produce the coordinated increase in mRNAs encoding ubiquitin and proteasome subunits occurring in muscles of acidotic rats.

Acidosis↗
PubMed1995

Effect of stretch on contraction and the Ca2+ transient in ferret ventricular muscles during hypoxia and acidosis.

The effect of stretch on cardiac muscle contraction and the Ca2+ transient was studied during hypoxia and acidosis in isolated ferret ventricular muscles. In control conditions, a maintained stretch produced an immediate increase in tension followed by a slow increase in tension and the Ca2+ transient. A stretch between contractions (diastolic stretch) caused only a slow increase in tension and the Ca2+ transient, whereas a stretch during the period of contraction (systolic stretch) produced an immediate increase in tension followed by a small slow increase in tension and the Ca2+ transient. In hypoxia, the immediate percent increase in tension was the same as in control. However, the slow increase was smaller during all three types of stretch. In acidosis, the immediate percent increase in tension was larger than in control. The slow change was the same during maintained stretch. However, the slow increase in tension was smaller during diastolic stretch and larger during systolic stretch. Thus the stretch-dependent increase in contraction is inhibited during hypoxia and modulated by acidosis.

Acidosis↗
PubMed1979

Glucose intolerance following chronic metabolic acidosis in man.

The effect of chronic metabolic acidosis (0.1 g/(kg . day) X 3 days) on carbohydrate metabolism was examined with the glucose-clamp technique in 16 healthy volunteers. Hyperglycemic clamp. Plasma glucose concentration is acutely raised and maintained 125 mg/dl above the basal level. Because the glucose concentration is held constant, the glucose infusion rate is an index of glucose metabolism (M). Following NH4Cl, M decreased from 8.95 +/- 1.12 to 7.35 +/- 0.76 (P less than 0.05) despite an increased plasma insulin concentration (I) 23 +/- 9%, P less than 0.05). Consequently the M/I ratio, an index of tissue sensitivity to insulin, decreased by 32 +/- 5% (P less than 0.005). Euglycemic clamp. Plasma insulin concentration is acutely raised and maintained 101 +/- 3 microU/ml above basal and plasma glucose is held constant at the fasting level by a variable glucose infusion (M). Following NH4Cl both M and M/I decreased by 15 +/- 4% (P = 0.005) and 15 +/- 5% (P = 0.01), respectively. Metabolic acidosis had no effect on basal [3-3H]glucose production or the percent of decline (91 +/- 4%) following hyperinsulinemia. Both hyperglycemic and euglycemic clamp studies indicate that impaired glucose metabolism following metabolic acidosis results from impaired tissue sensitivity to insulin.

Acidosis↗
PubMed1982

Inhibition of 25-hydroxyvitamin D3-1-hydroxylase by chronic metabolic acidosis.

Chronic metabolic acidosis had been shown to influence the renal metabolism of 25-hydroxyvitamin D3. Using the isolated perfused rat kidney model, we evaluated the rates of synthesis of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] in vitamin D-depleted [D(-)] and 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] in vitamin D-replete [D(+)] rats. Metabolic acidosis was induced in both groups of rats by feeding aqueous ammonium chloride for 9 days. Kidneys isolated from D(-) acidotic rats (mean pH, 7.11) exhibited a decreased rate of 1,25(OH)2D3 synthesis (0.79 +/- 0.17 pmol produce . h-1 . g kidney-1) when compared with that (1.27 +/- 0.09) of D(-) nonacidotic (mean pH, 7.33) rats. There was a significant negative linear correlation between the rate of synthesis of 1,25(OH)2D3 and the hydrogen ion concentration of the animal (r = 0.79, P less than 0.005). The rate of synthesis of 24,25(OH)2D3 by the kidneys from D(+) acidotic (mean pH, 7.06) and nonacidotic (mean pH, 7.39) rats did not differ (0.81 +/- 0.21 vs. 0.60 +/- 0.12 pmol product . h-1 . g kidney-1). It is concluded that chronic acidosis suppressed 1-hydroxylase activity, but does not suppress 24-hydroxylase activity.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1984

Vasopressin in plasma and cerebrospinal fluid of dogs during hypoxia or acidosis.

