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PubMed1987

Effects of hypoxia, hyperkalemia, and metabolic acidosis on canine subendocardial action potential conduction.

We have studied the individual and combined effects of elevated external potassium concentration (8 mM [K+], metabolic acidosis (pH = 6.8), and hypoxia at different stimulation 400 milliseconds) on Purkinje (P) and ventricular (V) conduction velocities and on Purkinje-ventricular junctional conduction delay (PVJ delay) in in vitro preparations from canine ventricles. Elevated [K+] had opposite effects on P and V velocities, increasing V velocity by 8% while reducing P velocity by 7%. Acidosis reduced P velocity by 9% while reducing V velocity by only 4%. Hypoxia and rapid stimulation rates had no significant effect on either P or V velocities. All test solutions (except hypoxia alone) significantly increased the PVJ delay. The magnitude of the increase in PVJ delay was much greater than the effects on either P or V velocity. In addition, hypoxia and rapid stimulation augmented the increase in PVJ delay in the presence of elevated [K+] and/or acidosis. The special features of conduction at the PV junctional sites may produce altered pathways of excitation of the ventricles during myocardial ischemia.

Acidosis↗
PubMed1991

Mechanical alternans during acidosis in ferret heart muscle.

Acidosis leads to mechanical alternans (i.e., alternation of large and small contractions) in ferret papillary muscles. This alternation in the size of the contraction is paralleled by alternation in the size of the intracellular Ca2+ transient (monitored using the photoprotein aequorin). In isolated myocytes, the large contraction is accompanied by a prolonged action potential. Mechanical alternans also can be induced by acidosis in isolated myocytes during a train of voltage-clamp pulses. Thus, it appears unlikely that the mechanical alternans is secondary to changes in action potential duration; it is more likely that the observed changes in action potential duration are secondary to changes in the size of the Ca2+ transient. The observation that a Ca2(+)-activated inward current also shows alternation during mechanical alternans provides a possible mechanism for the link between Ca2+ and action potential duration. The alternation in the size of the Ca2+ transient may be secondary to the slowed mechanical restitution observed in papillary muscles during acidosis. This also could explain the observation that decreasing stimulation rate can abolish the alternans.

Acidosis↗
PubMed1992

Endothelin reverses the effects of acidosis on the intracellular Ca2+ transient and contractility in ferret myocardium.

Endothelin may play an important role in modulating myocardial contractility under certain pathophysiological conditions. To determine whether endothelin beneficially modulates myocardial contractility in the common clinical condition of acidosis, we compared the effects of endothelin-1 on intracellular Ca2+ transients and isometric contractions under normal (extracellular pH [pH(o)] 7.4) and acidotic (pH(o) 6.4) conditions in ferret papillary muscles (n = 33) loaded with the Ca(2+)-regulated bioluminescent indicator aequorin. A pH(o) of 6.4 was induced by replacing 92% of HCO3- with Cl- in the bathing medium. The effects of endothelin at pH(o) 6.4 differed from the effects at pH(o) 7.4 in that 1) the minimally effective concentration of endothelin was 30-fold lower (1 x 10(-10) M at pH(o) 6.4; 3 x 10(-9) M at pH(o) 7.4) and the concentration-response curve of endothelin was significantly shifted to the left with a decrease in log EC50 from -7.83 +/- 0.13 to -8.92 +/- 0.10 (p less than 0.001), indicating an increased sensitivity of myocardium to endothelin; 2) endothelin produced an increase of approximately 375% in tension development at pH(o) 6.4 (approximately 62% at pH(o) 7.4) (p less than 0.001) without increasing peak [Ca2+]i (approximately 13% increase at pH(o) 7.4, p less than 0.001), indicating an increase in myofilament Ca2+ responsiveness; and 3) endothelin significantly abbreviated (approximately -19%, p less than 0.001) the prolonged intracellular Ca2+ transient induced by acidosis (pH(o) 6.4). In addition, pretreatment with 10 microM of the Na(+)-H+ exchange inhibitor 5-(N-methyl-N-isobutyl)-amiloride significantly attenuated endothelin-induced effects on the intracellular Ca2+ transient and contraction during acidosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis↗
PubMed1995

Neonatal ischemic neuroprotection by modest hypothermia is associated with attenuated brain acidosis.

