Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acetazolamide, a carbonic anhydrase inhibitor, has proved to be useful in the assessment of "vasodilatory capacity" in cerebrovascular disease. To obtain further information on the nature of interictal low-flow regions in migraine, we reinvestigated 20 asymptomatic patients suffering from migraine with aura (n = 15) or without aura (n = 5) and who had either minor (n = 12) or marked (n = 8) regional hypoperfusion when examined in a previous 99mTc-HMPAO SPECT investigation. These patients received acetazolamide IV prior to tracer application. In 14/20 cases regional hypoperfusion resolved. Three patients with migraine with aura had less pronounced regional hypoperfusion compared to baseline. No change in baseline hypoperfusion was detectable in three older patients. No further decreases in flow were measured. In contrast to patients with cerebrovascular ischemia, in whom acetazolamide usually enhances low-flow regions, vasodilatory capacity appears intact in most migraine patients with interictal regional hypoperfusion. Thus, the "acetazolamide test" might be useful in the differential diagnosis of migraine with aura from transient cerebrovascular ischemia.
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PMID:The influence of acetazolamide on cerebral low-flow regions in migraine--an interictal 99mTc-HMPAO SPECT study. 142 58

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.
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PMID:Alkaline and acid transients in cerebellar microenvironment. 683 1

The gastric mucosal barrier is that property which defends against acid and which impedes diffusion of acid from the lumen into the mucosa. The disappearance of luminal H+ is linearly related to luminal (H+) both in the normal stomach and in stomachs exposed to barrier breakers. The latter invaribaly produce anatomic evidence of surface cellular injury. Strong direct evidence for back diffusion of luminal H+ derives from the recent demonstration of a highly significant correlation between the disappearance of luminal H+ and the pH of the lamina propria measured by an implanted microelectrode. The permeabilities of the antrum and fundus to H+ differ from each other in the same species and in different species. Gastric ulceration does not occur in the absence of luminal acid and is not dependent upon the absolute loss of H+ from the luminal solution. Mucosal ischemia induced by hemorrhage reduces tolerance against ulceration as does inhibition of acid secretion, acidification of the tissue caused by absence of nutrient bicarbonate, inhibition of carbonic anhydrase, and blockade of anion exchange by SITS. A tentative schema is proposed by which defense against luminal acid is accomplished in gastric mucosa.
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PMID:The gastric mucosal barrier and ulceration. 699 46

A 14-year-old black boy with sickle cell trait, who sustained a traumatic hyphema, developed moderately elevated intraocular pressure that failed to respond to carbonic anhydrase inhibitors and osmotic agents. On the tenth postinjury day, a sudden increased cupping of the optic disc and partial central retinal artery obstruction caused painless loss of vision. Reversal of the cupping, the retinal ischemia, and the intraocular pressure was documented following anterior chamber paracentesis, and visual acuity returned to 6/6. Pathophysiology of the posterior ischemia is discussed. This case documents the potentially debilitating course of traumatic hyphema in "benign" sickle cell trait and its avoidance with proper management. The authors endorse recent suggestions for careful observation of any sickle cell patient with traumatic hyphema, and recommend anterior chamber paracentesis, supplemental oxygen, and avoidance of osmotic agents, if secondary glaucoma develops following the initial trauma.
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PMID:Reversal of retinal and optic disc ischemia in a patient with sickle cell trait and glaucoma secondary to traumatic hyphema. 712 55

Tonometric measurement of an elevated intragastric Pco2 and a decreased calculated gastric intramucosal pH can be used to detect gastric mucosal ischemia, provided that intraluminal production of CO2 through acid buffering by bicarbonate is avoided by adequate acid secretion suppression. If the diffusion rate is known, steady state Pco2 can be calculated when measurement intervals are used that are shorter than needed for complete equilibration. The CO2 diffusion might be influenced by the choice of acid-suppressive drugs, since some of them inhibit gastric carbonic anhydrase (CA) and CA facilitates diffusion of CO2/bicarbonate over the gastrointestinal mucosa. We therefore performed gastric Pco2 tonometry, using acid-suppressive regimens with and without CA inhibition. The diffusion rate of CO2 in a gastric tonometer was studied in healthy volunteers, following intravenously administered ranitidine (group I, N = 8) or ranitidine plus pirenzepine (group II, N = 12), a muscarinic antagonist with CA inhibiting capacities. Measurement intervals were 10, 20, 30 and 60 min. Neither the diffusion rate of CO2 (k = 0.13 +/- 0.02/min in group I and 0.11 +/- 0.02/min in group II), nor the steady-state Pco2 (38 +/- 3 mm Hg in group I and 40 +/- 4 mm Hg in group II), nor the gastric-blood differences in Pco2 and pH differed between groups. These results indicate that diffusion of CO2 into the tonometer balloon is independent of CA and thus of the type of gastric acid secretion inhibition.
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PMID:Gastric PCO2 tonometry is independent of carbonic anhydrase inhibition. 900 22

