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PubMed1990

Forskolin-induced HCO3- current across apical membrane of the frog corneal epithelium.

Forskolin (and other Cl- secretagogues) does not affect the very small Na(+)-originated short-circuit current (Isc) across frog corneal epithelium bathed in Cl- free solutions. However, forskolin in combination with increased PCO2 bubbling of the solutions (5-20% CO2) stimulated Isc proportionally to PCO2 to a maximum of approximately 8 microA/cm2. This current could be eliminated and reinstated by sequentially changing the gas composition of the bubbling to 100% air and 20% CO2-80% air. The same effects were observed when PCO2 changes were limited to the apical-side solution. Stroma-to-tear HCO3- movement was deemed unlikely, since the increase in Isc was observed with a HCO3(-)-free solution on the stromal side and CO2 gassing limited to the tear side. From the effects of ouabain and tryptamine, at least 80% of the Isc across the basolateral membrane can be accounted for by the Na+ pump current plus K+ movement from cell to bath. Methazolamide also inhibited Isc. Current across the apical membrane cannot be attributed to an electronegative Na(+)-HCO3- symport given the insensitivity of Isc to a disulfonic stilbene and the fact that stroma-to-tear Na+ fluxes did not increase on stimulation of Isc. The tear-to-stroma Na+ flux also remained unaltered, negating an increased apical bath-to-cell Na+ flow. The forskolin-20% CO2 manipulation produced a depolarization of the intracellular potential, a reduction in the apical-to-basolateral resistance ratio, and a decrease in transepithelial resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2003

NHE3 inhibition activates duodenal bicarbonate secretion in the rat.

We examined the effect of inhibition of Na+/H+ exchange (NHE) on duodenal bicarbonate secretion (DBS) in rats to further understand DBS regulation. DBS was measured by using the pH-stat method and by using CO2-sensitive electrodes. 5-(N,N-dimethyl)-amiloride (50 microM; DMA), a concentration that selectively inhibits the NHE isoforms NHE1 and NHE2, but not NHE3, did not affect DBS. Nevertheless, 3 mM DMA, a higher concentration that inhibits NHE1, NHE2, and NHE3, significantly increased DBS. Moreover, S1611 and S3226, both specific inhibitors of NHE3 only, or perfusion with Na+-free solutions, dose dependently increased DBS, as measured by pH-stat and CO2-sensitive electrode, without affecting intracellular pH. Coperfusion with 0.1 microM indomethacin, 0.5 mM DIDS, or 1 mM methazolamide did not affect S3226-induced DBS. Nevertheless, coperfusion with 0.1 and 0.3 mM 5-nitro-2-(3-phenylpropylamino) benzoic acid, which inhibits the cystic fibrosis transmembrane conductor regulator (CFTR), dose dependently inhibited S3226-induced DBS. In conclusion, only specific apical NHE3 inhibition increased DBS, whereas prostaglandin synthesis, Na+-HCO3- cotransporter activation, or intracellular HCO3- formation by carbonic anhydrase was not involved. Because NHE3 inhibition-increased DBS was inhibited by an anion channel inhibitor and because reciprocal CFTR regulation has been previously shown between NHE3 and apical membrane anion transporters, we speculate that NHE3 inhibition increased DBS by altering anion transporter function.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1993

Effect of intracellular acidification on colonic NaCl absorption.

