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PubMed2000

Acid-base and endocrine effects of aldosterone and angiotensin II inhibition in metabolic acidosis in human patients.

Chronic metabolic acidosis (CMA) in human beings is characterized by increased renin-angiotensin-aldosterone (RAA) activity and cortisol secretion as well as nitrogen wasting. The purpose of this study was to examine whether and to what extent increased RAA activity (i.e., angiotensin II or aldosterone) regulates acid-base equilibrium in CMA and thus might co-determine the severity of acidosis. CMA was induced in 8 normal subjects by oral NH4Cl administration (2.1 mmol/kg body weight per day) for 7 days, followed by a 7-day period of spironolactone (100 mg, 4 times a day by mouth), followed by a 4-day period of spironolactone and losartan (100 mg, every day by mouth). NH4Cl feeding was continued during all study periods. Spironolactone resulted in exacerbation of acidosis ((HCO3)p decreased from 19.8+/-0.4 mmol/L to 17.7+/-0.6 mmol/L, P<.005) because of a large increase in endogenous acid production, as evidenced by significant increases in net acid excretion (116 to 185 mmol/day, P<.005), urinary anion gap (+31 mEq/day, P<.05), and sulfate excretion (+32 mEq/day, P<.05). Plasma potassium increased from 4.2 to 4.6 mmol/L (P<.05) because of decreased urinary potassium excretion (from 108 to 92 mmol/day, P<.05). Plasma angiotensin II, cortisol, aldosterone, urinary aldosterone, urinary tetrahydrocortisol, free cortisol, and nitrogen excretion increased significantly. The subsequent addition of losartan to spironolactone administration resulted in further exacerbation of acidosis ((HCO3)p decreased to 15.7+/-0.4 mmol/L, P<.05) and hyperkalemia (5.0 mmol/L, P<.05) with no change in plasma anion gap. Renal potassium excretion decreased from 92 to 73 mmol/day (P<.05) on day 1. Exacerbation of acidosis was accounted for by a renal mechanism, as evidenced by the significant decrease in net acid excretion and unchanged urinary unmeasured anion and nitrogen excretion. We conclude the following: (1) AT-1 blockade by losartan exacerbates acidosis by inducing a distal-tubular acidification defect. Angiotensin II is an important modulator of the renal acid excretory response to CMA in human beings. (2) Inhibition of aldosterone action by spironolactone in CMA results in an increase in endogenous acid production and exacerbates acidosis by a non-renal mechanism that is mediated, at least in part, by exacerbated hyperglucocorticoidism.

Acid-Base Equilibrium↗
PubMed2005

Convergent signaling by acidosis and receptor activator of NF-kappaB ligand (RANKL) on the calcium/calcineurin/NFAT pathway in osteoclasts.

Systemic acidosis has detrimental effects on the skeleton, and local acidosis coincides with bone destruction in inflammatory and metastatic diseases. Acidification dramatically enhances osteoclastic resorption, although the underlying mechanism has remained elusive. We investigated the effect of acidosis on the osteoclastogenic transcription factor NFATc1, which upon dephosphorylation translocates from the cytoplasm to nuclei. Lowering extracellular pH dramatically increased accumulation of NFATc1 in nuclei of rat and rabbit osteoclasts to levels comparable with those induced by the proresorptive cytokine receptor activator of NF-kappaB ligand (RANKL). Activation of NFATc1 by RANKL was mediated by means of prolonged stimulation of the Ca2+/calmodulin-dependent protein phosphatase, calcineurin. In contrast, NFATc1 activation by acidosis involved stimulation of calcineurin and suppression of NFATc1 inactivation. Acidosis, like RANKL, induced transient elevation of cytosolic free Ca2+ concentration ([Ca2+]i), which persisted in Ca2+-free media and was abolished by inhibition of phospholipase C or depletion of intracellular Ca2+ stores. Real-time-PCR of osteoclast-like cells generated from RAW 264.7 cells revealed high levels of expression of ovarian cancer G protein-coupled receptor 1, which links extracellular acidification to elevation of [Ca2+]i. In addition, the calcineurin inhibitor cyclosporin A suppressed the stimulatory effect of acidification on resorption, implicating NFAT in mediating the actions of acidosis on osteoclast activity. In summary, acidification and RANKL induce signals in osteoclasts that converge on the Ca2+/calcineurin/NFAT pathway. Acidosis acts directly on osteoclasts to activate NFATc1 and stimulate resorption.