Hypoxia and hypercapnia have been shown to cause an increase in the concentration of vasopressin in plasma, but their effects on vasopressin in cerebrospinal fluid (CSF) are not known. In addition, the effect of metabolic acidosis on plasma and CSF vasopressin has not been reported. In this study, plasma and CSF vasopressin levels were measured in anesthetized dogs subjected to either hypoxia, hypercapnia, or metabolic acidosis. Rate and depth of respiration were closely regulated with the aid of muscle paralysis and mechanical ventilation. Vasopressin increased markedly in both plasma and CSF during severe hypoxia (10% O2) and during hypercapnia (10% CO2) but did not change during either mild (15% O2) or moderate (12.5% O2) hypoxia. Although mild hypoxia by itself did not affect either plasma or CSF vasopressin, it did potentiate the increase in plasma and CSF vasopressin that was induced by severe hypercapnia, thus suggesting that hypoxia and hypercapnia may exert synergistic effects on vasopressin secretion. Metabolic acidosis produced by slow intravenous infusion of 1 N hydrochloric acid decreased arterial pH to values comparable to those induced by hypercapnia and increased vasopressin in plasma; CSF vasopressin was unchanged. These results are consistent with the concept that the source of vasopressin secreted into plasma may be different from that secreted into CSF.

Acidosis↗
PubMed1987

Branched-chain amino acid metabolism in rat muscle: abnormal regulation in acidosis.

Branched-chain amino acid (BCAA) metabolism is frequently abnormal in pathological conditions accompanied by chronic metabolic acidosis. To study how metabolic acidosis affects BCAA metabolism in muscle, rats were gavage fed a 14% protein diet with or without 4 mmol NH4Cl X 100 g body wt-1 X day-1. Epitrochlearis muscles were incubated with L-[1-14C]-valine and L-[1-14C]leucine, and rates of decarboxylation, net transamination, and incorporation into muscle protein were measured. Plasma and muscle BCAA levels were lower (P less than 0.05) in acidotic rats. Rates of valine and leucine decarboxylation and net transamination were higher (P less than 0.05) in muscles from acidotic rats; these differences were associated with a 79% increase in the total activity of branched-chain alpha-keto acid dehydrogenase and a 146% increase in the activated form of the enzyme. We conclude that acidosis affects the regulation of BCAA metabolism by enhancing flux through the transaminase and by directly stimulating oxidative catabolism through activation of branched-chain alpha-keto acid dehydrogenase.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1987

Pathophysiology of type A hypoxic lactic acidosis in dogs.

Hypoxic lactic acidosis (HLA) was induced in dogs by ventilating them with a hypoxic gas mixture of 8% O2-92% N2. The animals were studied both in the control state and after development of HLA, where arterial lactate was above 5 mM, pH was below 7.2, bicarbonate was below 12 mM, and arterial PO2 was between 26 and 30 Torr. After hypoxia had been present for 90 min, most of the increase in arterial lactate vs. control was due to increased lactate production from gut and carcass in the presence of a decreased capacity of the liver to extract lactate. The capacity of the liver to extract lactate in the normoxic state was evaluated in another group of six dogs after infusion of L-lactic acid such that arterial pH, lactate, and bicarbonate were similar to hypoxic values. In these experiments it was found that the capacity of the liver to extract lactate was 14.8 +/- 1.7% of the delivered load vs. 4.9 +/- 1.3% observed in hypoxic animals. The decreased liver lactate extraction in HLA was probably secondary to both a decrease in liver oxygen uptake and a decrease in liver intracellular pH and was paralleled by an increase in liver tissue lactate levels. Cardiac output, in contrast to other forms of lactic acidosis, was increased by 40% vs. control and femoral artery flow by 35%, whereas liver blood flow was unchanged and renal blood flow decreased. Hypoxic lactic acidosis thus is the consequence of overproduction of lactate by both gut and carcass, in the presence of impaired utilization of lactate by the liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid-Base Equilibrium↗
PubMed1993

Correction of acidosis in humans with CRF decreases protein degradation and amino acid oxidation.