CO2 stimulates Na+ and Cl- absorption in rat distal colon. This is most likely due to intracellular generation of H+ and HCO3- and stimulation of apical Na(+)-H+ and Cl(-)-HCO3- exchangers. We examined whether intracellular acidification by means other than CO2 would also stimulate Na+ absorption. Stripped segments of distal colon from male Sprague-Dawley rats were studied under short-circuit conditions in Ussing chambers. Identically prepared tissues were used for intracellular pH (pHi) measurements with the pH-sensitive dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. When the Ringer PCO2 was increased from 20 to 34 mmHg, pHi decreased from 7.50 +/- 0.04 to 7.35 +/- 0.04 and net Na absorption increased from 2.4 +/- 0.7 to 3.7 +/- 0.7 mu eq.cm-2 x h-1. A similar degree of intracellular acidification was obtained with 2.6 microM nigericin, but no stimulation of Na+ absorption was seen. When Ringer-HCO3- concentration was reduced from 39 to 11 mM at constant PCO2 = 35 mmHg, pHi decreased from 7.55 +/- 0.02 to 7.11 +/- 0.02 with no effect on net Na+ absorption. A similar reduction in pHi in a CO2-HCO3(-)-free, N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-buffered Ringer also did not stimulate Na+ absorption. Methazolamide had no effect on steady-state pHi at any given PCO2 but caused marked reductions in net Na+ absorption (9.6 +/- 2.4 to 5.2 +/- 1.2 mu eq.cm-2 x h-1 at PCO2 = 70 mmHg). We conclude that Na+ absorption in rat distal colon is not stimulated by intracellular acidification per se but rather has an absolute requirement for CO2 and carbonic anhydrase activity.

Animals↗
PubMed1998

Dual role of CFTR in cAMP-stimulated HCO3- secretion across murine duodenum.

The role of the cystic fibrosis transmembrane conductance regulator (CFTR) in cAMP-stimulated HCO3- secretion across the murine duodenum was investigated. Serosal-to-mucosal flux of HCO3- (Js-->m, in mu eq.cm-2.h-1) and short-circuit current (Isc; in mu eq.cm-2.h-1) were measured by the pH stat method in duodenum from CFTR knockout [CFTR(-)] and normal [CFTR(+)] mice. Under control conditions, forskolin increased Js-->m and Isc (+1.7 and +3.5, respectively) across the CFTR(+) but not CFTR(-) duodenum. Both the forskolin-stimulated delta Js-->m and delta Isc were abolished by the CFTR channel blocker 5-nitro-2-(3-phenylpropylamino)benzoate, whereas inhibition of luminal Cl-/HCO3- exchange by luminal Cl- removal or DIDS reduced the Js-->m by approximately 18% without a consistent effect on the delta Isc. Methazolamide also reduced the Js-->m by 39% but did not affect the delta Isc. When carbonic anhydrase-dependent HCO3- secretion was isolated by using a CO2-gassed, HCO3(-)-free Ringer bath, forskolin stimulated the Js-->m and Isc (+0.7 and +2.0, respectively) across CFTR(+) but not CFTR(-) duodenum. Under these conditions, luminal Cl- substitution or DIDS abolished the Js-->m but not the delta Isc. It was concluded that cAMP-stimulated HCO3- secretion across the duodenum involves 1) electrogenic secretion via a CFTR HCO3- conductance and 2) electroneutral secretion via a CFTR-dependent Cl-/HCO3- exchange process that is closely associated with the carbonic anhydrase activity of the epithelium.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2000

Acid-base effects on electrolyte transport in CA II-deficient mouse colon.

To determine the role of carbonic anhydrase (CA) in colonic electrolyte transport, we studied Car-2(0) mice, mutants deficient in cytosolic CA II. Ion fluxes were measured under short-circuit conditions in an Ussing chamber. CA was analyzed by assay and Western blots. In Car-2(0) mouse colonic mucosa, total CA activity was reduced 80% and cytosolic CA I and membrane-bound CA IV activities were not increased. Western blots confirmed the absence of CA II in Car-2(0) mice. Normal mouse distal colon exhibited net Na(+) and Cl(-) absorption, a serosa-positive PD, and was specifically sensitive to pH. Decrease in pH stimulated active Na(+) and Cl(-) absorption whether it was caused by increasing solution PCO(2), reducing HCO(-)(3) concentration, or reducing pH in CO(2)/HCO(-)(3)-free HEPES-Ringer solution. Membrane-permeant methazolamide, but not impermeant benzolamide, at 0.1 mM prevented the effects of pH. Car-2(0) mice exhibited similar basal transport rates and responses to pH and CA inhibitors. We conclude that basal and pH-stimulated colonic electrolyte absorption in mice requires CA I. CA II and IV may have accessory roles.

Acid-Base Equilibrium↗
PubMed1988

Role of Na+-H+ antiport in rat proximal tubule NaCl absorption.

