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PubMed2000

Acidosis inhibits endothelial cell apoptosis and function and induces basic fibroblast growth factor and vascular endothelial growth factor expression.

Endothelial cells are exposed to an acidotic environment in a variety of pathological and physiological conditions. However, the effect of acidosis on endothelial cell function is still largely unknown, and it was evaluated in the present study. Bovine aortic endothelial cells (BAECs) were grown in bicarbonate buffer equilibrated either with 20% CO(2) (pH 7.0, acidosis) or 5% CO(2) (pH 7.4, control). Acidosis inhibited BAEC proliferation in 10% FCS, whereas by day 7 in serum-free medium, cell number was 3-fold higher in acidotic cells than in control cells. Serum deprivation enhanced BAEC apoptosis, and apoptotic cell death was markedly inhibited by acidosis. Additionally, acidosis inhibited FCS-stimulated migration in a modified Boyden chamber assay and FCS-stimulated differentiation into capillary-like structures on reconstituted basement membrane proteins. Conditioned media from BAECs cultured for 48 hours either at pH 7.0 or pH 7.4 enhanced BAEC proliferation and migration at pH 7.4, and both effects were more marked with conditioned medium from BAECs grown in acidotic than in control conditions. Acidosis enhanced vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) mRNA expression as well as bFGF secretion, and a blocking bFGF antibody inhibited enhanced BAEC migration in response to conditioned medium from acidotic cells. These results show that acidosis protects endothelial cells from apoptosis and inhibits their proangiogenic behavior despite enhanced VEGF and bFGF mRNA expression and bFGF secretion.

Acidosis↗
PubMed1997

Role of potassium channels in relaxations of isolated canine basilar arteries to acidosis.

BACKGROUND AND PURPOSE: Concentration of hydrogen ions is an important regulator of cerebral arterial tone under physiological and pathological conditions. Previous studies demonstrated that in cerebral arteries, relaxations to hypercapnia are due to decrease in extracellular pH. The present study was designed to determine the role of potassium channels in mediation of cerebral arterial relaxations induced by extracellular acidosis. METHODS: Rings of canine basilar arteries without endothelium were suspended for isometric force recording. Acidosis (pH 7.3 to 7.0) was produced by incremental addition of hydrochloric acid (1.0N). The concentration of hydrogen ions was continuously monitored with a pH meter. RESULTS: During contractions to UTP, acidosis (pH 7.3 to 7.0) induced pH-dependent relaxations. These relaxations were abolished in arteries contracted by potassium chloride (20 mmol/L). A nonselective potassium channel inhibitor, BaCl2 (10(-4) and 10(-4) mol/L), and an ATP-sensitive potassium channel inhibitor, glyburide (5 x 10(-6) mol/L), significantly reduced relaxations to acidosis. Furthermore, BaCl2 (10(-4) mol/L) and glyburide (5 x 10(-6) mol/L) abolished relaxations to an ATP-sensitive potassium channel opener, cromakalim (10(-8) to 3 x 10(-5) mol/L). However, these potassium channel inhibitors did not affect relaxations to a voltage-dependent calcium channel inhibitor, diltiazem (10(-8) to 10(-4) mol/L), and glyburide (5 x 10(-6) mol/L) did not alter relaxations to a nitric oxide donor, SIN-1 (10(-9) to 10(-4) mol/L). A calcium-activated potassium channel inhibitor, charybdotoxin (10(-7) mol/L), and a delayed rectifier potassium channel inhibitor, 4-aminopyridine (10(-3) mol/L), did not affect relaxations to acidosis. CONCLUSIONS: These results suggest that extracellular acidosis causes relaxations of cerebral arteries in part by activation of potassium channels. ATP-sensitive potassium channels appear to contribute to acidosis-induced decrease in cerebral arterial tone.

4-Aminopyridine↗
PubMed1999

Effects of glucose and PaO2 modulation on cortical intracellular acidosis, NADH redox state, and infarction in the ischemic penumbra.