The effect of correction of acidosis in chronic renal failure (CRF) was determined from the kinetics of infused L-[1-13C]leucine. Nine CRF patients were studied before (acid) and after two 4-wk treatment periods of sodium bicarbonate (NaHCO3) and sodium chloride (NaCl) (pH: acid 7.31 +/- 0.01, NaHCO3 7.38 +/- 0.01, NaCl 7.30 +/- 0.01). Leucine appearance from body protein (PD), leucine disappearance into body protein (PS) and leucine oxidation (O) decreased significantly with correction of acidosis (PD: acid 122.4 +/- 6.1, NaHCO3 88.3 +/- 6.9, NaCl 116.2 +/- 9.1 mumol.kg-1.h-1, acid vs. NaHCO3 P < 0.01, NaHCO3 vs. NaCl P < 0.01, acid vs. NaCl NS; PS: acid 109.4 +/- 5.6, NaHCO3 79.0 +/- 6.3, NaCl 101.3 +/- 7.7 mumol.kg-1.h-1, acid vs. NaHCO3 P < 0.01, NaHCO3 vs. NaCl P < 0.01, acid vs. NaCl NS; O: acid 13.0 +/- 1.2, NaHCO3 9.2 +/- 0.9, NaCl 15.0 +/- 1.9 mumol.kg-1.h-1, acid vs. NaHCO3 P < 0.05, NaHCO3 vs. NaCl P < 0.01, acid vs. NaCl NS). There were no significant changes in plasma amino acid concentrations. These results confirm that correction of acidosis in chronic renal failure removes a potential catabolic factor.

Acidosis↗
PubMed1983

Acute respiratory alkalosis and acidosis and rabbit intestinal ion transport in vivo.

The effects of acute respiratory alkalosis and acidosis on electrolyte transport in the rabbit ileum, colon, and gallbladder were studied. During in situ perfusion, anesthetized animals were ventilated with 0, 3, or 8% CO2 gas, creating states of alkalosis (pH 7.49 +/- 0.01, PCO2 = 27.0 +/- 0.9 mmHg, HCO3 = 21.7 mM), normocapnia (pH 7.38 +/- 0.02, PCO2 = 41.3 +/- 1.1 mmHg, HCO3 = 25.9 +/- 0.4 mM), and acidosis (pH 7.21 +/- 0.01, PCO2 = 66.3 +/- 1.3 mmHg, HCO3 = 28.1 +/- 0.8 mM). In the ileum alkalosis decreased the net absorption of water (-36%), sodium (-44%), and chloride (-27%), whereas acidosis had the opposite effect on water (+69%), sodium (+98%), and chloride (+32%) absorption and reduced bicarbonate secretion. Small changes in net potassium absorption occurred in the direction of water movement. There was no effect on the ileal transmural potential difference (PD). The colon and gallbladder did not respond to the acid-base disorders with changes in electrolyte transport or PD. These results suggest that systemic pH and/or PCO2 affect an electroneutral sodium chloride absorptive process in the rabbit ileum. The simple presence of this absorptive process in the gallbladder was not a sufficient basis for this organ to respond to alterations in systemic pH.

Acidosis, Respiratory↗
PubMed1994

Endotoxin-induced ileal mucosal hyperpermeability in pigs: role of tissue acidosis.