BACKGROUND AND PURPOSE: A 2.9 degrees C reduction in the intraischemic rectal temperature of neonatal piglets is associated with less brain damage compared with animals with normothermic rectal temperatures. This investigation studied one potential mechanism for this observation: better maintenance of energy stores and less brain acidosis secondary to reduced metabolic activity associated with modest hypothermia. METHODS: 31P MR spectroscopy was used to study piglets before, during, and after 15 minutes of partial brain ischemia with intraischemic rectal temperatures of either 38.3 +/- 0.4 degrees C (n = 10, normothermic) or 35.4 +/- 0.5 degrees C (n = 10, hypothermic). Animals were followed up for up to 72 hours after ischemia and were evaluated clinically and by brain histology. RESULTS: Values for pHi remained 0.15 to 0.20 pH units greater in modestly hypothermic than in normothermic piglets during ischemia and the initial 30 minutes after ischemia (P = .049, group effect). Phosphocreatine, beta-ATP, and inorganic phosphorus were similar between groups. The relationship between the intraischemic energy state and subsequent clinical evidence of brain damage (irrespective of group assignment) revealed lower pHi over the last 7 minutes of ischemia for abnormal compared with normal piglets (5.98 +/- 0.22 versus 6.39 +/- 0.24, respectively; P = .002). In contrast, intraischemic beta-ATP (41 +/- 19% versus 57 +/- 21% of control) and inorganic phosphorus (273 +/- 31% versus 224 +/- 92% of control) for abnormal and normal piglets, respectively, did not differ between groups. CONCLUSIONS: Intraischemic modest hypothermia attenuates the severity of brain acidosis during and 30 minutes after ischemia compared with normothermic animals and supports the concept that attenuated brain acidosis is a potential mechanism by which hypothermia may reduce ischemic brain damage.

Acidosis↗
PubMed1986

Effects of aminophylline and salbutamol on diaphragmatic force during compensated metabolic acidosis.

We investigated the effects of aminophylline and salbutamol on tetanic force generated by the diaphragm during compensated metabolic acidosis in dogs. Anesthetized, mechanically ventilated animals were prepared with an open thorax. A cast was placed around the abdomen to maintain length and geometry of the diaphragm during contractions. A thin-walled latex balloon was positioned beneath the diaphragm to measure transdiaphragmatic pressure (Pdi). Pdi served as the index of diaphragmatic force of contraction. We measured Pdi during supramaximal phrenic stimulation at low and high frequencies and also during spontaneous inspiratory efforts for a constant diaphragmatic EMG activity. Compensated metabolic acidosis significantly reduced Pdi at all stimulation frequencies (p less than 0.05). The mean percent decrease at low frequencies was greater than at high (p less than 0.05). Pdi was decreased during spontaneous contractions as well (p less than 0.05). Administration of aminophylline significantly improved Pdi at all frequencies of phrenic stimulation (p less than 0.05) and during spontaneous inspiratory efforts (p less than 0.05). Infusion of salbutamol did not have a significant effect on Pdi at any frequency of stimulation but did produce a small potentiating effect during spontaneous contractions (p less than 0.05). We also recorded and analyzed the Pdi response to a single supramaximal impulse to the phrenic nerve, referred to as a twitch, to gain insight into possible cellular mechanisms underlying alterations in tetanic force of contraction. Compensated metabolic acidosis led to a significant reduction in peak twitch tension (PTT) (p less than 0.05) and half relaxation time (1/2RT) (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis↗
PubMed2002

Hypercapnic acidosis is protective in an in vivo model of ventilator-induced lung injury.