We recently showed that, in the presence of physiological sodium concentrations, 4.3 mM luminal amiloride inhibits 90% of apical membrane Na+-H+ antiporter activity in the in vivo microperfused rat proximal convoluted tubule. In the present studies we examined the effect of 4.3 mM luminal amiloride on transepithelial NaCl absorption from a high-chloride, low-bicarbonate perfusate, simulating the tubular fluid of the late proximal tubule. Both chloride and volume absorption were inhibited approximately 44%, consistent with inhibition of most of transcellular NaCl absorption, and suggestive of parallel Na+-H+ and Cl(-)-base exchange as the mechanism of NaCl uptake across the apical membrane. Methazolamide (10(-4) M), a potent inhibitor of renal carbonic anhydrase, had no significant effect on either volume or chloride absorption, suggesting that a carbonic anhydrase-independent mechanism is at least partially involved in chloride absorption. Hydrochlorothiazide (1 mM), an inhibitor of electroneutral NaCl cotransport in tight epithelia, did not significantly affect either volume or chloride absorption. Thus these studies suggest that, in the rat, the mechanism of apical membrane electroneutral NaCl uptake is Na+-H+ and Cl- -base exchange.

Amiloride↗
PubMed1988

Secretion of endolymph by semicircular canals of the shark.

The semicircular canals of the vestibular labyrinth of the dogfish shark, Squalus acanthias, may serve as a simple in vitro system for the study of the ionic transport mechanisms involved in endolymph formation. Electron microscopy showed that the epithelium was made up of at least three distinct cell types divided into separate regions running the length of the canals. Secretion of endolymph was studied in isolated canals by the split droplet method; when the lumens of the canals were filled with shark Ringer a potassium-rich fluid was secreted into the lumen at a rate of 0.34 microliter.cm-2.min-1. The K concentration of the secreted fluid averaged 112 mM; the calculated rate of K secretion was 2.3 mumol.cm-2.h-1, comparable to recent measurements in mammalian utricle. Fluid secretion was dependent on active transport and was inhibited by ouabain, bumetanide, or methazolamide in the external bathing solution. Fluid secretion was unaffected by the K channel blocker, Ba, in the luminal droplet or by the adenylate cyclase stimulator, forskolin, in the external bathing solution. For electrophysiological analysis, isolated canals were perfused in a chamber designed for voltage/current clamping; an axial wire was inserted into the canal lumen and constant-current pulses were passed to determine tissue resistance. When the luminal fluid was high-K Ringer, transepithelial potential difference was -1.1 mV (lumen negative) and resistance 37 omega.cm2. Dilution and bi-ionic potential measurements showed that the epithelium of the canals exhibited only slight cation selectivity. These results are consistent with a model for endolymph secretion involving cotransport secondary to the ion gradients created by the Na+-K+-ATPase.

Animals↗
PubMed1991

Effect of thiazides on colonic NaCl absorption: role of carbonic anhydrase.

The mechanisms by which the benzothiadiazide class of diuretics inhibit electroneutral NaCl absorption are not fully understood. We studied the mechanisms of thiazide action in perfused loops of distal colon in anesthetized male Sprague-Dawley rats. Hydroflumethiazide (1 mM) reversibly inhibited greater than 40% of Na, Cl, and water absorption. Prior exposure of the colon to the carbonic anhydrase inhibitor methazolamide (0.1 mM) prevented the effects of hydroflumethiazide and metolazone, a thiazide-like drug, on colonic absorption. In Ussing flux chambers, addition of hydroflumethiazide to both the mucosal and serosal bathing solutions (but not to the mucosal solution alone) caused marked decreases in Na and Cl absorption. Such inhibition only occurred at concentrations of hydroflumethiazide (0.1 and 1.0 mM) that inhibited greater than 90% of carbonic anhydrase activity in homogenized colonic mucosa. We conclude that an important mechanism by which thiazides inhibit NaCl absorption in the rat distal colon is by inhibition of mucosal carbonic anhydrase. In tissues containing this enzyme, this mechanism of thiazide effect on ion flux must be considered.