Acidosis↗
PubMed1993

Hypomagnesemia following correction of metabolic acidosis: a case of hungry bones.

Severe symptomatic hypomagnesemia (0.15 mmol/L [0.3 mEq/L]) and hypocalcemia (1.47 mmol/L [5.9 mg/dL]) occurred in a 4-week-old infant coincidental with correction of a severe renal tubular acidosis with alkali therapy. The patient had no evidence of gastrointestinal abnormality and magnesium (Mg) intake was adequate for age and weight. Extreme renal conservation of Mg was observed, supporting the presence of Mg depletion. We suggest that Mg depletion in this infant occurred due to acidosis-induced bone demineralization and that symptomatic hypomagnesemia was precipitated by rapid remineralization accompanying correction of systemic acidosis. This patient represents a novel case of hungry bone syndrome (HBS). Since HBS has not been described previously in patients with acidosis undergoing therapy, several other factors may have contributed to this patient's severe hypomagnesemia, namely, prematurity, twin status, severity of acidosis, rapidity of correction of acidosis, catch-up growth and calcium supplementation. Clinicians should be vigilant for HBS in infants with severe acidosis undergoing alkali therapy.

Acidosis, Renal Tubular↗
PubMed1987

Acidosis facilitates spontaneous sarcoplasmic reticulum Ca2+ release in rat myocardium.

Previous studies have shown that acidosis increases myoplasmic [Ca2+] (Cai). We have investigated whether this facilitates spontaneous sarcoplasmic reticulum (SR) Ca2+ release and its functional sequelae. In unstimulated rat papillary muscles, exposure to an acid solution (produced by increasing the [CO2] of the perfusate from 5 to 20%) caused a rapid increase in the mean tissue Cai, as measured by the photoprotein aequorin. This was paralleled by an increase in spontaneous microscopic tissue motion caused by localized Ca2+ myofilament interactions, as monitored in fluctuations in the intensity of laser light scattered by the muscle. In regularly stimulated muscles, acidosis increased the size of the Ca2+ transient associated with each contraction and caused the appearance of Cai oscillations in the diastolic period. In unstimulated single myocytes, acidosis depolarized the resting membrane potential by approximately 5 mV and enhanced the frequency of spontaneous contractile waves. The small sarcolemmal depolarization associated with each contractile wave increased and occasionally initiated spontaneous action potentials. In regularly stimulated myocytes, acidosis caused de novo spontaneous contractile waves between twitches; these waves were associated with a decrease in the amplitude of the subsequent stimulated twitch. Ryanodine (2 microM) abolished all evidence of spontaneous Ca2+ release during acidosis, markedly reduced the acidosis-induced increase in aequorin light, and reduced resting tension. We conclude that acidosis increases the likelihood for the occurrence of spontaneous SR Ca2+ release, which can cause spontaneous action potentials, increase resting tension, and negatively affect twitch tension.

Acidosis↗
PubMed2004

Chronic metabolic acidosis increases mRNA levels for components of the ubiquitin-mediated proteolytic pathway in skeletal muscle of dairy cows.