BACKGROUND AND PURPOSE: During focal cerebral ischemia, the ischemic penumbra or border-zone regions of moderate cortical blood flow reductions have a heterogeneous development of intracellular cortical acidosis. This experiment tested the hypotheses that (1) this acidosis is secondary to glucose utilization and (2) this intracellular acidosis leads to recruitment of potentially salvageable tissue into infarction. METHODS: Brain pHi, regional cortical blood flow, and NADH redox state were measured by in vivo fluorescent imaging, and infarct volume was assessed by triphenyltetrazolium chloride histology. Thirty fasted rabbits divided into 6 groups of 5 each were subjected to 4 hours of permanent focal ischemia in the presence of hypoglycemia ( approximately 2.8 mmol/L), moderate hyperglycemia ( approximately 11 mmol/L), and severe hyperglycemia (>28 mmol/L) under either normoxia or moderate hypoxia (PaO2 approximately 50 mm Hg). RESULTS: Preischemic hyperglycemia led to a more pronounced intracellular acidosis and retardation of NADH regeneration than in the hypoglycemia groups under both normoxia and moderate hypoxia in the ischemic penumbra. For example, 4 hours after ischemia, brain pHi in the severe hyperglycemia/normoxia group measured 6.46, compared with 6.84 in the hypoglycemia/normoxia group (P<0.01), and NADH fluorescence measured 173% compared with 114%. Infarct volume in the severe hyperglycemia/normoxia group measured 35.1+/-6.9% of total hemispheric volume, compared with 13.5+/-4.2% in the hypoglycemia/normoxia group (P<0.01). CONCLUSIONS: Hyperglycemia significantly worsened both cortical intracellular brain acidosis and mitochondrial function in the ischemic penumbra. This supports the hypothesis that the evolution of acidosis in the ischemic penumbra is related to glucose utilization. Furthermore, the observation that hypoglycemia significantly decreased infarct size supports the postulate that cortical acidosis leads to recruitment of ischemic penumbra into infarction.

Acidosis↗
PubMed2002

Role of endothelial nitric oxide and smooth muscle potassium channels in cerebral arteriolar dilation in response to acidosis.

BACKGROUND AND PURPOSE: Potassium channels or nitric oxide or both are major mediators of acidosis-induced dilation in the cerebral circulation. However, these contributions depend on a variety of factors such as species and vessel location. The present study was designed to clarify whether potassium channels and endothelial nitric oxide are involved in acidosis-induced dilation of isolated rat cerebral arterioles. METHODS: Cerebral arterioles were cannulated and monitored with an inverted microscope. Acidosis (pH 6.8 to 7.4) produced by adding hydrogen ions mediated dilation of the cerebral arterioles in a concentration-dependent manner. The role of nitric oxide and potassium channels in response to acidosis was examined with several specific inhibitors and endothelial damage. RESULTS: The dilation was significantly inhibited by potassium chloride (30 mmol/L) and glibenclamide (3 micromol/L; ATP-sensitive potassium channel inhibitor). We found that 30 micromol/L BaCl2 (concentration-dependent potassium channel inhibitor) also affected the dilation; however, an additional treatment of 3 micromol/L glibenclamide did not produce further inhibition. Tetraethylammonium ion (1 mmol/L; calcium-activated potassium channel inhibitor) and 4-aminopyridine (100 micromol/L; voltage-dependent potassium channel inhibitor) as well as ouabain (10 micromol/L; Na-K ATPase inhibitor) and N-methylsulphonyl-6-(2-proparglyloxyphenyl) hexanamide (1 micromol/L; cytochrome P450 epoxygenase inhibitor) did not alter acidotic dilation. N(omega)-Monomethyl-L-arginine (10 micromol/L) and N(omega)-nitro-L-arginine (10 micromol/L) as nitric oxide synthase inhibitor blunted the dilation. Furthermore, the dilation was significantly attenuated after the endothelial impairment. Additional treatment with glibenclamide (3 micromol/L) further reduced the dilation in response to acidosis. CONCLUSIONS: Endothelial nitric oxide and smooth muscle ATP-sensitive potassium channels contribute to acidosis-induced dilation of rat cerebral arterioles. Endothelial damage caused by pathological conditions such as subarachnoid hemorrhage or traumatic brain injury may contribute to reduced blood flow despite injury-induced cerebral acidosis.

