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PubMed1982

Effect of acute respiratory alkalosis and acidosis on intestinal ion transport in vivo.

The effects of acute respiratory alkalosis and acidosis on intestinal electrolyte transport were studied in adult Sprague-Dawley rats. During in situ intestinal perfusion, anesthetized animals were ventilated with 0, 3, or 8% CO2, creating states of alkalosis (pH 7.64 +/- 0.01), normocapnia (pH 7.45 +/- 0.01), or acidosis (pH 7.26 +/- 0.01), respectively. The plasma bicarbonate concentration decreased 2.0 mM during alkalosis and increased 2.1 mM during acidosis. The jejunum did not respond to the acid-base disturbances. In both the ileum and colon, alkalosis decreased the net absorption of water (-16%), sodium (-23%), and chloride (-42%) and the net secretion of bicarbonate (-33%), whereas acidosis had the opposite effect, i.e., the net absorption of water (41%), sodium (39%), and chloride (32%) increased as did net bicarbonate secretion (33%) (ileal values given). Changes in sodium chloride movement could be correlated with changes in systemic pH and CO2 tension (PCO2), and bicarbonate secretion paralleled changes in the plasma bicarbonate concentration. The acid-base disorders had no effect on ileal and colonic net potassium secretion and transmural potential difference. These studies suggest that systemic pH and/or PCO2 regulate sodium chloride absorption, and the plasma bicarbonate concentration regulates bicarbonate secretion.

Acidosis, Respiratory↗
PubMed2007

Prolonged transient acidosis during early reperfusion contributes to the cardioprotective effects of postconditioning.

We have previously reported that the prolonged transient acidosis during early reperfusion mediates the cardioprotective effects in canine hearts. Recently, postconditioning has been shown to be one of the novel strategies to mediate cardioprotection. We tested the contribution of the prolonged transient acidosis to the cardioprotection of postconditioning. Open-chest anesthetized dogs subjected to 90-min occlusion of the left anterior descending coronary artery and 6-h reperfusion were divided into four groups: 1) control group; no intervention after reperfusion (n = 6); 2) postconditioning (Postcon) group; four cycles of 1-min reperfusion and 1-min reocclusion (n = 7); 3) Postcon + sodium bicarbonate (NaHCO(3)) group; four cycles of 1-min reperfusion and 1-min reocclusion with the administration of NaHCO(3) (n = 8); and 4) NaHCO(3) group; administration of NaHCO(3) without postconditioning (n = 6). Infarct size, the area at risk (AAR), collateral blood flow during ischemia, and pH in coronary venous blood were measured. The phosphorylation of Akt and extracellular signal-regulated kinase (ERK) in ischemic myocardium was assessed by Western blot analysis. Systemic hemodynamic parameters, AAR, and collateral blood flow were not different among the four groups. Postconditioning induced prolonged transient acidosis during the early reperfusion phase. Administration of NaHCO(3) completely abolished the infarct size-limiting effects of postconditioning. Furthermore, the phosphorylation of Akt and ERK in ischemic myocardium induced by postconditioning was also blunted by the cotreatment of NaHCO(3). In conclusion, postconditioning mediates its cardioprotective effects possibly via prolonged transient acidosis during the early reperfusion phase with the activation of Akt and ERK.

Acidosis↗
PubMed1994

Effects of acidosis and alkalosis on mechanical properties of hypertrophied rat heart fiber bundles.