Ruminants fed high-grain diets often are subjected to ruminal acidosis, which can lead to excessive absorption of lactate into the blood stream, thereby causing metabolic acidosis. Metabolic acidosis leads to body protein loss, mainly due to increased skeletal muscle degradation. Our objective was to determine the effects of metabolic acidosis on the messenger RNA (mRNA) abundance of genes encoding components of the ubiquitin-mediated proteolytic pathway in the skeletal muscle of lactating Holstein cows. Cows (n = 20) were assigned to one of two treatments: 1) control; or 2) NutriChlor 18-8, an HCl-treated supplement, which was fed to induce chronic metabolic acidosis. The longissimus muscle was biopsied before and after 10 d of treatments. Total RNA isolated from muscle tissue was hybridized with (32)P-labeled cDNA probes encoding for 14-kDa ubiquitin carrier protein E2 (14-kDa E2), ubiquitin, and C8 and C9 subunits of the 20S proteasome. Induction of metabolic acidosis increased (P < 0.05) skeletal muscle mRNA levels for ubiquitin (25%), 14-kDa E2 (34%), and the C8 subunit (20%); however, mRNA abundance for the C9 subunit was unaffected (P > 0.05). These results suggest that up-regulation of the ubiquitin-proteasome pathway is the mechanism by which metabolic acidosis stimulates muscle wasting in ruminants.

Acidosis↗
PubMed1998

Bicarbonate-based haemofiltration in the management of acute renal failure with lactic acidosis.

Continuous haemofiltration with lactate-based replacement fluid is widely used for the treatment of acute renal failure (ARF). In the presence of lactic acidosis, such treatment exacerbates rather than improves the clinical state. Continuous haemofiltration using a locally-prepared bicarbonate-based replacement fluid was performed in 200 patients over 7 years. All the patients had ARF with concomitant lactic acidosis, or demonstrated lactate intolerance after starting haemofiltration with lactate-based replacement fluids. In every case it was possible to correct the acidosis without inducing either extracellular volume expansion or hypernatraemia. In 89 patients (45%), the lactic acidosis resolved while being treated with bicarbonate-based haemofiltration. Fifty-seven patients (28.5%) survived. Significant differences at presentation in the group who survived, compared with those who died, were seen in age (50.8 vs. 57.1), mean arterial pressure (68.5 vs. 60.0 mmHg) and APACHE II score (32.1 vs. 38.9). Neither the severity of the presenting acidosis nor the arterial blood lactate appeared to predict outcome. Patients who developed ARF and lactic acidosis after cardiac surgery had a low survival rate. The combination of ARF and lactic acidosis that cannot safely be treated by haemofiltration using lactate-based replacement fluids can be managed with bicarbonate-based haemofiltration.

Acidosis, Lactic↗
PubMed1998

Influence of acidosis on cardiotonic effects of milrinone.

BACKGROUND: The present study was designed to determine whether augmentation of cardiac performance by milrinone is affected by acidosis in in vivo canine and in vitro guinea pig preparations, and to elucidate a mechanism in relation to the cyclic adenosine monophosphate (cAMP) formation. METHODS: Halothane-anesthetized, ventilated dogs were randomly assigned to a control group (arterial pH [pHa] approximately 7.4, base excess [BE] > -2 mM; n = 7), mild acidosis group (pHa approximately 7.2, BE < -9 mM; n = 7); or severe acidosis group (pHa < 7, BE < -20 mM; n = 6). Arterial blood pressure, left ventricular pressure (including maximum rate of increase, LV dP/dtmax), and pulmonary blood flow (PBF) were measured. Acidosis was induced by transient hypoxia and maintained with hydrogen chloride infusion. Hemodynamic responses to milrinone infusions at 2 and 5 microg x kg(-1) x min(-1) were then studied. In addition, left atria and right ventricular strips were dissected from guinea pig hearts and suspended in HEPES-Tyrode solution, with pH values adjusted to 7.4, 7, or 6.6. The concentration-response relation of isometric contractions for milrinone (10(-7) to 10(-4) M) and 8-bromo-cAMP (10(-4) to 10(-3) M) were determined. RESULTS: In the control group of dogs, significant increases in LV dP/dtmax (2,674 +/- 822 to 3,999 +/- 1,016 mmHg/s [means +/- SD]) and PBF (2.04 +/- 0.98 to 2.44 +/- 0.96 l/min [means +/- SD]) were seen with a milrinone infusion of 5 microg x kg(-1) x min(-1). In the mild acidosis group, 5 microg x kg(-1) x min(-1) milrinone also increased LV dP/dtmax and PBF. However, neither LV dP/dtmax nor PBF changed in the severe acidosis group. In in vitro experiments, milrinone exerted a positive inotropic effect in a concentration-dependent manner on the right ventricular preparations at pH 7.4, but not at pH 7 and 6.6, whereas no significant difference was observed in inotropic responses to 8-bromo-cAMP at pH values of 6.6, 7, and 7.4 on the right ventricular strips. In the right ventricular in vitro preparation, 10(-4) M milrinone was accompanied by a significant increase in intracellular cAMP content at apH of 7.4 but not 7. CONCLUSIONS: These results indicate that the inotropic effect of milrinone is attenuated by acidosis due, at least in part, to decreased cAMP formation in acidotic muscle.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2000

