Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of ion-sensitive microelectrodes enabled us to follow the dynamic changes in extracellular pH (pHe) together with those in the extracellular concentration of some biologically important ions, particularly K+ and Ca2+. Activity-related changes in pHe were studied in isolated spinal cords of frogs and in spinal cords of rats in vivo. Repetitive electrical stimulation of an afferent input led either to triphasic alkaline-acid-acid changes (90% of frogs) or to triphasic alkaline-acid-alkaline changes (10% of frogs and rats) with the greatest changes in the lower dorsal horns. The transient acid shift by as much as 0.15-0.25 pH units is dominant and builds up during the stimulation. The changes in pHe were also found in response to various adequate stimuli applied to the skin on the hind limb. Using specific inhibitors of Na+/H+ exchange, K+-Cl- co-transport, Cl-/HCO3- exchange, the Na+/K+ pump and carbonic anhydrase, we found pHe homeostasis to be impaired and stimulation-induced changes in pHe decreased. We conclude that the pHe changes evoked by electrical or adequate stimulation of an afferent input are not determined by changes in extracellular strong ion concentration differences due to accumulation of lactate, since we found no effect of NaF, a metabolic blocker of lactate production. However, lactate accumulation has been demonstrated during seizures, spreading depression and anoxia. Recently, it has been recognized that the observed pHe changes can affect permeability of membrane ionic channels, neuronal excitability and glial cell function.
 ...
PMID:Extracellular pH and stimulated neurons. 320 66

Both surface pH (pHs) and intracellular pH (pHi) were measured using single- and double-barreled pH-sensitive microelectrodes in isolated sheep cardiac Purkinje strands, rabbit and cat papillary muscle, and mouse and rat soleus muscle. Superfusion of the preparations with a relatively low buffered solution (containing 5 mM HEPES buffered to control pH) causes surface acidosis that correlates with efflux of metabolically produced acids in the unstirred layer of fluid surrounding the tissue. Acidification of the surface layer induces a slower acid change of pHi and depresses the rate of proton extrusion following an imposed intracellular acid load. In cardiac preparations, the lowering of pHi correlates with depression of twitch tension. Transient changes of pHs and pHi are seen when a weak acid or base is suddenly added to, or removed from the superfusion solution. Indirect evidence of the presence of carbonic anhydrase in the extracellular surface layer is obtained from analysis of transient pHs changes in presence and absence of acetazolamide.
 ...
PMID:Surface pH and the control of intracellular pH in cardiac and skeletal muscle. 330 90

The ability of the kidney to reabsorb bicarbonate is held to be a function of plasma CO(2) tension, carbonic anhydrase activity, and potassium stores. The effects of alterations of extracellular volume on bicarbonate reabsorption were studied in dogs whose arterial Pco(2) was kept constant at 40 mm Hg (range 35-45 mm Hg). The effect of extracellular volume expansion was studied in dogs receiving hypertonic bicarbonate and isotonic saline, isotonic saline alone (two of the animals in this group received HCl to lower the plasma bicarbonate concentration), and isotonic bicarbonate. The results were similar in each group. Extracellular volume expansion depressed bicarbonate reabsorption. This depression was related not to changes in glomerular filtration rate (GFR) or bicarbonate concentration, but to the increase of fractional sodium excretion. In addition, volume expansion with bicarbonate increased chloride excretion. Bicarbonate loading was performed in two groups of dogs in which effective expansion of extracellular volume was minimized by hemorrhage or acute constriction of the thoracic vena cava. Both groups demonstrated enhanced bicarbonate reabsorption relative to that seen in the volume-expanded groups. Release of the caval ligature promptly decreased bicarbonate reabsorption. Plasma potassium decreased in all animals studied, but the changes in bicarbonate reabsorption noted could not be related to the decrease. This study demonstrates that the state of effective extracellular volume is a major determinant of bicarbonate reabsorption by the kidney.
 ...
PMID:Regulation of renal bicarbonate reabsorption by extracellular volume. 541 84