Effects of alkalosis (pH 7.4) or acidosis (pH 6.8) on the intrinsic mechanical properties of control and pressure-overloaded rat hearts were studied in Triton X-100-treated left ventricular fiber bundles. In control bundles, Ca sensitivity [pCa required for one-half maximal response (pCa50)] was 5.520 +/- 0.012 at pH 7.1. Alkalosis increased it by 0.357 +/- 0.018 pCa unit, whereas acidosis decreased it by 0.365 +/- 0.014 pCa unit with no change in Hill coefficient. Maximal tension was decreased by acidic pH and increased by alkaline pH. Stiffness was measured by the response to quick length changes. Acidosis decreased maximal stiffness but increased the stiffness-to-force ratio, whereas alkalosis increased maximal stiffness but had no effect on stiffness-to-force ratio, suggesting that acidosis decreased the force generated per cross bridge. Alkalosis increased the time constant of tension recovery following a quick stretch from 10.6 +/- 0.66 to 17.45 +/- 1.83 ms, suggesting a decreased cross-bridge cycling rate. Pressure overload induced by thoracic aortic stenosis for 4-6 wk led to a 200% cardiac hypertrophy associated with a shift from fast to slow ventricular myosin. pCa50 of hypertrophied bundles was not different from control (5.541 +/- 0.012). Ca sensitivity was increased by 0.383 +/- 0.008 in alkaline medium and decreased by 0.325 +/- 0.009 in acidic medium. Stiffness-to-force ratio was decreased in acidic pH, and the time constant of tension recovery was increased from 31.0 +/- 0.4 to 34.9 +/- 0.25 ms by alkalosis. In hypertrophied bundles, maximal tension was decreased by acidic pH but not changed by alkalosis. These results show that in the small pH range of our study 1) pH changes have symmetrical effects on Ca sensitivity in both control and hypertrophied bundles, 2) a decrease or an increase in H+ concentration does not have symmetrical effects on the mechanics of the cross bridges, and 3) changes in the phenotype of contractile proteins induced by aortic stenosis do not influence Ca sensitivity, only moderately influence the response to pH changes, and mainly affect the cross-bridge cycling rate.

Acidosis↗
PubMed1995

Inhibition of arteriole alpha 2- but not alpha 1-adrenoceptor constriction by acidosis and hypoxia in vitro.

We have found that hypoxia and acidosis inhibit constriction by alpha 2D-adrenoceptors but not by alpha 1D-adrenoceptors on arterioles of rat skeletal muscle, facilitating local metabolic control of blood flow. When activated by full agonists like norepinephrine, this alpha 2D-constriction relies on Ca2+ influx through dihydropyridine-sensitive, voltage-operated Ca2+ channels (VOC), while alpha 1D-constriction does not. The purpose of the present study was to examine the dose sensitivity of this selective metabolic inhibition of alpha 2D-constriction and determine whether inhibition of VOCs is involved. Changes in lumen diameter of microcannulated arterioles isolated from rat skeletal muscle (107 +/- 3 microns control diam) were measured by videomicroscopy for bath-added agents. Decreases in pH (7.4-7.0) or PO2 (70 to 10 mmHg) caused graded inhibition of alpha 2D-adrenoceptor constriction (UK-14304 plus prazosin); the half-maximum inhibitory concentration for acidosis was 7.1 and for PO2 was 24 mmHg. alpha 1D-Adrenoceptor constriction by the respective full and partial alpha 1-agonists, phenylephrine (PE) and St-587 (both plus rauwolscine), was unaffected. Because St-587 but not PE constriction was dependent on VOC activation, the sensitivity of alpha 2D- but not alpha 1D-constriction to acidosis and hypoxia appeared to be independent of reliance on VOCs. This was examined directly; contractile sensitivity to KCl and the VOC agonist, SDZ-202-791, was unaffected by pH 7.0 or PO2 10 mmHg. These data suggest that alpha 2D-constriction is sensitive to inhibition by hypoxia and acidosis through a mechanism that does not involve direct blockade of dihydropyridine-sensitive Ca2+ channels.

Acidosis↗
PubMed1999

Potentiation of stretch-induced atrial natriuretic peptide secretion by intracellular acidosis.

We sought to investigate whether atrial myocyte contraction and secretion of the atrial natriuretic peptide (ANP) are affected in the same manner by intervention in intracellular Ca(2+) handling by acidosis. The effects of propionate (20 mM)-induced intracellular acidosis on the stretch-induced changes in ANP secretion, contraction force, and intracellular Ca(2+) concentration ([Ca(2+)](i)) were studied in the isolated rat atrium. The stretch of the atrium was produced by increasing the intra-atrial pressure of the paced and superfused preparation. Contraction force was estimated from pressure pulses generated by the contraction of the atrium. Intracellular Ca(2+) was measured from indo 1-AM-loaded atria, and ANP was measured by radioimmunoassay from the perfusate samples collected during interventions. Intracellular pH of the atrial myocytes was measured by a fluorescent indicator (BCECF)-based imaging system. Intracellular acidification caused by 20 mM propionic acid (0.18 pH units) potentiated the stretch-induced (intra-atrial pressure from 1 to 4 mmHg) ANP secretion, causing a twofold secretion compared with nonacidotic controls. Simultaneously, the responsiveness of the atrial contraction to stretch was reduced (P < 0.05, n = 7). Stretch augmented the systolic indo 1-AM transients in acidic (P < 0.05, n = 6) and nonacidic atria (P < 0.05, n = 6). However, during acidosis this was accompanied by an increase of the diastolic indo 1-AM ratio (P < 0.05, n = 6). Cooccurrence of stretch and acidosis caused an increase in systolic and diastolic [Ca(2+)](i) and potentiated the stretch-induced ANP secretion, whereas the contraction force and its stretch sensitivity were decreased. This mechanism may be involved in ischemia-induced ANP secretion, suggesting a role for ANP secretion as an indicator of contractile dysfunction.