Acidosis↗
PubMed1999

Acidosis stimulates nitric oxide production and lung damage in rats.

Systemic hypotension during sepsis is thought to be due to nitric oxide (NO) overproduction, but it may also be due to acidosis. We evaluated in healthy rats the consequences of acid infusion on NO and blood pressure. Sprague-Dawley rats were anesthetized, and ventilated with room air. The animals were randomized into four groups. Group 1 (C, n = 10) received only normal saline at rates comparable to the other groups. Group 2 (A1, n = 10) received hydrochloric acid at 0.162 mmol in the first 15 to 30 min, followed by a continuous infusion of 0.058 mmol/h for 5 h. Group 3 (AG+A1, n = 6) was pretreated with aminoguanidine (AG, 50 mg/kg), and HCl was infused as above. Group 4 (A2, n = 7) received HCl at twice the rate used in A1. Nitric oxide concentration in the exhaled gas (ENO), blood gases, and mean arterial pressure were measured every 30 min. Acid infusion in A1 caused the pH to fall gradually from 7.43 +/- 0. 01 to 7.13 +/- 0.05. This moderate decrease in pH was associated with a marked increase in ENO (1.6 +/- 0.3 to 114.2 +/- 22.3 ppb), an increase in plasma nitrite/nitrate (17.3 +/- 3.7 to 35.2 +/- 4.3 microM), and a significant decrease in blood pressure (110.5 +/- 6.3 to 63.3 +/- 15.0 mm Hg). Furthermore, acidosis caused lung inflammation, as suggested by the increase in lung myeloperoxidase activity (282.2 +/- 24.7 to 679.3 +/- 57.3 U/min/g) and lung injury score (1.7 +/- 0.2 to 3.5 +/- 0.6). Acidosis after AG pretreatment was associated with a similar change in pH, but the increase in ENO, nitrite/nitrate, and systemic hypotension were prevented. Furthermore, lung injury was attenuated by AG, as suggested by a lower myeloperoxidase activity, though lung injury score was not altered. In this model, moderate acidosis causes increases in NO, hypotension, and lung inflammation. Lung inflammation and injury are due in part to acidosis and NO production. This is the first report to show a direct effect of chronic acidosis on NO production and lung injury. These results have profound implications on the role of acidosis on NO production and lung injury during sepsis.

Acidosis↗
PubMed2000

Buffering hypercapnic acidosis worsens acute lung injury.

Hypoventilation, associated with hypercapnic acidosis (HCA), may improve outcome in acute lung injury (ALI). We have recently reported that HCA per se protects against ALI. The current study explored whether the mechanisms of protection with HCA were related to acidosis versus hypercapnia. Because CO(2) equilibrates rapidly across cell membranes, we hypothesized that (1) HCA would afford greater protection than metabolic acidosis. We further hypothesized that (2) buffering HCA would attenuate its protection. Forty isolated perfused rabbit lung preparations were randomized to: control (normal pH, PCO(2)); HCA; metabolic acidosis; or buffered hypercapnia. After ischemia-reperfusion (IR) injury wet:dry ratio was greatest with control and buffered hypercapnia, and rank order of capillary filtration coefficient was: control approximately buffered hypercapnia > metabolic acidosis > HCA. Isogravimetric pressure reduction was greatest with buffered hypercapnia. Despite comparable injury, pulmonary artery pressure elevation was less with buffered hypercapnia versus control. In vitro xanthine oxidase (XO) activity depended on pH, not PCO(2). We conclude that: (1) HCA and metabolic acidosis are protective, but HCA is the most protective; (2) buffering HCA attenuates its protection; (3) buffering HCA causes pulmonary vasodilation; (4) because metabolic acidosis and HCA similarly inhibit in vitro XO activity, the differential effects cannot be explained solely on the basis of extracellular XO activity.

Acidosis, Respiratory↗
PubMed1970

Renal metabolic response to acid-base changes. II. The early effects of metabolic acidosis on renal metabolism in the rat.