We have examined the extracellular pH (pHe) during spreading depression and complete cerebral ischemia in rat parietal cortex utilizing double-barrelled H+ liquid ion exchanger microelectrodes. The baseline pHe of the parietal cortex was 7.33 at a mean arterial PCO2 of 38 mm Hg. Following spreading depression and cerebral ischemia, highly reproducible triphasic changes in pHe occurred, which were intimately related to the negative deflection in tissue potential (Ve). The changes in pHe for spreading depression (n = 23) were a small initial acidic shift, beginning before the rapid change in Ve, followed by a rapid transient alkaline shift of 0.16 pH units, the onset of which coincided with the negative deflection in Ve. A prolonged acidic shift of 0.42 pH units then occurred. The maximal decrease in pHe was to 6.97 and the mean duration of the triphasic pHe change was 7.8 min. The lactate concentration in brain cortex increased from baseline 1.2 mM to 7.0 mM (n = 6) during the maximal acidic change in spreading depression. In addition, lactate levels correlated well with resolution of the pHe changes during spreading depression. The triphasic pHe changes following complete cerebral ischemia were an initial acidic shift of 0.43 pH units which developed over 2 min, then an alkaline shift of 0.10 pH units coincident with the negative deflection in Ve, and a final acidic shift of 0.26 pH units. The terminal pHe was 6.75. Superfusion of the cortex with inhibitors of carbonic anhydrase (acetazolamide), Na+/H+ counter transport (amiloride), and Cl-/HCO-3 countertransport (4,4'-diisothiocyanostilbene-2,2'-disulfonic acid) altered the triphasic pHe changes in a similar fashion for both spreading depression and cerebral ischemia, providing insights into the pHe regulatory mechanisms in mammalian brain.
 ...
PMID:Extracellular pH changes during spreading depression and cerebral ischemia: mechanisms of brain pH regulation. 669 12

1. Extracellular pH (pHo) was measured in the cerebellar cortex of the rat using a recently developed liquid membrane ion-selective micropipette (ISM). pHo was determined during stimulus-evoked neuronal activity, elevated extracellular potassium concentration, [K+]o, spreading depression (SD), and complete ischemia. In many experiments [K+]o was simultaneously determined. 2. A train of local surface stimuli (LOC) produced an initial alkaline shift in pHo from a base line of 7.20-7.30 to 7.25-7.35. This was followed by a long-lasting acid phase that reached a plateau of 7.05-7.15 after 64 s of stimulation. pHo decrease was related to stimulus frequency, intensity, and duration. 3. Superfusion with Ringer solution containing manganese ions rapidly abolished parallel fiber-induced Purkinje cell synaptic depolarization together with the alkaline shifts while enhancing the acid shifts. 4. Superfusion of the cerebellar cortex with Ringer solution containing increasingly elevated [K+] progressively lowered pHo to a plateau of 6.95-7.05. The acidification occurred in the presence of ouabain but was reversed on return to the normal [K+]o or with the addition of the glycolytic blocker, fluoride. Stimulus-evoked alkaline shifts were enhanced by K+-Ringer superfusion. These experiments suggested that the acid shift was due to the metabolic production of an anion, possibly lactate. 5. Elevation of [K+]o above 8-12 mM often produced oscillation in pHo and [K+]o with a period of about 40 s. Sometimes these oscillations ended in a spontaneous SD or SD could be evoked by stimulation. Under these conditions of raised [K+]o, the SD consisted of a very pronounced alkaline transient followed by a small, long-lasting acid shift. When SD was induced by conditioning the cerebellum with proprionate or lowered NaCl, the alkaline phase was reduced and the acid enhanced. 6. Complete ischemia began with a progressive decrease of pHo and rise in [K+]o. When [K+]o reached 12 mM, a second more rapid rise in [K+]o to 40 mM or more occurred. This was correlated with 0.1-0.2 pHo transient increase similar to that seen during SD. pHo eventually reached a plateau of 6.60-6.80, close to neutrality. 7. Superfusion with Ringer solution containing acetazolamide immediately altered pHo homeostasis by increasing base-line pHo by about 0.10 and enhanced the induced pHo changes. These results suggest that carbonic anhydrase (CA) is important for acute buffering of the brain extracellular microenvironment. 8. The above results were interpreted in terms of changes in extracellular strong ion concentration differences ( [SID]o), extracellular concentration of total weak acid ( [Atot]o) and partial pressure of CO2 (Pco2) in the brain microenvironment. The results indicate that neuronal activity produces changes in many of the constituents of the microenvironment.
 ...
PMID:Alkaline and acid transients in cerebellar microenvironment. 683 1