To investigate whether hypercapnic acidosis protects against ventilator-induced lung injury (VILI) in vivo, we subjected 12 anesthetized, paralyzed rabbits to high tidal volume ventilation (25 cc/kg) at 32 breaths per minute and zero positive end-expiratory pressure for 4 hours. Each rabbit was randomized to receive either an FI(CO(2)) to achieve eucapnia (Pa(CO(2)) approximately 40 mm Hg; n = 6) or hypercapnic acidosis (Pa(CO(2)) 80-100 mm Hg; n = 6). Injury was assessed by measuring differences between the two groups' respiratory mechanics, gas exchange, wet:dry weight, bronchoalveolar lavage fluid protein concentration and cell count, and injury score. The eucapnic group showed significantly higher plateau pressures (27.0 +/- 2.5 versus 20.9 +/- 3.0; p = 0.016), change in Pa(O(2)) (165.2 +/- 19.4 versus 77.3 +/- 87.9 mm Hg; p = 0.02), wet:dry weight (9.7 +/- 2.3 versus 6.6 +/- 1.8; p = 0.04), bronchoalveolar lavage protein concentration (1,350 +/- 228 versus 656 +/- 511 micro g/ml; p = 0.03), cell count (6.86 x 10(5) +/- 0.18 x 10(5) versus 2.84 x 10(5) +/- 0.28 x 10(5) nucleated cells/ml; p = 0.021), and injury score (7.0 +/- 3.3 versus 0.7 +/- 0.9; p < 0.0001). We conclude that hypercapnic acidosis is protective against VILI in this model.

Acidosis, Respiratory↗
PubMed2003

Hypercapnic acidosis attenuates endotoxin-induced nuclear factor-[kappa]B activation.

Although permissive hypercapnia improves the prognosis of patients with acute respiratory distress syndrome, it has not been conclusively determined whether hypercapnic acidosis (HA) is harmful or beneficial to sustained inflammation of the lung. The present study was designed to explore the molecular mechanism of HA in modifying lipopolysaccharide (LPS)-associated signals in pulmonary endothelial cells. LPS elicited degradation of inhibitory protein kappaB (IkappaB)-alpha, but not IkappaB-beta, resulting in activation of nuclear factor (NF)-kappaB in human pulmonary artery endothelial cells. Exposure to HA significantly attenuated LPS-induced NF-kappaB activation through suppressing IkappaB-alpha degradation. Isocapnic acidosis and buffered hypercapnia showed qualitatively similar but quantitatively smaller effects. HA did not attenuate the LPS-enhanced activation of activator protein-1. Following the reduced NF-kappaB activation, HA suppressed the mRNA and protein levels of intercellular adhesion molecule-1 and interleukin-8, resulting in a decrease in both lactate dehydrogenase release into the medium and neutrophil adherence to LPS-activated human pulmonary artery endothelial cells. In contrast, HA did not inhibit LPS-enhanced neutrophil expression of integrin, Mac-1. Based on these findings, we concluded that hypercapnic acidosis would have anti-inflammatory effects essentially through a mechanism inhibiting NF-kappaB activation, leading to downregulation of intercellular adhesion molecule-1 and interleukin-8, which in turn inhibits neutrophil adherence to pulmonary endothelial cells.

Acidosis, Respiratory↗
PubMed1971

Regulatory mechanisms of hemoglobin oxygen affinity in acidosis and alkalosis.

The recent reports of the effect of 2,3-diphosphoglycerate (2,3-DPG) on hemoglobin affinity for oxygen suggested that this substance may play a role in man's adaptation to acidosis and alkalosis.A study of the effect of induced acidosis and alkalosis on the oxyhemoglobin dissociation curve of normal man was therefore carried out, and the mechanisms involved in the physiological regulation of hemoglobin oxygen affinity examined.In acute changes of plasma pH there was no alteration in red cell 2,3-DPG content. However, there were changes in hemoglobin oxygen affinity and these correlated with changes in mean corpuscular hemoglobin concentration (MCHC). With maintained acidosis and alkalosis, red cell 2,3-DPG content was altered and correlated with the changes in hemoglobin oxygen affinity. Both of these mechanisms shift the hemoglobin oxygen dissociation curve opposite to the direct pH (Bohr) effect, and providing the rate of pH change is neither too rapid nor too large, they counteract the direct pH effect and the in vivo hemoglobin oxygen affinity remains unchanged. It is also shown that approximately 35% of the change in hemoglobin oxygen affinity resulting from an alteration in red cell 2,3-DPG, is explained by effect of 2,3-DPG on the red cell pH.