Inhibitors of carbonic anhydrase activity have been found to increase blood and organ PCO2 and to increase blood flow (BF) in individual organs. To determine whether carbonic anhydrase inhibition coordinately induces an increase in BF in several organs, we assayed the effect of the carbonic anhydrase inhibitor, acetazolamide (AZ), on BF in rabbit organs using the colored microsphere (CM) assay. Eight female white rabbits were anesthetized with ketamine and urethane, and administered three sequential doses of 4 mg/kg AZ. After each dose, the rabbits were injected with 9 x 10(5) CMs of different colors, and arterial blood was collected. We found that AZ had no effect on blood pressure, body temperature, hemoglobin concentration, or PaCO2. In contrast, 12 mg/kg AZ significantly increased PaO2 and significantly decreased base excess. When we measured organ BF, we observed, in response to 12 mg/kg AZ, an 82% increase in brain BF and a 55% increase in kidney BF, but no change in BF of the liver, stomach wall, or abdominal muscle. These findings suggest that the inhibition of carbonic anhydrase activity by AZ, which decreases the rate of CO2 conversion to HCO3-, causes the retention of CO2 in tissues and organs, and thus increases BF in specific organs. Administration of carbonic anhydrase inhibitors, such as AZ, may increase BF to the brain and kidney without reducing PaO2, thereby increasing the supply of oxygen in conditions involving hypoxia such as ischemia and shock.
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PMID:Acetazolamide-induced increase in blood flow to rabbit organs is confirmed using colored microspheres. 998 39

Whereas intraocular pressure is considered a major risk factor in glaucoma, growing evidence now indicates that ocular ischemia plays a major role too. By virtue of this and because many existing medications are able to interact with vasculature, altering ocular blood flow, it is essential that current and future medications for glaucoma be evaluated for their effect on ocular circulation. The authors review published papers examining the effect of topical and some systemic medications on ocular blood flow, focusing mostly on data from the human eye. The authors provide a comprehensive review on the effect of subclasses of medications (eg, carbonic anhydrase inhibitors, beta-blockers, alpha-adrenergic agonists, and prostaglandin analogues on optic nerve head, and on retinal, choroidal, and retrobulbar circulation. The various claims for enhancements or reduction of ocular circulation within each class of medication are reviewed and evaluated.
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PMID:The impact of glaucoma medication on parameters of ocular perfusion. 1122 20

The oxygen tension of the optic nerve is regulated by the intraocular pressure and systemic blood pressure, the resistance in the blood vessels and oxygen consumption of the tissue. The oxygen tension is autoregulated and moderate changes in intraocular pressure or blood pressure do not affect the optic nerve oxygen tension. If the intraocular pressure is increased above 40 mmHg or the ocular perfusion pressure decreased below 50 mmHg the autoregulation is overwhelmed and the optic nerve becomes hypoxic. A disturbance in oxidative metabolism in the cytochromes of the optic nerve can be seen at similar levels of perfusion pressure. The levels of perfusion pressure that lead to optic nerve hypoxia in the laboratory correspond remarkably well to the levels that increase the risk of glaucomatous optic nerve atrophy in human glaucoma patients. The risk for progressive optic nerve atrophy in human glaucoma patients is six times higher at a perfusion pressure of 30 mmHg, which corresponds to a level where the optic nerve is hypoxic in experimental animals, as compared to perfusion pressure levels above 50 mmHg where the optic nerve is normoxic. Medical intervention can affect optic nerve oxygen tension. Lowering the intraocular pressure tends to increase the optic nerve oxygen tension, even though this effect may be masked by the autoregulation when the optic nerve oxygen tension and perfusion pressure is in the normal range. Carbonic anhydrase inhibitors increase the optic nerve oxygen tension through a mechanism of vasodilatation and lowering of the intraocular pressure. Carbonic anhydrase inhibition reduces the removal of CO2 from the tissue and the CO2 accumulation induces vasodilatation resulting in increased blood flow and improved oxygen supply. This effect is inhibited by the cyclo-oxygenase inhibitor, indomethacin, which indicates that prostaglandin metabolism plays a role. Laboratory studies suggest that carbonic anhydrase inhibitors might be useful for medical treatment of optic nerve and retinal ischemia, potentially in diseases such as glaucoma and diabetic retinopathy. However, clinical trials and needed to test this hypotheses.
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PMID:Optic nerve oxygenation. 1570 31