Role of pump prime in the etiology and pathogenesis of cardiopulmonary bypass-associated acidosis.

BACKGROUND: The development of metabolic acidosis during cardiopulmonary bypass (CPB) is well recognized but poorly understood. The authors hypothesized that the delivery of pump prime fluids is primarily responsible for its development. Accordingly, acid-base changes induced by the establishment of CPB were studied using two types of priming fluid (Haemaccel, a polygeline solution, and Ringer's Injection vs. Plasmalyte 148) using quantitative biophysical methods. METHODS: A prospective, double-blind, randomized trial was conducted at a tertiary institution with 22 patients undergoing CPB for coronary artery bypass surgery. Sampling of arterial blood was performed at three time intervals: before CPB (t1), 2 min after initiation of CPB at full flows (t2), and at the end of the case (t3). Measurements of Na+, K+, Mg2+, Cl-, HCO3-, phosphate, Ca2+, albumin, lactate, and arterial blood gases at each collection point were performed. Results were analyzed in a quantitative manner. RESULTS: Immediately on delivery of pump prime fluids, all patients developed a metabolic acidosis (base excess: 0. 95 mEq/l (t1) to -3.65 mEq/l (t2) (P < 0.001) for Haemaccel-Ringer's and 1.17 mEq/l (t1) to -3.20 mEq/l (t2). The decrease in base excess was the same for both primes (-4.60 vs. -4.37; not significant). However, the mechanism of metabolic acidosis was different. With the Haemaccel-Ringer's prime, the metabolic acidosis was hyperchloremic (Delta Cl-, +9.50 mEq/l; confidence interval, 7.00-11.50). With Plasmalyte 148, the acidosis was induced by an increase in unmeasured anions, most probably acetate and gluconate. The resolution of these two processes was different because the excretion of chloride was slower than that of the unmeasured anions (Delta base excess from t1 to t3 = -1.60 for Haemaccel-Ringer's vs. +1.15 for Plasmalyte 148; P = 0.0062). CONCLUSIONS: Cardiopulmonary bypass-induced metabolic acidosis appears to be iatrogenic in nature and derived from the effect of pump prime fluid on acid-base balance. The extent of such acidosis and its duration varies according to the type of pump prime.

Acid-Base Equilibrium↗
PubMed1997

Type B lactic acidosis following cardiopulmonary bypass.