Administration of lipopolysaccharide (LPS) to experimental animals leads to diminished mesenteric perfusion, increased ileal mucosal [H+] , and increased gut epithelial permeability to hydrophilic solutes. We sought to determine whether these phenomena are causally related. Experiments were performed in anesthetized pigs. Permeability was assessed by measuring the plasma-to-lumen clearance of fluorescein isothiocyanate dextran (4,000 Da; FD-4) by a segment of ileum perfused with Ringer lactate solution. Mucosal perfusion (Qmuc) and [H4+] were estimated using laser-Doppler flowmetry and tonometry, respectively. In an initial series of experiments, we showed that mucosal permeability was linearly correlated with mucosal [H+] in animals subjected to graded degrees of mechanically induced mesenteric ischemia (n = 14, R2 = 0.58, P < 0.002) or injected with graded doses of LPS (n = 11, R2 = 0.93, P < 0.0001). In a second series of experiments, we induced mucosal acidosis in normal pigs by mechanical ventilation with either a hypoxic (n = 7) or a hypercapnic (n = 5) gas mixture. In both groups, ileal mucosal permeability to FD-4 increased significantly (P < 0.05), although transmesenteric release of lactate increased significantly only in the hypoxic group. Qmuc was unchanged in both groups. These data suggest that mucosal acidosis, even in the absence of tissue ischemia or hypoxia, increases intestinal permeability to a macromolecular hydrophilic solute. Tissue acidosis may be an important factor contributing to LPS-induced gut mucosal hyperpermeability.

Acidosis↗
PubMed2002

Hypoxia and acidosis impair cGMP synthesis in microvascular coronary endothelial cells.

To characterize the effects of ischemia on cGMP synthesis in microvascular endothelium, cultured endothelial cells from adult rat hearts were exposed to hypoxia or normoxia at pH 6.4 or 7.4. Cellular cGMP and soluble (sGC) and membrane guanylyl cyclase (mGC) activities were measured after stimulation of sGC (S-nitroso-N-acetyl-penicillamine) or mGC (urodilatin) or after no stimulation. Cell death (lactate dehydrogenase release) was negligible in all experiments. Hypoxia at pH 6.4 induced a rapid approximately 90% decrease in cellular cGMP after sGC and mGC stimulation. This effect was reproduced by acidosis. Hypoxia at pH 7.4 elicited a less pronounced (approximately 50%) and slower reduction in cGMP synthesis. Reoxygenation after 2 h of hypoxia at either pH 6.4 or 7.4 normalized the response to mGC stimulation but further deteriorated the sGC response; normalization of pH rapidly reversed the effects of acidosis. At pH 7.4, the response to GC stimulation correlated well with cellular ATP. We conclude that simulated ischemia severely depresses cGMP synthesis in microvascular coronary endothelial cells through ATP depletion and acidosis without intrinsic protein alteration.

Acidosis↗
PubMed1984

Purkinje-muscle coupling and endocardial response to hyperkalemia, hypoxia, and acidosis.

Previously we found that combined hyperkalemia, hypoxia, and acidosis depressed the electrical activity of canine epicardium more than that of endocardium or Purkinje fibers. In this study, we determined whether the resistance of endocardium to these components of ischemia was due to electrotonic interactions with Purkinje fibers. The effects of combined hyperkalemia, hypoxia, and acidosis were tested on endocardial cells that were electrically uncoupled from Purkinje cells ("uncoupled" endocardium), due to their location or to prior exposure to elevated [Ca2+]. During control, action potentials in uncoupled endocardium had shorter durations than endocardium coupled to Purkinje ("coupled" endocardium), but had similar amplitudes, upstroke velocities, and resting potentials. During combined hyperkalemia, hypoxia, and acidosis, action potentials in uncoupled endocardium were more depressed than in coupled endocardium and resembled those in depressed epicardium. In addition, the combination of these components of ischemia produced electrical uncoupling at the Purkinje-muscle junction, although each component alone did not. Thus the resistance of endocardial cells to some components of ischemia appears to involve electrotonic interactions with Purkinje cells, which may be prevented by ischemia-induced electrical uncoupling.

Acidosis↗
PubMed1987

Influence of acidosis on inotropic effect of catecholamines in newborn rabbit hearts.