The early renal metabolic response was studied in rats made acidotic by oral feeding of ammonium chloride. 2 hr after feeding of ammonium chloride there was already significant acidosis. Urinary ammonia also increased after ammonium chloride ingestion and at 1(1/2) hr was significantly elevated. In vitro gluconeogenesis by renal cortical slices was increased at 2 hr and thereafter increased steadily. Ammonia production by the same slices was also increased at 2 hr, but thereafter fell and at 6 hr had decreased to levels which, although higher than those of the control, were lower than those obtained from the rats acidotic for only 2 hr. There was no correlation between in vitro gluconeogenesis and ammonia production by kidney slices from rats during the first 6 hr of acidosis, but after 48 hr of ammonium chloride feeding, these two processes were significantly correlated. The early increase in renal gluconeogenesis was demonstrable with both glutamine and succinate as substrates. The activity of the enzyme phosphoenolpyruvate carboxykinase was increased after 4-6 hr of acidosis. During this time there was a decrease in renal RNA synthesis as shown by decreased uptake of orotic acid-(5)H into RNA. Metabolic intermediates were also measured in quick-frozen kidneys at varying times after induction of acidosis. There was an immediate rise in aspartate and a fall in alpha-ketoglutarate and malate levels. There was never any difference in pyruvate or lactate levels or lactate:pyruvate ratios between control and acidotic rats. Phosphoenolpyruvate rose significantly after 6 hr of acidosis. All the data indicate that increased gluconeogenesis is an early response to metabolic acidosis and will facilitate ammonia production by utilization of glutamate which inhibits the glutaminase I enzyme. The pattern of change in metabolic intermediates can also be interpreted as showing that there is not only enhanced gluconeogenesis, but also that there may be significant increase of activity of glutaminase II as part of the very early response to metabolic acidosis.

Acidosis↗
PubMed1970

A comparison of the effects of glucose ingestion and NH4Cl acidosis on urinary calcium and magnesium excretion in man.

Both glucose ingestion and NH(4)Cl acidosis have been reported to augment urinary calcium (U(Ca) V) and magnesium (U(Mg) V) excretion. Both also cause acidification of the urine and an increase in renal acid excretion. To examine whether a common mechanism of action was involved, the effects of glucose ingestion and NH(4)Cl acidosis on U(Ca) V and U(Mg) V were tested in the same subjects. Glucose ingestion caused significant increases in both U(Ca) V and U(Mg) V. During stable NH(4)Cl acidosis, U(Ca) V increased significantly, while U(Mg) V was unaffected. When a glucose load was given during acidosis, the separate effects of acidosis and glucose on U(Ca) V were additive, whereas U(Mg) V increased less than observed during normal acid-base balance. Although renal acid excretion increased and the urine was acidified after glucose in the normal steady state, when glucose was administered during NH(4)Cl acidosis urine pH rose and there was no change in renal acid excretion. We concluded that NH(4)Cl acidosis and glucose ingestion reduce the renal tubular reabsorption of magnesium and (or) calcium, but they act through separate mechanisms.

Acidosis↗
PubMed1982

Renal ammoniagenesis in an early stage of metabolic acidosis in man.

Total renal ammonia production and ammonia precursor utilization were evaluated in patients under normal acid-base balance and in patients with 24-h NH4Cl acidosis by measuring (a) ammonia excreted with urine and that added to renal venous blood, and (b) amino acid exchange across the kidney. In 24-h acidosis not only urinary ammonia excretion is increased, but also total ammonia production is augmented (P less than 0.005) in comparison with controls. By evaluating the individual role of acid-base parameters, urine pH and urine flow in influencing renal ammonia production, it was shown that the degree of acidosis and urine flow are likely major factors stimulating ammoniagenesis. Both urine pH and urine flow are determinant in the preferential shift of ammonia into urine. In 1-d acidosis, renal extraction of glutamine was not increased and the total ammonia produced/glutamine N extracted ratio was higher than in controls (P less than 0.005) and was inversely correlated with the log of arterial bicarbonate concentration (P less than 0.001). In the same condition, renal glycine and ornithine uptake took place; the more severe the acidosis, the greater was the renal extraction of these amino acids (P less than 0.001). These data indicate that at the early stages of metabolic acidosis, in spite of a brisk increase in ammonia production, the mechanisms responsible for the increased glutamine use, which are operative in chronic acidosis, are not activated and other ammonia precursors, besides glutamine, are probably used for ammonia production.