Inhibition of red cell carbonic anhydrase (CA) activity resulted in the rapid development of a respiratory acidosis (0.25 pH depression within 15 min post-injection) in the blood of trout. In the lamprey, however, the onset of the respiratory acidosis was delayed and its magnitude was less (0.18 pH depression at 6 h post-injection). Erythrocyte pH of both species decreased by about 0.12 units by 1 h after CA inhibition. These data, combined with the lack of rapid anion (Cl-/HCO3-) exchange in the red cells of agnathans but not in other lower vertebrates, support the hypotheses that (1) the majority of total CO2 in lamprey is transported within the erythrocyte, and (2) the limiting step in the evolution of a functioning Jacobs-Stewart cycle, and thus the evolution of the common mechanism of systemic CO2 transport in vertebrate blood, was the incorporation of the band-3 anion exchange protein into the membrane of the red cell.
 ...
PMID:Effects of carbonic anhydrase inhibition on the acid base status in lamprey and trout. 777 7

Acetazolamide (Diamox) is a carbonic anhydrase inhibitor commonly used in patients with glaucoma in order to reduce intraocular pressure. Acetazolamide (AZ) is mostly excreted in the urine, therefore, the blood levels of AZ often tend to increase in patients with chronic renal failure. We experienced a case of chronic renal failure in a patient suffering from acute hemorrhagic gastritis associated with AZ intoxication. A 66-year-old female with chronic renal failure was referred to our hospital because of drowsiness and an acute deterioration of renal function. She had been treated with AZ, 500 mg per every day for eleven days for the treatment of glaucoma. Laboratory studies showed leukocyturia, thrombocytopenia, severe anemia, and tarry stools. The serum concentration of AZ was elevated to a maximum of 76.5 mg/ml. She was thus diagnosed as having AZ intoxication. On further examination, acute extensive hemorrhagic gastritis was also found by gastroscopy. Despite of the administration of intensive therapies, she died of disseminated intravascular coagulation (DIC) and septic shock due to bone marrow depression 6 days after admission. It is generally known that excessive blood levels of AZ inhibit not only the gastric juices but also prostaglandin levels and HCO3- excretion in the gastric mucosal barrier. We thus concluded that an excessive dose of AZ had probably destroyed the gastric mucosal barrier or thrombocytopenia due to bone marrow disorder and thus eventually led to the development of hemorrhagic gastritis. As far as we know, this is the first case report of acute hemorrhagic gastritis associated with AZ intoxication. Even though AZ tends to strongly bind to plasma protein and its clearance is generally poor by hemodialysis (HD), in our patient, HD was observed to be rather effective since the clearance of AZ was 45.8 ml/min on HD and 66 ml/min on direct hemoperfusion (DHP). DHP often reduces the number of platelets, also DHP needs a lot of heparin, therefore, we should have performed HD alone instead of DHP. In patients with an impaired renal function, AZ should therefore be administered very carefully in order to avoid an accumulation of the drug. In addition, HD alone should be used to remove any excessive amounts of AZ from the blood.
 ...
PMID:Acute hemorrhagic gastritis associated with acetazolamide intoxication in a patient with chronic renal failure. 935 64

Mechanisms of primary fluid formation by macropodine mandibular glands were investigated in anaesthetized red kangaroos using ion-transport and carbonic anhydrase inhibitors. Bumetanide at carotid plasma concentrations of 0.005-0.1 mmol/l progressively reduced a stable, acetylcholine-evoked flow rate of 1.02 +/- 0.024 ml/min to 0.16 +/- 0.016 ml/min (mean +/- SEM). Concurrently, saliva [Na], [Cl] and osmolality decreased, [K] and [HCO3] increased and HCO3 excretion was unaffected. High-rate cholinergic stimulation was unable to increase salivary flow above 12 +/- 1.5% of that for equivalent pre-bumetanide stimulation. Furosemide (1.0 mmol/l) and ethacrynate (0.5 mmol/l) caused depression of salivary flow and qualitatively similar effects on ion concentrations to those of bumetanide. Amiloride (up to 0.5 mmol/l) caused no reduction in salivary flow rates or [Na] but decreased [K] and [Cl] and increased [HCO3]. When compared with bumetanide alone, amiloride combined with bumetanide further augmented [K] and [HCO3] and lowered [Cl], but had no additional effects on Na or flow. At the higher level, 4-acetamido-4'- isothiocyanatostilbene-2,2'disulphonic acid (SITS) (0.05 and 0.5 mmol/l) stimulated fluid output, increased [HCO3] and [protein], and depressed [Na], [K] and [Cl]. Relative to bumetanide alone, SITS given with bumetanide had no additional effects on salivary flow or electrolytes. Methazolamide (0.5 mmol/l) in combination with bumetanide curtailed the decrease in [Cl] and the increases in [K] and [HCO3] associated with bumetanide. The residual methazolamide-resistant HCO3 excretion was sufficient to support 2-6% of primary fluid secretion. It was concluded that secretion of primary fluid by the kangaroo mandibular gland is initiated mainly (> 90%) by Cl transport resulting from Na-K-2Cl symport activity. A small proportion of the fluid secretion (up to 6%) appears to be supported by HCO3 secretion. No evidence was found for fluid secretion being dependent on Cl transport involving Na/H and Cl/HCO3 antiports or on HCO3 synthesis involving carbonic anhydrase.
 ...
PMID:The effect of transport-blocking drugs on secretion of fluid and electrolytes by the mandibular gland of red kangaroos, Macropus rufus. 944 60