Acidosis↗
PubMed1973

Glucose utilization and production by the dog kidney in vivo in metabolic acidosis and alkalosis.

Using D-[1-(14)C]glucose as a tracer, renal glucose utilization and production was measured in chronic metabolic acidosis and alkalosis in dog kidney in vivo. In six experiments in acidosis, mean total renal glucose production was 4.447+/-1.655 SE mumol/min and glucose utilization was 4.187+/-0.576 SE mumol/min. In five alkalotic experiments it was found that mean total glucose production was 12.227+/-2.026 SE mumol/min and glucose utilization was 18.186+/-2.054 SE mumol/min. Renal glucose utilization and production are therefore significantly higher in alkalosis than in acidosis in vivo. Since glucose production is maximal under conditions when glutamine extraction is minimal (i.e. alkalosis), it is apparent that in alkalosis glutamine is not a major precursor of glucose.

Acidosis↗
PubMed1974

Studies on the pathogenesis of type I (distal) renal tubular acidosis as revealed by the urinary PCO2 tensions.

This study was designed to investigate the pathogenesis of type I (distal) renal tubular acidosis. Urinary and blood Pco(2) tensions were determined when the pH of the urine was equal to or exceeded the corresponding blood pH. This provided an indication of net hydrogen ion secretion in the distal nephron. In 16 normal subjects, the Pco(2) of the urine exceeded blood values (U-B Pco(2)) by 32.7+/-3.1 mm Hg. In contrast, the urinary Pco(2) tensions in 10 patients with type I (distal) renal tubular acidosis were not significantly greater than blood values (U-B Pco(2) = 2.0+/-2.2 mm Hg). These results indicate that type I (distal) renal tubular acidosis is caused by failure of the cells of the distal nephron to secrete hydrogen ions rather than to gradient-limited hydrogen ion addition to the urine. This is suggested by the fact that urinary Pco(2) levels should be higher than blood Pco(2) levels when hydrogen ions are secreted into urine containing bicarbonate in the distal nephron and they were not in this study despite the presence of a favorable hydrogen ion gradient (tubular fluid pH exceeded blood pH).

Acidosis, Renal Tubular↗
PubMed1985

Validation of the difference in urine and blood carbon dioxide tension during bicarbonate loading as an index of distal nephron acidification in experimental models of distal renal tubular acidosis.

Recent classifications of the several pathophysiologic types of distal renal tubular acidosis (secretory, voltage dependent, and gradient) have been based on the response of acidification parameters to a series of provocative maneuvers in vivo and in vitro. A reduction in the difference in urine and blood CO2 tension during bicarbonate loading (U-B pCO2 gradient), a widely applied parameter, has been employed as an index of reduced distal nephron proton secretion. This study was designed to test the validity of the U-B pCO2 gradient in a variety of experimental models of distal renal tubular acidosis by measuring and comparing disequilibrium pH (a direct technique to detect H+ secretion in situ) with the pCO2 in the papillary collecting duct of the rat in vivo during bicarbonate loading. Chronic amiloride, lithium chloride, and amphotericin-B administration, and the post-obstructed kidney models were employed. Amiloride resulted in an acidification defect which did not respond to sulfate infusion (urine pH = 6.15 +/- 0.08), and was associated with an obliteration of the acid disequilibrium pH (-0.26 +/- 0.05- -0.08 +/- 0.03) and reduction in papillary pCO2 (116.9 +/- 3.2 - 66.9 +/- 2.5 mmHg). The defect induced by lithium administration responded to Na2SO4 (urine pH = 5.21 +/- 0.06) but was similar to amiloride with respect to the observed reduction in disequilibrium pH (-0.04 +/- 0.02) and pCO2 (90.3 +/- 3.0 mmHg). The post-obstructed kidney model was characterized by an abnormally alkaline urine pH unresponsive to sulfate (6.59 +/- 0.06) and a reduction in disequilibrium pH (+0.02 +/- 0.06) and pCO2 (77.6 +/- 3.6 mmHg). Amphotericin-B resulted in a gradient defect as characterized by excretion of an acid urine after infusion of sodium sulfate (5.13 +/- 0.06). Unlike other models, however, amphotericin-B was associated with a significant acid disequilibrium pH (-0.11 +/- 0.05) and an appropriately elevated urine pCO2 (119.8 +/- 6.4 mmHg) which did not differ from the respective values in control rats. Thus, these findings support the use of the U-B pCO2 as a reliable means of demonstrating impaired distal nephron proton secretion in secretory and voltage-dependent forms of distal renal tubular acidosis (RTA) and supports the view that proton secretion is not impaired in gradient forms of distal RTA.