Cyclooxygenase-2 (COX-2) is up-regulated in stromal and inflammatory cells. The inducible COX-2 isoform is expressed during inflammation, in some cancers, and in brain tissue after global and focal ischemia. Tissue acidosis is a dominant factor in inflammation, and contributes to pain and hyperalgesia. Recently, compelling epidemiological and clinical evidence has documented the COX-independent effects of some COX-2 inhibitors (i.e., celecoxib, valdecoxib, and rofecoxib); among these effects are carbonic anhydrase (CA) inhibition. Carbonic anhydrases are zinc metalloenzymes expressed in various cell types, including those of the kidney, where they act as general acid-base catalysts. The kidneys are also known to express the highest concentration of COX-2 messenger ribonucleic acid. Celecoxib, like the prototypic CA inhibitor acetazolamide, is structurally characterized by an unsubstituted sulfonamide moiety. In the present study, we report that celecoxib exhibits the characteristics of a potent CA inhibitor, showing inhibitory human carbonic anhydrase II (hCAII) activity in the nanomolar range. Valdecoxib was relatively less potent. Rofecoxib, which lacks the unsubstituted sulfonamide moiety characteristic of CA inhibitors, showed no significant hCAII inhibitory activity. The current study corroborates our earlier report of structure-activity relationships as predictors of such metabolic events as hyperchloremia, acidosis, and changes in calcium and phosphate disposition; and clinical manifestations associated with CA inhibition reported with celecoxib. These data showing inhibition of hCAII by the unsubstituted sulfonamides celecoxib and valdecoxib, but not by rofecoxib, may have important implications for the elucidation of the mechanisms of action as well as the side effects associated with COX-2 inhibitors.
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PMID:The cyclooxygenase-2 inhibitor celecoxib is a potent inhibitor of human carbonic anhydrase II. 1613 2

The transcription factor HIF-1alpha has been identified as a key regulator in the cellular and systemic response to hypoxia. Because hypoxia is frequently associated with acidosis, like in ischemia or tumour growth, we studied the impact of acidosis on the expression of the HIF-1alpha and HIF-2alpha proteins and that of the three HIF target genes carbonic anhydrase-9 (CA-9), glucose transporter-1 (Glut-1) and erythropoietin (EPO). Since the HIF-prolyl hydroxylases (PHD) modulate cellular HIF-alpha protein levels we also investigated changes in PHD mRNA expression under hypoxia and acidosis. HIF-1alpha immunoblots revealed, depending on the cell line investigated, a moderate induction of HIF-alpha protein levels by acidosis in normoxia (Hep3B cells) or hypoxia (HeLa cells). Concordantly, the activity of HIF-driven luciferase reporters was slightly enhanced at pH 7.0. In contrast, HIF target genes exhibited divergent responses to acidosis: basal and hypoxia-induced CA-9 mRNA levels were further increased, whereas hypoxic EPO mRNA induction was attenuated, and Glut-1 mRNA levels were not altered by acidosis. Except from a small increase of hypoxia-induced PHD3 mRNA levels in HeLa cells, there was also no significant effect of acidosis on PHD expression. In conclusion, albeit HIF protein levels slightly induced by acidosis and the inconsistent regulation of HIF target genes under acidosis suggest additional, yet unidentified pH-sensitive factors to be involved in the regulation of these genes.
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PMID:Inconsistent effects of acidosis on HIF-alpha protein and its target genes. 1620 22


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