Acidosis↗
PubMed2000

Effect of acidosis on transient outward potassium current in isolated rat ventricular myocytes.

The effect of acidosis on the transient outward K(+) current (I(to)) of rat ventricular myocytes has been investigated using the perforated patch-clamp technique. When the holding potential was -80 mV, depolarizing pulses to potentials positive to -20 mV activated I(to) in subepicardial cells but activated little I(to) in subendocardial cells. Exposure to an acid solution (pH 6.5) had no significant effect on I(to) activated from this holding potential in either subepicardial or subendocardial cells. When the holding potential was -40 mV, acidosis significantly increased I(to) at potentials positive to -20 mV in subepicardial cells but had little effect on I(to) in subendocardial cells. The increase in I(to) in subepicardial cells was inhibited by 10 mM 4-aminopyridine. In subepicardial cells, acidosis caused a +8.57-mV shift in the steady-state inactivation curve. It is concluded that in subepicardial rat ventricular myocytes acidosis increases the amplitude of I(to) as a consequence of a depolarizing shift in the voltage dependence of inactivation.

Acidosis↗
PubMed1983

Aortic and carotid chemoreceptor responses to metabolic acidosis in the cat.

The effect of metabolic acidosis on the activity of aortic chemoreceptor afferents and their responses to hypoxia and hypercapnia were investigated in nine cats anesthetized with alpha-chloralose, paralyzed, and artificially ventilated. This effect was compared with that on simultaneously recorded activity of carotid chemoreceptor afferents in three separate cats. The activity of a single or paucifiber preparation of chemoreceptor afferents was recorded at five steady-state levels of arterial O2 tension (PaO2) at a constant arterial CO2 tension (PaCO2) and at three levels of PaCO2 during hyperoxia (PaO2 greater than 400 Torr) before and after slow injection of 1 M lactic acid in the average dose of 2.6 +/- 0.6 mmol X kg-1. On the average, arterial pH decreased from 7.445 +/- 0.046 to 7.222 +/- 0.041 at PaO2 of 98 +/- 5 Torr and PaCO2 of 34 +/- 1 Torr. This decrease in pHa during normoxia increased the aortic chemoreceptor activity from 0.8 +/- 0.2 to 1.4 +/- 0.3 imp X s-1. Metabolic acidosis increased the excitatory effect of hypoxia and hypercapnia. The stimulatory effect of CO2 for the same increase in arterial [H+] was greater than that of metabolic acidosis, indicating a dominant effect of molecular CO2 on aortic chemoreceptors. Simultaneous measurements of carotid and aortic chemoreceptor activities showed that their responses to metabolic acidosis were qualitatively similar. Quantitatively, the response of aortic chemoreceptor afferents was less than that of carotid chemoreceptors.

Acidosis↗
PubMed1990

Role of vasopressin in renal vascular changes with hypoxemia and hypercapnic acidosis in conscious dogs.