OBJECTIVE: To describe, characterize, and identify the associations of postcardiac surgical lactic acidosis occurring in the absence of clinical evidence of tissue hypoperfusion. DESIGN: The preliminary study is a report of a series of observations in 12 patients. The prospective study is also observational, involving the structured collection of hemodynamic and metabolic variables in a prescribed series of patients. SETTING: Cardiac surgical intensive care unit of a university teaching hospital. PATIENTS: Twelve patients who developed an unexplained lactic acidosis after cardiac surgery are reported in the preliminary study. The prospective study involved observations in 112 consecutive patients undergoing cardiopulmonary bypass for cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Preliminary study: Cardiac index was increased before, during and after recovery from lactic acidosis. Recovery from lactic acidosis was associated with a decrease in oxygen transport index and significant increases in oxygen consumption index and oxygen extraction ratio. PROSPECTIVE STUDY: Hemodynamic, oxygen transport, and oxygen consumption variables, together with arterial blood gas and lactate concentrations, were assessed every 6 hrs for 24 hrs after surgery. Sixteen patients developed lactic acidosis (peak lactate concentration > 5.0 mmol/L). Compared with the remainder of the patients, this subgroup had longer duration of cardiopulmonary bypass (116 +/- 31 vs. 76 +/- 31 mins, p < .01), greater intraoperative hypothermia (24.9 +/- 2.0 degrees vs. 26.6 +/- 2.3 degrees C, p < .01), more frequent requirement for vasopressor agents (14/16 vs. 35/96, p < .05) and a higher frequency of hyperglycemia (15/16 vs. 28/96, p < .01). Hemodynamic variables, including cardiac index, were remarkably similar in the acidotic and nonacidotic groups. All of the acidotic patients, in both parts of this study, recovered from their acidosis. Eleven of the patients in the preliminary study and all of the 16 acidotic patients in the prospective study were ultimately discharged from the hospital. CONCLUSIONS: This report documents the occurrence of lactic acidosis in a subgroup of patients undergoing cardiopulmonary bypass. The pathogenesis of this disorder is uncertain, but it appears to not relate to inadequate oxygen delivery. Systemic vasodilation and reduced oxygen extraction appear to be features of this disorder, which has an excellent prognosis.

Acidosis, Lactic↗
PubMed2001

Renal excretion of calcium and phosphorus in premature infants with incipient late metabolic acidosis.

BACKGROUND: Premature infants receiving alimentation with cow milk-based formulas run a considerably high risk of incipient late metabolic acidosis, an early stage developing of manifest late metabolic acidosis. Is bone metabolism involved in pathophysiologic mechanisms characterizing this early stage of retention acidosis? METHODS: Urinary ionography was performed in 10 premature infants with spontaneous development of incipient late metabolic acidosis (indicated by urine pH < 5.4 on 2 consecutive days) and 10 pair-matched premature infants with normal values of urine pH; both groups were receiving full oral nutrition with the same standard formula. Moreover, in 37 premature infants with incipient late metabolic acidosis who were randomly allocated to oral therapy with 2 mmol. kg(-1). d(-1) of either NaHCO 3 or NaCl over a period of 7 days, urinary excretion of calcium and phosphorus was assessed on day 1 and day 7. RESULTS: Incipient late metabolic acidosis was accompanied by increased phosphaturia in premature infants receiving full oral nutrition. Seventeen premature infants receiving NaCl therapy (19 treatment periods) showed increased calciuria from day 1 to day 7, whereas, in 20 premature infants receiving NaHCO 3 therapy (23 treatment periods), calcium or phosphorus excretion in urine did not increase. CONCLUSIONS: The data of urinary calcium and phosphorus excretion in premature infants support the hypothesis that bone mineralization may already be impaired in the early stage of incipient late metabolic acidosis.

Acidosis, Renal Tubular↗
PubMed2006

Hypercapnic acidosis and mortality in acute lung injury.

OBJECTIVE: We tested the hypothesis that hypercapnic acidosis is associated with reduced mortality rate in patients with acute lung injury independent of changes in mechanical ventilation. DESIGN: Secondary analysis of randomized clinical trial data using hypothesis-driven multivariate logistic regression. SETTING: Randomized, multiple-center trial (n = 861) comparing 12 mL/kg to 6 mL/kg predicted body weight tidal volumes previously published by the National Institutes of Health Acute Respiratory Distress Syndrome (ARDS) Network. PATIENTS: Acute lung injury patients enrolled in a randomized, multiple-center trial (n = 861). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The adjusted odds ratio and 95% confidence intervals (CI) for 28-day mortality rate associated with hypercapnic acidosis defined as day 1 pH <7.35 and Pa(CO2) >45 mm Hg were 0.14 (95% CI 0.03-0.70, p = .016) in the 12 mL/kg predicted body weight tidal volume group and 1.18 (95% CI 0.59-2.35, p = .639) in the 6 mL/kg predicted body weight tidal volume group. Other definitions of hypercapnic acidosis spanning a range of magnitudes suggest a dose-response association between hypercapnic acidosis and 28-day mortality in the 12 mL/kg predicted body weight tidal volume group. None of our definitions of hypercapnic acidosis were associated with reduction in 28-day mortality in the 6 mL/kg predicted body weight tidal volume group. CONCLUSIONS: Hypercapnic acidosis was associated with reduced 28-day mortality in the 12 mL/kg predicted body weight tidal volume group after controlling for comorbidities and severity of lung injury. These results are consistent with a protective effect of hypercapnic acidosis against ventilator-associated lung injury that was not found when the further ongoing injury was reduced by 6 mL/kg predicted body weight tidal volumes.