Acetazolamide↗
PubMed2000

CO(2)/H(+) chemoreception in the cat pre-Bötzinger complex in vivo.

We examined the effects of focal tissue acidosis in the pre-Bötzinger complex (pre-BötC; the proposed locus of respiratory rhythm generation) on phrenic nerve discharge in chloralose-anesthetized, vagotomized, paralyzed, mechanically ventilated cats. Focal tissue acidosis was produced by unilateral microinjection of 10-20 nl of the carbonic anhydrase inhibitors acetazolamide (AZ; 50 microM) or methazolamide (MZ; 50 microM). Microinjection of AZ and MZ into 14 sites in the pre-BötC reversibly increased the peak amplitude of integrated phrenic nerve discharge and, in some sites, produced augmented bursts (i.e., eupneic breath ending with a high-amplitude, short-duration burst). Microinjection of AZ and MZ into this region also reversibly increased the frequency of eupneic phrenic bursts in seven sites and produced premature bursts (i.e., doublets) in five sites. Phrenic nerve discharge increased within 5-15 min of microinjection of either agent; however, the time to the peak increase and the time to recovery were less with AZ than with MZ, consistent with the different pharmacological properties of AZ and MZ. In contrast to other CO(2)/H(+) brain stem respiratory chemosensitive sites demonstrated in vivo, which have only shown increases in amplitude of integrated phrenic nerve activity, focal tissue acidosis in the pre-BötC increases frequency of phrenic bursts and produces premature (i.e., doublet) bursts. These data indicate that the pre-BötC has the potential to play a role in the modulation of respiratory rhythm and pattern elicited by increased CO(2)/H(+) and lend additional support to the concept that the proposed locus for respiratory rhythm generation has intrinsic chemosensitivity.

Acetazolamide↗
PubMed2002

Discovery of molecular mechanisms of neuroprotection using cell-based bioassays and oligonucleotide arrays.

Oxidative injury and the resulting death of neurons is a major pathological factor involved in numerous neurodegenerative diseases. However, the development of drugs that target this mechanism remains limited. The goal of this study was to test a compound library of approved Food and Drug Administration drugs against a hydrogen peroxide-induced oxidant injury model in neuroblastoma cells. We identified 26 neuroprotective compounds, of which megestrol, meclizine, verapamil, methazolamide, sulindac, and retinol were examined in greater detail. Using large-scale oligonucleotide microarray analysis, we identified genes modulated by these drugs that might underlie the cytoprotection. Five key genes were either uniformly upregulated or downregulated by all six drug treatments, namely, tissue inhibitor of matrix metalloproteinase (TIMP1), ret-proto-oncogene, clusterin, galanin, and growth associated protein (GAP43). Exogenous addition of the neuropeptide galanin alone conferred survival to oxidant-stressed cells, comparable to that seen with the drugs. Our approach, which we term "interventional profiling," represents a general and powerful strategy for identifying new bioactive agents for any biological process, as well as identifying key downstream genes and pathways that are involved.

Biological Assay↗
PubMed1986

Effect of carbonic anhydrase inhibition on (U-B)pCO2 in the alkaline urine of the rabbit.

We studied factors influencing urine pCO2 minus blood pCO2 [(U-B)pCO2] in rabbits infused with sodium bicarbonate solutions. Unlike other species, the rabbit does not develop a significant (U-B)pCO2 (urine pCO2 greater than blood pCO2) after alkali or acid buffer infusion. However, intravenous acetazolamide immediately induced a significant (U-B)pCO2. The effect could not be related to the blood pH or pCO2, the urinary concentration of bicarbonate or inorganic phosphate, or to changes in plasma potassium concentration. Methazolamide was also effective in increasing (U-B)pCO2. This significant (U-B)pCO2 was present after carbonic anhydrase inhibition in rabbits subjected to chronic partial obstruction of urinary flow and in rabbits treated with 11-desoxycorticosterone acetate (DOCA). We propose that carbon dioxide is normally dissipated from the alkaline urine of the rabbit by a distal tubular mechanism, which involves catalytic conversion of carbon dioxide to bicarbonate. Inhibition of carbonic anhydrase leads to the formation of a significant (U-B)pCO2. In the rabbit, pCO2 may be an index of collecting duct acidification under certain circumstances; however, the relation of collecting duct acidification to the high (U-B)pCO2 during the inhibition of carbonic anhydrase remains to be determined.