To evaluate the role of vasopressin in the renal changes during combined acute hypoxemia and acute hypercapnic acidosis, eight conscious female mongrel dogs prepared with controlled sodium intake at 80 meq/24 h for 4 days were studied in one of the following six protocols: acute hypoxemia (80 min, arterial PO2 34 +/- 1 mmHg) followed by combined acute hypoxemia and hypercapnic acidosis (40 min, arterial PO2 35 +/- 1 mmHg, arterial PCO2 58 +/- 1 mmHg, pH = 7.20 +/- 0.01) during 1) intrarenal vehicle at 0.5 ml/min (N = 8); or 2) intrarenal infusion of vasopressin V1-receptor antagonist [d(CH2)5Tyr(Me)]AVP at 5 ng.kg-1.min-1 (N = 5); and with normal gas exchange during 3) intrarenal vasopressin at 0.05 mU.kg-1.min-1 (N = 8); 4) simultaneous infusion of intrarenal vasopressin and [d(CH2)5Tyr(Me)]AVP, 5 ng.kg-1.min-1 (N = 4); 5) intrarenal [d(CH2)5Tyr(Me)]AVP, 5 ng.kg-1.min-1 (N =4); and 6) intrarenal vehicle at 0.5 ml/min (N = 7). Intrarenal infusion of a subpressor dose of vasopressin resulted in a transient decrease in glomerular filtration rate and effective renal plasma flow over the first 20 min of infusion, suggesting that vasopressin induced nonsustained vasoconstriction of the renal vasculature. Intrarenal administration of [d(CH2)5Tyr-(Me)]AVP failed to block the fall in glomerular filtration rate or effective renal plasma flow when renal arterial blood vasopressin levels were elevated by intrarenal administration of exogenous vasopressin or by elevated systemic arterial endogenous circulating vasopressin during combined acute hypoxemia and hypercapnic acidosis. These data suggest that vasopressin (V1-receptor stimulation) does not play an important role in the renal vasoconstriction during combined acute hypoxemia and hypercapnic acidosis in conscious dogs.

Acidosis↗
PubMed1991

Is fetal acidosis in the human fetus maternogenic during labor? A reanalysis.

The purpose of this study was to investigate whether maternogenic fetal acidosis can occur at the time of labor and delivery and to evaluate the extent of the possible maternal contribution to fetal acidosis. We have therefore determined fetal and maternal lactate concentrations and acid-base status under various conditions in 589 women at the end of gestation and during labor. The results show that metabolic acidosis develops in all fetuses because of increased production of lactic acidosis is primarily of fetal origin: 1) the umbilical arteriovenous lactate differences were positive and large in steady-state conditions as well as in depressed newborns; 2) the conditions that could produce a net transfer of lactate from the mother to the fetus, namely a positive maternofetal gradient of lactate and proton, were rarely observed; and 3) the correlation between fetal and maternal lactate levels was very weak, with regression coefficients decreasing from near steady-state conditions to acute stress conditions, indicating that the increase in lactate in the fetus and mother occurs independently. This correlation indicates also that increased maternal lactate production under conditions of labor and delivery can make a contribution by affecting the rate of net transfer from fetus to mother. This is possible in approximately 6% of the fetuses.

Acidosis↗
PubMed1997

Effect of oxidative stress and acidosis on diaphragm contractile function.

Acidosis during exercise has long been associated with skeletal muscle fatigue. Recent evidence also has linked reactive oxygen species (ROS) with fatigue in skeletal muscle, including the diaphragm. We hypothesized that acidosis (designed to mimic blood pH during maximal exercise) would worsen ROS-induced depression of diaphragm contractility. The xanthine oxidase (XO) reaction in solution (0.01 U/ml) allows direct assessment of the effects of oxidant stress by ROS. Costal diaphragm fiber bundles from 24 Sprague-Dawley rats (200-250 g) were divided into four treatment groups: 1) pH 7.4, no XO (H); 2) pH 7.4 + XO (HXO); 3) pH 7.0, no XO (L); and 4) pH 7.0 + XO (LXO). Baseline twitch mechanics and force-frequency relationships (Pre) were determined in control Krebs solution (pH 7.4, no XO) before treatment. Treatment solutions were introduced, and the diaphragm underwent 2 min of contractions at 25 Hz (250 ms) at a rate of 1/s. After 10 min of recovery, the control solution was reintroduced into the bath and postcontractile function (Post) was measured. Significant reductions in twitch tension and low-frequency tetanic tension were greater in HXO and LXO compared with H, without an effect on maximal tetanic tension. One-half relaxation time was prolonged only by the combination of acidosis and oxidative stress. Addition of superoxide dismutase (50 U/ml) worsened and catalase (1,800 U/ml) attenuated XO-induced depression of diaphragm contractility. We concluded that XO induced a reduction of low-frequency tension in the fatigued diaphragm, which was mediated directly or indirectly through hydrogen peroxide and was exacerbated to a modest extent with acidosis.

Acidosis↗
PubMed1998

Catechol activation in rat rostral ventrolateral medulla after systemic isocapnic metabolic acidosis.