The influence of acidosis on the inotropic effect of isoproterenol was studied in the isolated arterially perfused heart of the newborn rabbits. Baseline mechanical function during acidosis (pH 6.8) was not different from control (pH 7.4). However, the inotropic effect of isoproterenol was significantly suppressed in the acidotic muscles. The increment of myocardial adenosine 3',5'-cyclic monophosphate (cAMP) content during isoproterenol infusion was also reduced in acidosis. Inotropic effects of Ca and dibutyryl cAMP in the acidotic muscles were not significantly different from those in the control muscles. beta-Receptor number and affinity in the respiratory acidotic muscle was similar to those in the control muscle. Effects of pH on myocardial beta-receptor and adenylate cyclase activity were further determined in the membrane fraction by changing the pH of the reaction medium from 7.4 (control) to 6.8 or 6.0. beta-Receptor numbers were significantly decreased at pH 6.0 but not at pH 6.8. Adenylate cyclase activity was depressed at pH 6.8 and 6.0. These data suggest that the inotropic effect of isoproterenol is diminished in the acidotic muscle. This may be due to the decreased activation of cAMP production, which in turn most likely results from depressed adenylate cyclase activity.

Acidosis↗
PubMed1988

Mechanism of diminished contractile response to catecholamines during acidosis.

To examine mechanisms of diminished contractile response to catecholamines during acidosis, we studied contractile properties, beta-adrenergic receptor properties, and intracellular pH of intact, cultured myocardial cells from chick embryo ventricle at pH 7.4 and 6.8. Contractile response was measured with an optical-video system. On changing the superfusing buffer from pH 7.4 to 6.8 there was a decline in contractile amplitude to 80% of control by 20 min. Fluorimetrically determined intracellular pH declined over a similar time course from 7.11 +/- 0.05 to 6.96 +/- 0.07 (P less than 0.05). After 45 min at pH 6.8 the contractile response to 1 microM isoproterenol was less than half of the response at pH 7.4. Antagonist and agonist ligand-binding properties of the beta-adrenergic receptor were determined in the intact cells under conditions identical to those for the contractility studies. With the use of the hydrophilic antagonist [3H]CGP-12177 that selectively labels cell-surface receptors, agonist competition studies demonstrated that acidosis had no significant effect on antagonist or agonist affinity but decreased beta-receptor number from 21 +/- 3 to 11 +/- 3 fmol/mg protein (P less than 0.02). It is probable that a decline in the number of beta-receptors on the cell surface contributes to contractile hyporesponsiveness to catecholamines during acidosis.

Acidosis↗
PubMed1998

Intracellular acidosis differentially regulates KV channels in coronary and pulmonary vascular muscle.

Decreases in intracellular pH (pHi) potently dilate coronary resistance arteries but constrict small pulmonary arteries. To define the ionic mechanisms of these responses, this study investigated whether acute decreases in pHi differentially regulate K+ currents in single vascular smooth muscle (VSM) cells isolated from rat coronary and pulmonary resistance arteries. In patch-clamp studies, whole cell K+ currents were elicited by 10-mV depolarizing steps between -60 and 0 mV in VSM cells obtained from 50- to 150-micrometers-OD arterial branches, and pHi was lowered by altering the NH4Cl gradient across the cell membrane. Progressively lowering pHi from calculated values of 7.0 to 6.7 and 6.4 increased the peak amplitude of K+ current in coronary VSM cells by 15 +/- 5 and 23 +/- 3% but reduced K+ current in pulmonary VSM cells by 18 +/- 3 and 21 +/- 3%, respectively. These changes were reversed by returning cells to the control pHi of 7.0 and were eliminated by dialyzing cells with pipette solution containing 50 mmol/l HEPES to buffer NH4Cl-induced changes in pHi. Pharmacological block of ATP-sensitive K+ channels and Ca2+-activated K+ channels by 1 micromol/l glibenclamide and 100 nmol/l iberiotoxin, respectively, did not prevent changes in K+ current levels induced by acidotic pHi. However, block of voltage-gated K+ channels by 3 mmol/l 4-aminopyridine abolished acidosis-induced changes in K+ current amplitudes in both VSM cell types. Interestingly, alpha-dendrotoxin (100 nmol/l), which blocks only select subtypes of voltage-gated K+ channels, abolished the acidosis-induced decrease in K+ current in pulmonary VSM cells but did not affect the acidosis-induced increase in K+ current observed in coronary VSM cells. These findings suggest that opposing, tissue-specific effects of pHi on distinct subtypes of voltage-gated K+ channels in coronary and pulmonary VSM membranes may differentially regulate vascular reactivity in these two circulations under conditions of acidotic stress.