Absorption↗
PubMed1986

Ammonia production by isolated mouse proximal tubules perfused in vitro. Effect of metabolic acidosis.

We examined the effects of metabolic acidosis in vivo and reduced bath and luminal pH in vitro on total NH3 (NH3 + NH+4) production rates by isolated mouse proximal tubule segments. Midproximal tubule segments were obtained from mice with NH4Cl-induced metabolic acidosis and from nonacidotic controls. The segments were perfused with modified Krebs-Ringer bicarbonate (KRB) buffer, incubated in KRB buffer containing 0.5 mM L-glutamine and 1.0 mM sodium acetate, and gassed with 95% O2 and 5% CO2. Isolated unperfused and perfused proximal tubules from acidotic mice produced total NH3 at higher rates than corresponding tubules from nonacidotic mice. Perfusion of the tubular lumen stimulated total NH3 production by tubules from both acidotic and nonacidotic mice. In contrast, lowering the bath pH to 7.0 by lowering the HCO3- concentration increased total NH3 production rates by tubules from nonacidotic mice but not by tubules from acidotic mice. Reducing the HCO3- concentration of the bath buffer to 10 mM while maintaining a pH of 7.4 had no significant effect on total NH3 production by tubules from nonacidotic mice. Lowering the luminal fluid pH by reducing the perfusate HCO-3 from 25 mM to 10, 5, or 1.2 mM while maintaining a bath pH of 7.4 lowered collected luminal fluid pH but had no effect on total NH3 production by proximal tubules from nonacidotic mice. These observations demonstrated that metabolic acidosis in vivo stimulated total NH3 production in isolated mouse proximal tubule segments and that low peritubular pH and HCO-3 stimulated total NH3 production by proximal tubule segments from nonacidotic mice in vitro.

Acidosis↗
PubMed1987

Parallel adaptation of the rabbit renal cortical sodium/proton antiporter and sodium/bicarbonate cotransporter in metabolic acidosis and alkalosis.

Recent studies have shown that the bicarbonate reabsorptive capacity of the proximal tubule is increased in metabolic acidosis. For net bicarbonate reabsorption to be regulated, there may be changes in the rate of apical H+ secretion as well as in the basolateral base exit step. The present studies examined the rate of Na+/H+ exchange (acridine orange method) and Na+/HCO3 cotransport (22Na uptake) in apical and basolateral membranes prepared from the rabbit renal cortex by sucrose density gradient centrifugation. NH4Cl loading was used to produce acidosis (arterial pH, 7.27 +/- 0.03), and Cl-deficient diet with furosemide was used to produce alkalosis (arterial pH, 7.51 +/- 0.02). Maximal transport rate (Vmax) of Na+/H+ antiporter and Na+/HCO3 cotransporter were inversely related with plasma bicarbonate concentration from 6 to 39 mM. Furthermore, the maximal transport rates of both systems varied in parallel; when Vmax for the Na+/HCO3 cotransporter was plotted against Vmax for the Na+/H+ antiporter for each of the 24 groups of rabbits, the regression coefficient (r) was 0.648 (P less than 0.001). There was no effect of acidosis or alkalosis on affinity for Na+ of either transporter. We conclude that both apical and basolateral H+/HCO3 transporters adapt during acid-base disturbances, and that the maximal transport rates of both systems vary in parallel during such acid-base perturbations.

Acidosis↗
PubMed1992

The ATP-sensitive K+ channel mediates hypotension in endotoxemia and hypoxic lactic acidosis in dog.