The catechol signal recorded using in vivo voltammetry within the rat rostral ventrolateral medulla (RVLM) can be interpreted as a catechol-specific index of the integrated activity of RVLM adrenergic barosensitive bulbospinal and nonbulbospinal neurons. To test the hypothesis that systemic acidosis leads to the activation of RVLM adrenergic neurons, the RVLM catechol signal was observed in rats after mild systemic acidosis (pH 7.20-7.25 for 30 min) induced by 1 M HCl under halothane anesthesia, controlled mechanical ventilation, and continuous infusion of Ringer lactate. Particular attention was paid to ensure that changes in mean arterial pressure (MAP) were <15 mmHg during HCl challenge. Saline administration was not associated with any significant change in all considered variables (n = 5). Mild isocapnic systemic acidosis was associated with an increase in catechol signal (n = 5), irrespective of carotid sinus nerve section (n = 5). In keeping with the aim of the study, there were minor (<15 mmHg) but significant changes in MAP among saline, intact, and deafferented groups. Changes in heart rate were not significant. In conclusion, a catechol activation is observed in the RVLM when arterial pressure is maintained during isocapnic systemic metabolic acidosis. This catechol activation appears primarily centrally mediated. Therefore, adrenergic RVLM neurons may relay inputs from the central respiratory generator to the sympathetic system and/or act as chemosensors for H+ next to the surface of the ventrolateral medulla.

Acidosis↗
PubMed2006

Regulation of renal amino acid transporters during metabolic acidosis.

The kidney plays a major role in acid-base homeostasis by adapting the excretion of acid equivalents to dietary intake and metabolism. Urinary acid excretion is mediated by the secretion of protons and titratable acids, particularly ammonia. NH(3) is synthesized in proximal tubule cells from glutamine taken up via specific amino acid transporters. We tested whether kidney amino acid transporters are regulated in mice in which metabolic acidosis was induced with NH(4)Cl. Blood gas and urine analysis confirmed metabolic acidosis. Real-time RT-PCR was performed to quantify the mRNAs of 16 amino acid transporters. The mRNA of phosphoenolpyruvate carboxykinase (PEPCK) was quantified as positive control for the regulation and that of GAPDH, as internal standard. In acidosis, the mRNA of kidney system N amino acid transporter SNAT3 (SLC38A3/SN1) showed a strong induction similar to that of PEPCK, whereas all other tested mRNAs encoding glutamine or glutamate transporters were unchanged or reduced in abundance. At the protein level, Western blotting and immunohistochemistry demonstrated an increased abundance of SNAT3 and reduced expression of the basolateral cationic amino acid/neutral amino acid exchanger subunit y(+)-LAT1 (SLC7A7). SNAT3 was localized to the basolateral membrane of the late proximal tubule S3 segment in control animals, whereas its expression was extended to the earlier S2 segment of the proximal tubule during acidosis. Our results suggest that the selective regulation of SNAT3 and y(+)LAT1 expression may serve a major role in the renal adaptation to acid secretion and thus for systemic acid-base balance.

Acidosis, Renal Tubular↗
PubMed2002

Acute acidosis-induced alteration in bone bicarbonate and phosphate.

During an acute fall in systemic pH due to a decrease in the concentration of serum bicarbonate ([HCO(3)(-)]), metabolic acidosis, there is an influx of hydrogen ions into the mineral phase of bone, buffering the decrement in pH. When bone is cultured in medium modeling acute metabolic acidosis, the influx of hydrogen ions is coupled to an efflux of sodium and potassium and a depletion of mineral carbonate. These ionic fluxes would be expected to neutralize some of the excess hydrogen ions and restore the pH toward normal. Approximately one-third of bone carbonate is located on the hydration shell of apatite, where it is readily accessible to the systemic circulation, whereas the remainder is located in less accessible areas. We hypothesize that the surface of bone would respond to acidosis in a different manner than the interior of bone, with depletion of carbonate preferentially occurring on the bone surface. We utilized a high-resolution scanning ion microprobe with secondary ion mass spectroscopy to localize the changes in bone carbonate, as measured by HCO(3)(-), and phosphate and determine their relative contribution to the buffering of hydrogen ions during acute metabolic acidosis. Neonatal mouse calvariae were incubated in control medium (pH approximately 7.44, [HCO(3)(-)] approximately 27 mM) or in medium acidified by a reduction in [HCO(3)(-)] (pH approximately 7.14, [HCO(3)(-)] approximately 13). Compared with control, after a 3-h incubation in acidic medium there is a fivefold decrease in surface HCO(3)(-) with respect to the carbon-carbon bond (C(2)) and a threefold decrease in surface HCO(3)(-) with respect to the carbon-nitrogen bond (CN) with no change in cross-sectional HCO(3)(-). Compared with control, after a 3-h incubation in acidic medium there is a 10-fold decrease in cross-sectional phosphate with respect to C(2) and a 10-fold decrease in cross-sectional phosphate with respect to CN, with no change in surface phosphate. On the bone surface, there is a fourfold depletion of HCO(3)(-) in relation to phosphate, and, in cross section, a sevenfold depletion of phosphate in relation to HCO(3)(-). Thus acute hydrogen ion buffering by bone involves preferential dissolution of surface HCO(3)(-) and of cross-sectional phosphate.