Acidosis, Respiratory↗
PubMed2005

Independent contributions of hypothermia and acidosis to coagulopathy in swine.

BACKGROUND: Clinical coagulopathy occurs frequently in the presence of acidosis and hypothermia. The purpose of this study was to determine the relative contributions of acidosis and hypothermia to coagulopathy, as measured by current standard bedside and clinical laboratory analyses (i.e., bleeding time and prothrombin time). In addition, we investigated possible mechanisms of these effects using a modified prothrombin time test, thromboelastography, and thrombin kinetics analyses. An improved understanding of coagulopathy should facilitate hemorrhage control. METHODS: Twenty-four pigs were randomly allocated into normal (pH, 7.4; 39 degrees C), acidotic (pH, 7.1; 39 degrees C), hypothermic (pH, 7.4; 32 degrees C), and acidotic and hypothermic (pH, 7.1; 32 degrees C) combined groups. Acidosis was induced by the infusion of 0.2N hydrochloric acid in lactated Ringer's solution. Hypothermia was induced by using a blanket with circulating water at 4 degrees C. Development of a clinical coagulopathy was defined as a significant increase in splenic bleeding time. Measurements were compared before (pre) and 10 minutes after (post) the target condition was achieved. RESULTS: Acidosis, hypothermia, or both caused the development of coagulopathy, as indicated by 47%, 57%, and 72% increases in splenic bleeding time (p < 0.05, pre vs. post). Plasma fibrinogen concentration was decreased by 18% and 17% in the acidotic and combined groups, respectively, but not in the hypothermic group. Hypothermia caused a delay in the onset of thrombin generation, whereas acidosis primarily caused a decrease in thrombin generation rates. At 4 minutes' quench time, thrombin generation in the acidotic, hypothermic, and combined groups were 47.0%, 12.5%, and 5.7%, respectively, of the value in the control group. There were no changes in serum tumor necrosis factor-alpha and interleukin-6 in any group during the study. CONCLUSION: Acidosis and hypothermia cause a clinical coagulopathy with different thrombin generation kinetics. These results confirm the need to prevent or correct hypothermia and acidosis and indicate the need for improved techniques to monitor coagulopathy in the trauma population.

Acidosis↗
PubMedDate not supplied

Metabolic acidosis and malnutrition in dialysis patients.

Acidosis is a classic uremic toxin that causes protein catabolism, mainly by selective breakdown of skeletal muscle protein. However, the importance of acidosis is often overlooked in dialysis patients. In the presence of acidosis, there is activation of the ubiquitin-proteasome machinery as well as the branched-chain keto acid dehydrogenase, resulting in catabolism of muscle protein. Acidosis acts synergistically with other catabolic factors, such as inflammatory cytokines and insulin resistance, in inducing protein catabolism. There is ample laboratory evidence showing that correction of acidosis prevents the up-regulation of the ubiquitin-proteasome machinery and reduces protein degradation. Randomized control trials further show that acidosis in dialysis patients can be treated successfully by a higher dialysate bicarbonate or lactate concentration, or by oral bicarbonate supplement. Correction of mild acidosis in dialysis patients is effective in improving nutritional status and reducing the duration of hospitalization.