Acidosis↗
PubMed1994

Metabolic acidosis stimulates muscle protein degradation by activating the adenosine triphosphate-dependent pathway involving ubiquitin and proteasomes.

Metabolic acidosis often leads to loss of body protein due mainly to accelerated protein breakdown in muscle. To identify which proteolytic pathway is activated, we measured protein degradation in incubated epitrochlearis muscles from acidotic (NH4Cl-treated) and pair-fed rats under conditions that block different proteolytic systems. Inhibiting lysosomal and calcium-activated proteases did not reduce the acidosis-induced increase in muscle proteolysis. However, when ATP production was also blocked, proteolysis fell to the same low level in muscles of acidotic and control rats. Acidosis, therefore, stimulates selectively an ATP-dependent, nonlysosomal, proteolytic process. We also examined whether the activated pathway involves ubiquitin and proteasomes (multicatalytic proteinases). Acidosis was associated with a 2.5- to 4-fold increase in ubiquitin mRNA in muscle. There was no increase in muscle heat shock protein 70 mRNA or in kidney ubiquitin mRNA, suggesting specificity of the response. Ubiquitin mRNA in muscle returned to control levels within 24 h after cessation of acidosis. mRNA for subunits of the proteasome (C2 and C3) in muscle were also increased 4-fold and 2.5-fold, respectively, with acidosis; mRNA for cathepsin B did not change. These results are consistent with, but do not prove that acidosis stimulates muscle proteolysis by activating the ATP-ubiquitin-proteasome-dependent, proteolytic pathway.

Acidosis↗
PubMed1995

Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans.

Chronic metabolic acidosis has been previously shown to stimulate protein degradation. To evaluate the effects of chronic metabolic acidosis on nitrogen balance and protein synthesis we measured albumin synthesis rates and urinary nitrogen excretion in eight male subjects on a constant metabolic diet before and during two different degrees of chronic metabolic acidosis (NH4Cl 2.1 mmol/kg body weight, low dose group, and 4.2 mmol/kg body weight, high dose group, orally for 7 d). Albumin synthesis rates were measured by intravenous injection of [2H5ring]phenylalanine (43 mg/kg body weight, 7.5 atom percent and 15 atom percent, respectively) after an overnight fast. In the low dose group, fractional synthesis rates of albumin decreased from 9.9 +/- 1.0% per day in the control period to 8.4 +/- 0.7 (n.s.) in the acidosis period, and from 8.3 +/- 1.3% per day to 6.3 +/- 1.1 (P < 0.001) in the high dose group. Urinary nitrogen excretion increased significantly in the acidosis period (sigma delta 634 mmol in the low dose group, 2,554 mmol in the high dose group). Plasma concentrations of insulin-like growth factor-I, free thyroxine and tri-iodothyronine were significantly lower during acidosis. In conclusion, chronic metabolic acidosis causes negative nitrogen balance and decreases albumin synthesis in humans. The effect on albumin synthesis may be mediated, at least in part, by a suppression of insulin-like growth factor-I, free thyroxine and tri-iodothyronine.

Acidosis↗
PubMed1999

Pulmonary vascular responses during acute and sustained respiratory alkalosis or acidosis in intact newborn piglets.

Acute alkalosis-induced pulmonary vasodilation and acidosis-induced pulmonary vasoconstriction have been well described, but responses were generally measured within 5-30 min of changing pH. In contrast, several in vitro studies have found that relatively brief periods of sustained alkalosis can enhance, and sustained acidosis can decrease, vascular reactivity. In this study of intact newborn piglets, effects of acute (20 min) and sustained (60-80 min) alkalosis or acidosis on baseline (35% O2) and hypoxic (12% O2) pulmonary vascular resistance (PVR) were compared with control piglets exposed only to eucapnia. Acute alkalosis decreased hypoxic PVR, but sustained alkalosis failed to attenuate either baseline PVR or the subsequent hypoxic response. Acute acidosis did not significantly increase hypoxic PVR, but sustained acidosis markedly increased both baseline PVR and the subsequent hypoxic response. Baseline PVR was similar in all piglets after resumption of eucapnic ventilation, but the final hypoxic response was greater in piglets previously exposed to alkalosis than in controls. Thus, hypoxic pulmonary vasoconstriction was not attenuated during sustained alkalosis, but was accentuated during sustained acidosis and after the resumption of eucapnia in alkalosis-treated piglets. Although extrapolation of data from normal piglets to infants and children with pulmonary hypertension must be done with caution, this study suggests that sustained alkalosis may be of limited efficacy in treating acute hypoxia-induced pulmonary hypertension and the risks of pulmonary hypertension must be considered when using ventilator strategies resulting in permissive hypercapnic acidosis.