Acidosis↗
PubMed2002

Regulation of the apical Cl-/HCO-3 exchanger pendrin in rat cortical collecting duct in metabolic acidosis.

Pendrin is an apical Cl(-)/OH(-)/HCO(3)(-) exchanger in beta-intercalated cells (beta-ICs) of rat and mouse cortical collecting duct (CCD). However, little is known about its regulation in acid-base disorders. Here, we examined the regulation of pendrin in metabolic acidosis, a condition known to decrease HCO(3)(-) secretion in CCD. Rats were subjected to NH(4)Cl loading for 4 days, which resulted in metabolic acidosis. Apical Cl(-)/HCO(3)(-) exchanger activity in beta-ICs was determined as amplitude and rate of intracellular pH change when Cl was removed in isolated, microperfused CCDs. Intracellular pH was measured by single-cell digital ratiometric imaging using fluorescent pH-sensitive dye 2',7'-bis-(3-carboxypropyl)-5-(and-6)-carboxyfluorescein-AM. Pendrin mRNA expression in kidney cortex was examined by Northern blot hybridizations. Expression of pendrin protein was assessed by indirect immunofluorescence. Microperfused CCDs isolated from acidotic rats demonstrated approximately 60% reduction in apical Cl(-)/HCO(3)(-) exchanger activity in beta-ICs (P < 0.001 vs. control). Northern blot hybridizations indicated that the mRNA expression of pendrin in kidney cortex decreased by 68% in acidotic animals (P < 0.02 vs. control). Immunofluorescence labeling demonstrated significant reduction in pendrin expression in CCDs of acidotic rats. We conclude that metabolic acidosis decreases the activity of the apical Cl(-)/HCO(3)(-) exchanger in beta-ICs of the rat CCD by reducing the expression of pendrin. Adaptive downregulation of pendrin in metabolic acidosis indicates the important role of this exchanger in acid-base regulation in the CCD.

Acid-Base Equilibrium↗
PubMed2006

Metabolic acidosis has dual effects on sodium handling by rat kidney.

Chronic metabolic acidosis (CMA) is associated with decreased NaCl reabsorption in the proximal tubule (PT). However, the effect of CMA on Na(+) transport in the distal tubule (DT) and collecting duct (CD) is poorly understood. Rats were placed in metabolic cages and had access to water (control), 0.28 M NH(4)Cl, or 0.28 M KCl solutions in a pair-feeding protocol for 5 days (5d). Metabolic acidosis developed within 24 h in NH(4)Cl-, but not in KCl-loaded rats. Interestingly, NH(4)Cl- but not KCl-loaded rats exhibited a significant natriuresis after 24 h of treatment. Urinary Na(+) excretion increased from 1.94 to 2.97 meq/24 h (P < 0.001) and returned to below baseline level (1.67 meq/l) after 5d of CMA. The protein abundance of the cortical Na-Cl cotransporter (NCC) remained unchanged at 24 h, but increased significantly (P < 0.01) after 5d of CMA. The protein abundance of alpha-, beta-, and gamma-subunits of the epithelial Na(+) channel (ENaC) in the cortex decreased sharply during the first 24 h and then returned to baseline levels after 5d of CMA. Interestingly, Sgk1 expression decreased after 24 h (-31%, P < 0.05) and then returned to baseline after 5d of CMA. Nedd4-2 expression was not altered during CMA. CMA enhanced serum aldosterone levels by 54% and increased the expression of aldosterone synthase in the adrenal gland by 134% after 5d of CMA. In conclusion, metabolic acidosis has dual effects on urinary Na(+) excretion. The early natriuresis results from decreased Na(+) reabsorption in the PT and Sgk1-related decreased ENaC activity in the DT and CD. Aldosterone-induced upregulation of NCC, Sgk1, and ENaC likely contributes to the antinatriuretic phase of metabolic acidosis. This adaptation prevents Na(+) wasting and volume depletion during chronic acid insult.