Acidosis↗
PubMed1998

On the cellular mechanism for the effect of acidosis on vascular tone.

The role of smooth muscle [Ca2+]i and membrane potential for the relaxation to hypercapnic (increased CO2) and normocapnic (unchanged CO2) acidosis is not complete understood. It is often stated that membrane hyperpolarization plays an important role but this has not been vigorously tested. In this study we investigated isolated rat cerebral small arteries under isobaric conditions. Lumen diameter was measured simultaneously with either [Ca2+]i or membrane potential, and acidosis was induced by increasing PCO2 or reducing HCO3- of the bathing solution or by adding HCI to a nominally bicarbonate-free solution. Confocal microscopy verified loading of smooth muscle cells with fluorescent dyes. Acidosis always reduced myogenic tone at transmural pressures between 20 and 120 mmHg. Acidification at a transmural pressure of 40 mmHg caused an increase in diameter and a decrease in [Ca2+]i. This was also seen in the presence of L-NNA and after depolarization with 50 mM K+. The response to hypercapnic and normocapnic acidosis was similar. However, while hypercapnic acidosis caused hyperpolarization, normocapnic acidosis caused depolarization. Dilatation, decrease of [Ca2+]i and depolarization, was also seen with reduction of pH in bicarbonate-free solution. We conclude that the isobaric relaxation to both hypercapnic and normocapnic acidosis is most likely mediated by a reduction of [Ca2+]i. Membrane potential may on the other hand not play a major role for this reduction of [Ca2+]i and it is possible that molecular CO2 has an effect on the membrane potential.

Acidosis↗
PubMed1991

The effect of acidosis on the interval-force relation and mechanical restitution in ferret papillary muscle.

1. The effect of a respiratory acidosis on the interval-force relation and on mechanical restitution was investigated in ferret papillary muscles. 2. Acidosis (pH 6.85) decreased developed force over a range of stimulation frequencies (1.0.06 Hz); the percentage decrease was greatest at the lowest stimulation frequencies. Qualitatively similar effects of acidosis on developed force were observed in the presence of the sarcoplasmic reticulum (SR) inhibitor ryanodine. 3. Mechanical restitution curves were constructed by interpolating extra-systoles at different test intervals following a train of steady-state beats. Mechanical restitution in ferret papillary muscle was triphasic: an initial, rapid, exponential increase in force with test intervals to 2 s, a further increase with test intervals between 60 and 90 s and then a slow decline, with a plateau at about 30 min (0.33 Hz, 30 degrees C). 4. Acidosis slowed the initial phase of mechanical restitution. The degree of slowing depended on the steady-state stimulation frequency, being greatest at low frequencies. 5. Inhibition of the SR abolished the initial phase of mechanical restitution, suggesting that this phase depends on Ca2+ release from the SR. 6. The strength of the first contraction after the extra-systole varied inversely with the size of the extra-systole under all conditions studied. 7. It is concluded that acidosis may inhibit the SR by altering the time required for Ca2+ recycling between contractions. This effect may alter Ca2+ release from the SR during acidosis, and may underlie the mechanical alternans (the alternation of small and large contractions) that can occur during acidosis.

Acidosis, Respiratory↗
PubMed2003

Upregulation of collecting duct aquaporin-2 by metabolic acidosis: role of vasopressin.

Metabolic acidosis is associated with alteration in fluid and electrolyte reabsorption in a number of nephron segments. However, the effects of metabolic acidosis on urine osmolality and aquaporin-2 (AQP-2) remain poorly understood. In these studies, we examined the effects of chronic metabolic acidosis on water handling by the kidney. Rats were placed in metabolic cages and subjected to water (control) or 280 mM NH(4)Cl loading for 120 h to induce metabolic acidosis. The results indicated a significant increase in urine osmolality with no change in urine volume or urinary Na(+) excretion in acid-loaded animals. This effect was independent of alteration in fluid intake or salt/Cl(-) loading. Immunoblotting and Northern hybridization studies indicated that AQP-2 protein abundance and mRNA expression levels increased significantly along the collecting duct system of NH(4)Cl-but not NaCl-loaded animals. RIA results indicated that metabolic acidosis was associated with a fourfold increase in circulating levels of vasopressin (AVP) and a significant increase in brain AVP mRNA expression levels. In conclusion, metabolic acidosis upregulates the expression levels of AQP-2 and increases urine osmolality, suggesting an adaptive increase in water reabsorption in the collecting duct. A concomitant increase in AVP synthesis and secretion likely plays an essential role in the adaptation of AQP-2 in metabolic acidosis.