Rapid extracellular alkalinizations accompany normal neuronal activity and have been implicated in the modulation of N-methyl-D-aspartate (NMDA) receptors. Particularly large alkaline transients also occur at the onset of spreading depression (SD). To test whether these endogenous pH shifts can modulate SD, the alkaline shift was amplified using benzolamide, a poorly permeant inhibitor of interstitial carbonic anhydrase. SD was evoked by microinjection of 1.2 M KCl into the CA1 stratum radiatum of rat hippocampal slices and recorded by a proximal double-barreled pH microelectrode and a distal potential electrode. In Ringer solution of pH 7.1 containing picrotoxin (but not at a bath pH of 7.4), addition of 10 microM benzolamide increased the SD alkaline shift from 0.20 +/- 0.07 to 0.38 +/- 0.17 unit pH (means +/- SE). This was correlated with a significant shortening of the latency and an increase in the conduction velocity by 26 +/- 16%. In the presence of the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV), benzolamide still amplified the alkaline transient, however, its effect on the SD latency and propagation velocity was abolished. The intrinsic modulation of SD by its alkaline transient may play an important role under focal ischemic conditions by removing the proton block of NMDA receptors where interstitial acidosis would otherwise limit NMDA receptor activity.
 ...
PMID:Endogenous pH shifts facilitate spreading depression by effect on NMDA receptors. 1020 Feb 36

Spreading depression (SD) and related phenomena have been implicated in hypoxic-ischemic injury. In such settings, SD occurs in the presence of marked extracellular acidosis. SD itself can also generate changes in extracellular pH (pH(o)), including a pronounced early alkaline shift. In a hippocampal slice model, we investigated the effect of interstitial acidosis on the generation and propagation of SD in the CA1 stratum radiatum. In addition, a carbonic anhydrase inhibitor (benzolamide) was used to decrease buffering of the alkaline shift to investigate its role in the modulation of SD. pH(o) was lowered by a decrease in saline HCO(3)(-) (from 26 to 13 to 6.5 mM at 5% CO(2)), or by an increase in the CO(2) content (from 5 to 15% in 26 mM HCO(3)(-)). Recordings with pH microelectrodes revealed respective pHo values of 7.23 +/- 0. 13, 6.95 +/- 0.10, 6.67 +/- 0.09, and 6.97 +/- 0.12. The overall effect of acidosis was an increase in the threshold for SD induction, a decrease in velocity, and a shortened SD duration. This inhibition was most pronounced at the lowest pH(o) (in 6.5 mM HCO(3)(-)) where SD was often blocked. The effects of acidosis were reversible on return to control saline. Benzolamide (10 microM) caused an approximate doubling of the early alkaline shift to an amplitude of 0.3-0.4 U pH. The amplified alkalosis was associated with an increased duration and/or increased velocity of the wave. These effects were most pronounced in acidic media (13 mM HCO(3)(-)/5% CO(2)) where benzolamide increased the SD duration by 55 +/- 32%. The initial velocity (including time for induction) and propagation velocity (measured between distal electrodes) were enhanced by 35 +/- 25 and 26 +/- 16%, respectively. Measurements of [Ca(2+)](o) demonstrated an increase in duration of the Ca(2+) transient when the alkaline shift was amplified by benzolamide. The augmentation of SD caused by benzolamide was blocked in media containing the N-methyl-D-aspartate (NMDA) receptor antagonist DL-2-amino-5-phosphonovaleric acid. These data indicate that the induction and propagation of SD is inhibited by a fall in baseline pH characteristic of ischemic conditions and that the early alkaline shift can remove this inhibition by relieving the proton block on NMDA receptors. Under ischemic conditions, the intrinsic alkalosis may therefore enable SD and thereby contribute to NMDA receptor-mediated injury.
 ...
PMID:Modulation of spreading depression by changes in extracellular pH. 1106 87


<< Previous 1 2 3 4 Next >>