Acetazolamide↗
PubMed2005

Carbonic anhydrase in the adult mosquito midgut.

We have previously demonstrated the involvement of carbonic anhydrase (CA) in larval mosquito midgut physiology. In this study, we used Hansson's histochemistry to examine the distribution of the enzyme in the midgut of Aedes aegypti, Aedes albopictus, Culex quinquefasciatus, Culex nigripalpus, Ochlerotatus taeniorhynchus, Anopheles albimanus and Anopheles quadrimaculatus adult mosquitoes. Additionally, we quantitated CA content in the anterior and posterior midgut of adult males and females from these species using the 18O isotope exchange method coupled to mass spectrometry. We also tested the effect of CA inhibitors such as methazolamide and acetazolamide in the alkalization of the midgut in females from these species. Our results indicate that CA is present in the midgut of adults from the species studied and that it appears to be preferentially associated with the posterior midgut in both males and females. CA inhibitors appear to have a profound effect on midgut pH indicating that this enzyme might play a key role in the maintenance of this pH.

Acetazolamide↗
PubMed1981

Effect of acetazolamide on the anticonvulsant potency of phenobarbital in mice.

Effect of acetazolamide (AZA) on the anticonvulsant potency of phenobarbital (PHB) was investigated in mice by maximal electroshock seizure (MES) test. By coadministration with AZA, a remarkable increase an prolongation of the anticonvulsant activity of PHB was brought about. The type of the synergism of PHB with AZA was not additive but of potentiation. The potentiation of the anticonvulsant activity of PHB with AZA was rather related to inhibition of carbonic anhydrase (CA) in brain than in blood. The anticonvulsant activity of PHB was also increased by coadministration with methazolamide which had a great ability to inhibit brain CA. Furosemide, which had no inhibitory effect on brain CA, on the other hand, failed to show any potentiation on the anticonvulsant activity of PHB. Thus it was inferred that the inhibition of brain CA may play a significant role for the potentiation of the anticonvulsant activity of PHB. Although reserpinization completely abolished the protective effect of AZA on MES, the potentiation of the anticonvulsant activity of PHB was still observed by AZA. These results suggest that pharmacodynamic and/or pharmacokinetic effect of AZA independent of its anticonvulsant action may contribute to the potentiation of the PHB action.

Acetazolamide↗
PubMed1976

Acute respiratory failure precipitated by a carbonic anhydrase inhibitor.

A 60-year-old white man with chronic bronchitis was noted to develop acute respiratory failure and metabolic acidosis four days after being started on methazolamide (Neptazane) for an ophthalmologic problem. The patient was intubated with ventilator support and improved after his metabolic acidosis resolved. Caution is emphasized in the use of carbonic anhydrase inhibitors in patients with obstructive airway disease.

Acidosis, Respiratory↗
PubMed1984

The effects of separate and combined topical treatment with timolol maleate and trifluormethazolamide on the intraocular pressure in normal rabbits.

The effects of separate and combined topical treatment with timolol maleate and trifluormethazolamide (TFM) on the intraocular pressure (IOP) were studied in normotensive rabbits. Timolol had a distinct, albeit small, dose related hypotensive effect. Unilateral application of timolol resulted in dose related decrease in IOP in the untreated fellow eye. These effects could be observed only by using a protocol that reduces the contribution of individual and diurnal variations to the overall variability in IOP in the rabbit. Topical treatment with TFM caused a reduction in the calculated outflow pressure of 32%, similar to that observed after systemic administration of acetazolamide and methazolamide. At the concentration and dosage employed here there was no significant difference between the hypotensive effects of timolol and TFM. The maximal decrease in the calculated outflow pressure for the different doses of timolol varied between 24% to 37%. The hypotensive effect of the combined timolol and TFM treatment (delta IOP = -2.4 +/- 0.4 mmHg, n = 12) was greater than that observed in rabbits treated with TFM alone (delta IOP = -1.6 +/- 0.5 mmHg, n = 12). The increment was smaller than the initial effect of either drug alone.