Endotoxemia causes hypotension characterized by vasodilation and resistance to vasopressor agents. The molecular mechanisms responsible for these changes are unclear. The ATP-regulated K+ (K+ATP) channel has recently been found to be an important modulator of vascular smooth muscle tone which may transduce local metabolic changes into alterations of vascular flow. We report here that in endotoxic hypotension, the sulfonylurea glyburide, a specific inhibitor for the K+ATP channel, caused vasoconstriction and restoration of blood pressure. Glyburide also induced vasoconstriction and restoration of blood pressure in the vasodilatory hypotension caused by hypoxic lactic acidosis, while it was ineffective in the hypotension induced by sodium nitroprusside. Thus, vasodilation and hypotension in septic shock are, at least in part, due to activation of the K+ATP channel in vascular smooth muscle, and anaerobic metabolism with acidosis is a sufficient stimulus for channel activation. Because anaerobic metabolism and acidosis are common features in shock of any etiology, sulfonylureas may be effective therapeutic agents in the treatment of shock.

Acidosis, Lactic↗
PubMed1988

Post-convulsive lactic acidosis in diabetic patients.

Diabetic patients have an increased risk of developing epileptic convulsions compared with the non-diabetic population. Generalised seizures may cause a severe, but self-correcting, lactic acidosis for which specific treatment is both unnecessary and potentially hazardous. Two cases of post-convulsive lactic acidosis occurring in diabetic patients are reported. The cause of the acidosis was confirmed only in retrospect in each case.

Acidosis, Lactic↗
PubMed2002

Continuous pH monitoring using the Paratrend 7 inserted into a peripheral vein in a patient with shock and congenital lactic acidosis.

The authors present a 25-year-old woman who was admitted to the ICU for treatment of shock, respiratory failure, and acidosis related to congenital lactic acidosis from pyruvate dehydrogenase deficiency. To aid in ongoing management of the metabolic acidosis, the Paratrend blood gas monitoring sensor was inserted through a peripheral venous site to provide a continuous measurement of pH and partial pressure of carbon dioxide (Pco2). With the venous insertion of the Paratrend, a clinically useful correlation with arterial blood gas values was noted. Linear regression analysis of the pH values from the venous blood gas analyses and the Paratrend monitor revealed r2 = 0.71 with p = 0.001 and r2 = 0.78 with a p = 0.0003 for the Pco2 values. Our preliminary experience suggests that venous placement of the Paratrend monitor can be used to provide clinically useful, continuous measurement of pH and Pco2.

Acidosis, Lactic↗
PubMed1976

Renal tubular acidosis: practical guides to diagnosis and treatment.

The syndrome of renal tubular acidosis in some one of its various forms should be suspected when an infant or child has failure to thrive, metabolic acidosis, constipation, diarrhea, vomiting, anorexia, polyuria, or dehydration in infancy. Confirmatory biochemical findings include an inappropriately high urinary pH, inadequate acid excretion and/or abnormal tubular reabsorption of filtered bicarbonate. Growth can be normal when there is sustained correction of the metabolic acidosis through appropriate alkaline therapy.

Acidosis, Renal Tubular↗
PubMed1984

Grocery store baking soda. A source of sodium bicarbonate in the management of chronic metabolic acidosis.

Oral sodium bicarbonate is used to treat metabolic acidosis in patients with renal tubular acidosis. Since infants and young children are unable to swallow tablets, those affected must ingest sodium bicarbonate in a powder or liquid form. Pharmacy-weighed sodium bicarbonate is expensive and inconvenient to obtain; some pharmacists are reluctant to provide it. We determined that the sodium bicarbonate contained in 8-oz boxes of Arm and Hammer Baking Soda was sufficiently constant in weight that, dissolved in water to a given volume, it yielded a quantitatively acceptable therapeutic solution of sodium bicarbonate at a cost of approximately 3 percent of that of pharmacy-weighed sodium bicarbonate. Grocery store baking soda can be a safe, economical, and convenient source of sodium bicarbonate for the treatment of chronic metabolic acidosis in infants and young children.

Acidosis, Renal Tubular↗