Acidosis, Respiratory↗
PubMed1976

Acidosis activation of the pituitary-adrenal-renal glutaminase I axis.

Previous studies have demonstrated that the adrenal glands were necessary for acidosis activation of the mitochondrial glutaminase I pathway. The present studies were undertaken to determine if corticosterone levels are elevated in acidotic rats and if so, whether acidosis stimulates the adrenal glands directly or via the pituitary-adrenal axis. Metabolic acidosis induced by NH4Cl, either acute or chronic, increased corticosterone levels 100 to 130% in intact rats. Acute metabolic acidosis did not activate the mitochondrial pathway in adrenalectomized rats; corticosterone levels were not elevated in hypophysectomized rats nor did activation of the mitochondrial pathway occur in response to acidosis. Therefore, acidosis does not stimulate the adrenal gland directly; rather, it requires the intact pituitary. Administering exogenous corticotropin to hypophysectomized rats resulted in elevation of plasma corticosterone levels and activation of the mitochondrial pathway. The pituitary-adrenal cortex-renal glutaminase I axis apparently operates as a functional unit in the homeostatic response to metabolic acidosis.

Acidosis↗
PubMed1983

The effect of chronic metabolic acidosis on the end organ responsiveness to parathyroid hormone in man.

To examine the effect of prolonged metabolic acidosis on the responsiveness of end organs to PTH, we measured the changes in serum ionized calcium and the urinary excretion of calcium and phosphorus in response to a 10-h infusion of parathyroid extract (PTE) before and after 9 days of metabolic acidosis. During the first hours of PTE infusion, the increases in ionized calcium were slower during acidosis, but the maximal increments in ionized calcium (0.5 +/- 0.1 and 0.4 +/- 0.1 mg/dl, respectively) were not different. Moreover, the PTE-induced increments in the fractional excretion of phosphate during acidosis and the control study were not different. Fractional excretion of calcium before the infusion of PTE was higher in acidosis than in control (3.7 +/- 0.3% compared to 0.8 +/- 0.3%; P less than 0.01). However, at 10 h of the infusion, when the maximal effect of PTE was observed, the fractional excretions of calcium in control and acidosis were not significantly different. These data suggest that prolonged metabolic acidosis has little or no effect on bone or renal responsiveness to PTH.

Acidosis↗
PubMed1999

Metabolic acidosis and coma following a severe acetaminophen overdose.

OBJECTIVE: To report a case of metabolic acidosis and coma in a severe acetaminophen overdose. CASE SUMMARY: A 29-year-old white woman was admitted to the emergency department with a diminished level of consciousness and metabolic acidosis. The toxicology screen revealed a serum acetaminophen concentration of 1072 microg/mL, and she was consequently treated with intravenous acetylcysteine. Despite the elevated concentration, the patient did not manifest signs of hepatotoxicity. DISCUSSION: Metabolic acidosis and coma are rare manifestations in acetaminophen overdoses. In published case reports, severe acetaminophen ingestion independently causes metabolic acidosis and coma in the absence of hepatotoxicity. The mechanism by which metabolic acidosis occurs is not clearly defined. Studies conducted on animals demonstrated that in severe overdoses, acetaminophen may cause lactic acidosis by inhibiting mitochondrial respiration. The mechanism by which acetaminophen can cause coma is still unknown. CONCLUSIONS: Severe acetaminophen overdoses can independently cause metabolic acidosis and coma in the absence of hepatotoxicity.

Acetaminophen↗
PubMed1997

Correction of acidosis in hemodialysis patients increases the sensitivity of the parathyroid glands to calcium.