Administration, Topical↗
PubMed1989

Coupling of 22Na and 36Cl uptake in cultured pigmented ciliary epithelial cells: a proposed role for the isoenzymes of carbonic anhydrase.

Uptake studies with 22Na and 36Cl were performed in cultured bovine pigmented ciliary epithelial cells (PE) to investigate interdependence of Na+ and Cl- transport. (1) 22Na uptake into NaCl depleted cells was stimulated by Cl-. This stimulation was abolished by the simultaneous application of amiloride (1 mM) and bumetanide (0.1 mM), indicating two independent mechanism for Cl- stimulated Na+ uptake: loop diuretic sensitive Na+/Cl- symport and an indirect stimulation of Na+/H+ exchange by Cl-. The latter component of Cl- stimulated Na+ uptake was HCO3- dependent. (2) 36Cl uptake was increased by extracellular Na+. Na+-stimulated Cl- uptake also consisted of two components. One was bumetanide sensitive and the other was blockable by amiloride and partly inhibited by the carbonic anhydrase (CA) inhibitor methazolamide (0.1 mM). (3) Homogenized PE cells were tested for biochemical CA activity using an electrometric method. The cytoplasmic as well as the membrane fraction contained specific CA activity. (4) A model is presented for Na+ and Cl- transport into PE: in addition to Na+/Cl- symport, Na+/H+ and Cl-/HCO3- double exchange may operate in the ciliary epithelium. The latter mechanism provides NaCl uptake into the cell in exchange for H+ and HCO3-, which recycle as CO2 across the membrane. This recycling of CO2 and HCO3-/H+ (and hence indirectly NaCl uptake) is facilitated by the cooperation between membrane bound and cytoplasmic CA.

Amiloride↗
PubMed1979

[The broncholytic effect of carboanhydrase inhibitors in subjects with healthy lungs (author's transl)].

Carboanhydrase inhibitors are said to have a positive effect on respiratory insufficiency. We examined this, especially regarding the bronchial system. Actions and reactions of the human bronchial system can be followed by measurement of the anatomical dead space breath by breath. We have developed a new method which was tested by classical broncho-effective substances. Our experiments show in case of two men with healthy lungs that the three carboanhydrase inhibitors acetazolamide, methazolamide, and dichlorphenamide have a pronounced broncholytic effect. The effect is greater than that of fenoterol. In addition the bronchial peristalsis and the bronchial compliance are increased. In contrast to fenoterol carboanhydrase inhibitors have no cardiac side effect.

Acetazolamide↗
PubMed1977

Physiology and chemistry of cerebrospinal fluid, aqueous humor and endolymph in Squalus acanthias.

By means of the appropriate isotopes injected into the spiny dogfish, Squalus acanthias, the transfer of all major ions into cerebrospinal fluid (CSF), aqueous humor (A) and endolymph (E) was studied. In addition, the effect of raising pCO2 in sea-water upon HCO3- concentration of these fluids was measured. In the several types of experiments, acetazolamide or methazolamide was used to inhibit completely carbonic anhydrase. The rates of fluid formation and ion transfer in CSF and A were fairly close, but those for E were far slower. The general pattern of ion transport in the three fluids were the same, Na+ (or Na+ + K+ in E) entry greater than Cl - entry, and the difference was HCO3-. The greater rate constants for HCO3-, increase in its entry rate by elevation of pCO2, and inhibition of its appearance by the sulfonamides, show that this is a special case of transport; the ion is formed in secretory cells from gaseous CO2 + OH-. Secretory cells at sites of formation of all the fluids contain both carbonic anhydrase and Na+-K+-ATP-ase, which subserve HCO3- formation and Na+ (or K+) transport. Comparison of these results with studies in mammals show that the vertebrate pattern for secretion of these three fluids is well established in the elasmobranch.

Adenosine Triphosphatases↗