Acidosis, Renal Tubular↗
PubMed2004

Acidosis impairs insulin receptor substrate-1-associated phosphoinositide 3-kinase signaling in muscle cells: consequences on proteolysis.

Chronic acidosis is a stimulus for proteolysis in muscle in vivo, but the mechanism of this response is unknown. We tested the hypothesis that acidosis or TNF-alpha, a cytokine whose production increases in acidosis, regulates proteolysis by inhibiting insulin signaling through phosphoinositide 3-kinase (PI3K). In cultured L6 myotubes, acidified (pH 7.1) media did not accelerate the basal protein degradation rate, but it inhibited insulin's ability to suppress proteolysis. Insulin receptor substrate-1 (IRS-1)-associated PI3K activity was not altered in cells acidified for 10 min but was strongly inhibited in cells incubated at pH 7.1 for 24 h. Phosphorylation of Akt was also suppressed by acidification for 24 h. Acidification did not induce changes in IRS-1 abundance, insulin-stimulated IRS-1 tyrosine phosphorylation, or the amount of PI3K p85 regulatory subunit. In contrast to acidification, TNF-alpha suppressed proteolysis in the presence or absence of insulin but had no effect on IRS-1-associated PI3K activity. To establish that the PI3K pathway can regulate protein degradation in muscle, we measured proteolysis in cells after inhibition of PI3K activity with LY-294002 or infection with an adenovirus encoding a dominant negative PI3K p85alpha-subunit. Both approaches inhibited insulin-induced suppression of proteolysis to a degree similar to that seen with acidification. We conclude that acidosis accelerates protein degradation by impairing insulin signaling through PI3K in muscle cells.

Acidosis↗
PubMed1983

Cellular response to acute respiratory acidosis in rat medullary collecting duct.

The collecting duct of the mammalian kidney is involved in urine acidification. Recent studies in the turtle bladder suggest that hydrogen ion secretion in response to elevated CO2 is regulated by insertion of hydrogen pumps into the luminal membrane of the mitochondria-rich cells. Because intercalated cells of the collecting duct are structurally similar to mitochondria-rich cells of the amphibian bladder, we studied the rat outer medullary collecting duct (OMCD) during respiratory acidosis to determine whether changes compatible with hydrogen ion secretion occur in the intercalated cells. Rats were studied during normal acid-base conditions and after 4-5 h of respiratory acidosis. After collection of physiologic data, the kidneys were fixed by in vivo perfusion and processed for electron microscopy. No changes were observed in the principal cells of the OMCD. Morphometric analysis revealed a significant increase in the surface density of the apical plasma membrane and a decrease in the number of tubulovesicular profiles in the apical region of the intercalated cells throughout the OMCD with respiratory acidosis. There were no changes in surface density of the basolateral membrane. These findings suggest that in response to respiratory acidosis there is transport of membrane from the tubulovesicular membrane compartment to the apical plasma membrane of the intercalated cells.

Acidosis, Respiratory↗
PubMed1984

Skeletal carbon dioxide stores during metabolic acidosis.

These experiments were performed to examine the buffering functions of skeletal carbon dioxide during metabolic acidosis. Acidosis of several days duration was produced in rats either by inclusion of acidogenic substances in the diet or by chemical induction of diabetic ketoacidosis. Titrimetric methods were used to measure the carbon dioxide content of bone, which was divided into readily exchangeable and slowly exchangeable pools according to a model described in the text. Acid feeding resulted in a mild acidemia (blood pH greater than 7.25), whereas profound metabolic acidemia occurred during diabetic ketoacidosis (blood pH less than 7.00). Total bone carbon dioxide was reduced during both forms of metabolic acidosis. This reduction in skeletal carbon dioxide occurred within the first 24 h after the onset of metabolic acidosis, was associated with a decline in the readily exchangeable fraction of skeletal carbon dioxide, and was directly proportional to the declines in extracellular bicarbonate concentration and plasma carbon dioxide tension.

Acidosis↗