Acidosis↗
PubMed1991

Effect of partial Na pump and Na-H exchange inhibition on [Ca]i during acidosis in cardiac cells.

This study investigated the effects of partial Na pump inhibition and Na-H exchange inhibition on contractile function, intracellular pH (pHi), and intracellular Ca concentration ([Ca]i) during intracellular acidosis, using the fluorescent dyes 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein and fura-2 in isolated cardiac cells of adult rabbits. Intracellular acidosis with normal extracellular pH was induced by an NH4Cl (10 mM) prepulse technique. A nontoxic concentration (0.5 microM) of ouabain was used to inhibit the Na pump. 5-(N-ethyl-N-isopropyl)amiloride (EIPA) was used to inhibit Na-H exchange. In both the absence and presence of ouabain, pHi fell transiently and then recovered after removal of NH4Cl. Ouabain did not alter the pHi changes observed after removal of NH4Cl. Diastolic and systolic [Ca]i increased during acidosis after NH4Cl removal. In the presence of ouabain, the increase in [Ca]i during acidosis was greater than that in the absence of this drug. Ouabain enhanced the recovery of contractile function during acidosis. In both the absence and presence of ouabain, Na-H exchange inhibition by EIPA reduced the recovery of pHi and mechanical function and the increase in [Ca]i, which were normally observed after NH4Cl removal. These data suggest that in adult rabbit myocytes the Na pump inhibition enhances the increase in [Ca]i during acidosis, and the Na-H exchange inhibition reduces it. The [Ca]i increase during acidosis may be in part due to the altered Na-Ca exchange, which in turn results from the increased Na-H exchange.

Acidosis↗
PubMed1994

Enhanced Na(+)-H+ exchanger activity and NHE-1 mRNA levels in human lymphocytes during metabolic acidosis.

It has recently been demonstrated that uremic metabolic acidosis and experimental metabolic acidosis caused by ingestion of ammonium chloride coincide with increased Na(+)-H+ exchanger (NHE-1) activity in human blood cells. In the present study, we investigated whether an increased level of NHE-1 specific mRNA in human lymphocytes during the course of an experimental metabolic acidosis could explain the enhanced transport activity during metabolic acidosis. Six healthy individuals were studied before and after 5 days of taking 15 g of ammonium chloride daily. Plasma pH and bicarbonate decreased significantly, from 7.42 +/- 0.027 to 7.28 +/- 0.05 and from 26.7 +/- 2.0 to 15.6 +/- 2.9 mM, respectively. Basal cytosolic pH (pHi) and Na(+)-H+ exchange activity were measured in lymphocytes loaded with the fluorescent pHi indicator 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein. Basal pHi remained unchanged during metabolic acidosis (7.03 +/- 0.07 vs. 7.03 +/- 0.06). Ethylisopropylamiloride-sensitive pHi recovery increased from 0.046 +/- 0.007 to 0.076 +/- 0.012 dpHi/min (P < 0.0001). The transcript level of NHE-1 mRNA was measured by reverse-transcription polymerase chain reaction in comparison with a constitutively expressed reference gene (glyceraldehyde-3-phosphate dehydrogenase). NHE-1 mRNA in human lymphocytes increased 1.5-fold in metabolic acidosis. These data suggest that the increased Na(+)-H+ exchange activity in metabolic acidosis may be caused by de novo synthesis of antiport protein.

Acidosis↗