Correction of acidosis in hemodialysis patients increases the sensitivity of the parathyroid glands to calcium. In this study, the parathyroid response to the correction of acidosis in eight hemodialysis patients was determined by performing dynamic assessment of parathyroid function before and after the correction of acidosis. The parathyroid response to intravenous calcitriol before and after the correction of acidosis was also assessed. After optimal correction of acidosis, there were no significant changes in blood pH, ionized calcium, phosphate, or alkaline phosphatase values, but the level of venous total CO2 increased significantly. Parathyroid hormone/ionized calcium curves were displaced downward after correction of acidosis, but not after the administration of intravenous calcitriol. The correction of metabolic acidosis in hemodialysis patients with secondary hyperparathyroidism can suppress parathyroid hormone secretion by increasing the sensitivity of the parathyroid glands to ionized calcium.

Acidosis↗
PubMed1999

Incidence of lactic acidosis in metformin users.

OBJECTIVE: The purpose of this study was to determine the incidence of lactic acidosis in a geographically defined population of metformin users. RESEARCH DESIGN AND METHODS: The study was based on a historical cohort from the Saskatchewan Health administrative databases. Individuals with a metformin prescription dispensed between 1980 and 1995 inclusive were eligible for the cohort. Person-years of exposure were calculated. Cases were defined by hospital discharge with a diagnosis of acidosis (International Classification of Diseases, Ninth Revision code: 276.2) and confirmation by chart review of a blood lactate level > or = 5 mmol/l. Death registrations of individuals dying within 120 days of a metformin prescription were also reviewed. RESULTS: During the study period, 11,797 residents received one or more metformin prescriptions, resulting in 22,296 person-years of exposure. There were 10 subjects who had hospital discharges with a diagnosis of acidosis. However, primary record review revealed only two cases with laboratory findings of elevated blood lactate levels, for an incidence rate of 9 cases per 100,000 person-years of metformin exposure. In both cases, other factors besides metformin could have contributed to the lactic acidosis. No additional cases were found on review of death registrations. CONCLUSIONS: From 1980 through 1995, the incidence rate of lactic acidosis was 9 per 100,000 person-years (95% CI 0-21) in patients dispensed metformin in Saskatchewan, Canada. This incidence rate was derived from a population with complete ascertainment of hospitalizations and deaths associated with lactic acidosis in metformin users. It is similar to previously published rates based on passive reporting of cases, and it is well below the lactic acidosis rate of 40-64 per 100,000 patient-years in patients prescribed phenformin.

Acidosis, Lactic↗
PubMed1995

The effect of slaframine on salivary output and subacute and acute acidosis in growing beef steers.

Experiments were conducted to determine 1) the effect of injecting slaframine (SF) on salivary output in growing beef steers and 2) whether increased salivary output after SF injection would inhibit the decrease in ruminal pH that occurs after experimentally induced subacute and acute ruminal acidosis. In Exp. 1 and 2, we measured ruminal pH and salivary output in ruminally and esophageally cannulated beef steers fed an 88% concentrate diet. Injections of 66 or 100 micrograms of SF/kg BW increased salivary flow approximately 50% compared with controls. Those doses were tested in subacute and acute acidosis models using ruminally cannulated beef steers in Exp. 3 and 4, respectively. In these experiments, salivation was assessed indirectly using a visual scoring system. In the subacute acidosis model, SF reduced (P < .10) the decrease in ruminal pH (1.1, .7, and .6 pH units for control, 66, and 100 micrograms of SF/kg BW doses, respectively), and excessive salivation was observed in all SF-injected steers. In the acute acidosis model, there were no differences (P > .10) in ruminal pH at 12 h after injection between control and SF-treated steers. Mean ruminal lactate concentrations for all treatment groups were between 87 and 112 mM. Although treatment with 66 micrograms of SF/kg BW reduced (P < .10) ruminal lactate concentrations, all ruminal lactate concentrations were indicative of acute acidosis. These results indicate that SF will reduce the decrease in ruminal pH associated with subacute acidosis in growing beef steers, but SF does not attenuate acute ruminal acidosis.

Acidosis↗