4-Aminopyridine↗
PubMed1975

Distribution of H+ and HCO3 minus between CSF and blood during metabolic acidosis in dogs.

To determine whether the regulation of brain extracellular fluid acid-base balance is by active ion transport or passive distribution, changes in cisternal and lumbar cerebrospinal fluid (CSF) (H+) and (HCO3 minus) were assessed in five dogs with normal acid-base status and in six dogs during metabolic acidosis. Both groups were mechanically ventilated to maintain a constant PaCO2. The pH, PCO2, (HCO3 minus), and (lactate) in CSF and arterial plasma and the CSF/plasma DC potential difference were determined at intervals, and the electrochemical potential differnces (mu) for H+ and HCO3 minus were calculated. Following control measurements at pHa equal to 7.40, metabolic acidosis was induced by infusion of 0.6 N HCl. Measurements were made 0, 3, 4.5, and 6 h thereafter and at 0, 3, and 6 h in the control series. A steady state for ion distribution was reached by 4.5 h. In the control series at 6 h the values of mu for H+ and HCO3 minus were within minus 0.2 and +0.5 mV of initial values at the cistern and +0.1 and +0.9 mV at the lumbar site. During metabolic acidosis, the 6-h values at the cistern returned to 0.0 and +0.7 mV of control for muH+ and muHCO3 minus while lumbar values returned to +0.5 and minus 0.4 mV. The closeness of these 6-h values of mu to control is compatible with passive distribution of H+ and HCO3 minus between CSF and blood.

Acid-Base Equilibrium↗
PubMed1975

Skeletal buffering of acute metabolic acidosis.

Decreases in the sodium content of bone were measured to evaluate the role of this tissue in the buffering of acute metabolic acidosis. The bones of rats and dogs were labeled with radiosodium prior to the infusion of HCl, and changes in the radioactivity were used to indicate the loss of bone sodium. Significant reductions in the skeletal sodium occurred within the first 5 h of acidosis, and these losses can only be partially attributed to the hyponatremia accompanying the acid infusion. Decreases were greatest in the smaller bones of the rat; and, in the dog, the losses from flat bones exceeded those of the long bones. Only the rapidly exchangeable sodium of bone was involved in the changes due to acidosis. Soft tissue buffering may be more important initially; during 1.5-h experiments, the skeletal losses were small and could be ascribed almost entirely to the decrease in the amount of sodium contained in bone water. However, at the end of 5.0 h, the quantity of sodium released from the skeleton is sufficient to account for much of the tissue buffering.

Acid-Base Equilibrium↗
PubMed1976

Acid-base changes in milk and blood of rats in acidosis and alkalosis.

Lactating white rats (Rattus norvegicus) were subjected to metabolic and respiratory acidosis and metabolic alkalosis. Before and during the various treatments, the acid-base status of heart blood and milk was determined. Acute metabolic acidosis lowered the pH of plasma and milk; Pco(2) and bicarbonate concentrations in plasma were lowered, and in milk Pco(2) was raised and the bicarbonate concentration remained unchanged. Respiratory acidosis and acetazolamide caused a drop in blood pH and in blood and milk bicarbonate concentrations; milk pH remained unchanged, but Pco(2) was raised in both plasma and milk. Acute metabolic alkalosis raised the blood pH and milk Pco(2); plasma Pco(2) and bicarbonate concentrations in blood and milk remained unchanged. The data show that greater changes occur in acid-base parameters of blood than milk when animals are exposed to acidifying and alkalinizing stimuli.

Acid-Base Equilibrium↗