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PubMed1980

The relation of choroid plexus carbonic anhydrase activity to cerebrospinal fluid formation: study of three inhibitors in cat with extrapolation to man.

Drugs which inhibit carbonic anhydrase (CA) reduce cerebrospinal fluid (CSF) flow. This study relates the inhibition of CSF flow in cats after 1 to 30 mg/kg of methazolamide, acetazolamide or benzolamide (inhibitors of differing pharmacokinetic properties) to plasma and choroid plexus levels of these drugs. From plasma concentrations of unbound drug and the dissociation constants for the interaction of drugs with choroid plexus CA, it is shown that the concentration of residual active CA in choroid plexus of cats must be reduced from approximately 22 microM to the range of 5 to 10 nM to reduce CSF flow significantly. This represents at least 99.95% inhibition of CA of choroid plexus. This level of inhibition was achieved by an i.v. dose of 30 mg/kg of methazolamide, acetazolamide or benzolamide, whereas doses of 10 mg/kg of methazolamide or acetazolamide did not significantly decrease mean residual CSF flow. The data suggest that it is the residual flow after inhibition, not the absolute or percentage of decrease in flow, which should be used to evaluate the effectiveness of CA inhibition, because of the variability in individual control rates. Maximal effects of CA inhibition in cat reduce flow to 9 to 11 microliter/min from a mean of 21.7 microliter/min. In choroid plexus of man, the CA concentration is, at most, 40% that of cat. An attempt has been made to use CA concentration, drug binding data and other pharmacokinetic factors in predicting appropriate choices of drug and dose for man, extrapolating from the data for cats. These predictions are compared to existing data for plasma levels or CSF effects of CA inhibitors in man.

Acetazolamide↗
PubMed1997

Timolol decreases aqueous humor flow but not Na+ movement from plasma to aqueous.

PURPOSE: To determine whether the well-known effect of timolol in reducing ocular pressure and aqueous humor (AH) flow is a function of reduced Na+ movement from plasma to aqueous. Previously, the authors have shown this to be the case for carbonic anhydrase inhibitors. METHODS: The rate of appearance of 22Na in rabbit posterior aqueous was measured 1 to 3 minutes after the intravenous injection (time T) of the isotope. One hour before this, the animals received one of the following: two drops of 0.5% timolol, two drops of 3.5% pilocarpine, or 25 mg/kg intravenous methazolamide. At 1 minute (T + 1), a posterior chamber sample was taken; 2 minutes later (T + 3) a second sample was removed from the fellow eye. The rate constant of sodium accession is simply the difference between the two counts/2 minutes. Aqueous flow was measured by dilution of sulfacetamide marker as described previously. RESULTS: The rate constant (k(in)) for sodium entering the posterior chamber was 0.036 +/- 0.004 minute-1 (n = 17). Corresponding to previous findings, methazolamide (25 mg/kg intravenous) reduced this to 0.023 +/- 0.003 minute-1 (n = 14). Conversely, timolol (two drops of 0.5% solution) had no effect on kin, which measured 0.037 +/- 0.004 minute-1 (n = 12). Similarly, as expected, pilocarpine had no effect on k(in) (0.035 +/- 0.003 minute-1). Control flow was 3.9 microliters/minute +/- 0.4; after timolol, 2.5 microliters/minute +/-0.1; after methazolamide, 2.4 microliters/minute +/-0.2; after pilocarpine, 3.6 microliters/minute +/- 0.2. These are converted to rate constants by dividing by volume of posterior aqueous (60 microliters). The control rate constant for fluid entry was 0.065 minute-1, 1.8-fold higher than for sodium. CONCLUSIONS: A central dogma of the formation of AH (and cerebrospinal fluid) is that fluid moves isotonically from plasma to AH or cerebrospinal fluid and, therefore, that rate constant k(in) for fluid and for sodium are approximately the same. In the authors' hands, the fluid constant was modestly higher than for sodium. This holds for normal function and also for the reduced k(in) for fluid and sodium after carbonic anhydrase inhibition. The k(in) for neither flow nor sodium was affected by pilocarpine. Surprisingly, however timolol, which reduces flow, had no effect on Na+ entry.

Adrenergic beta-Antagonists↗
PubMed2005

Carbonic anhydrase inhibitors. Inhibition of the membrane-bound human and bovine isozymes IV with sulfonamides.

An inhibition study of the human and bovine membrane-associated isozymes of carbonic anhydrase (CA, EC 4.2.1.1), hCA IV and bCA IV, with a series of sulfonamides and sulfamates, some of which are widely clinically used, such as acetazolamide, methazolamide, ethoxzolamide, topiramate, dorzolamide, dichlorophenamide, celecoxib, and valdecoxib among others, is reported. In contrast to bCA IV, which is generally strongly inhibited by most of these derivatives, hCA IV has a rather different inhibition profile. Several of these compounds such as acetazolamide, ethoxzolamide, and bromosulfanilamide are potent hCA IV inhibitors (K(i)'s of 74-93 nM), others, such as celecoxib and some halogenated sulfanilamides are medium potency inhibitors (K(i)'s of 450-880 nM) whereas most of them are weak hCA IV inhibitors (methazolamide: 6.2 microM; dorzolamide 8.5 microM; topiramate 4.9 microM; dichlorophenamide: 15.3 microM). The hCA IV/bCA IV inhibition ratios for all the investigated compounds ranged between 1.05 (for acetazolamide) and 198.37 (for dorzolamide). Based on these results, we doubt that hCA IV is indeed one of the main contributors to the intraocular pressure (IOP) lowering effects of sulfonamide CA inhibitors, in addition to hCA II, as hypothesized earlier by Maren et al. (Mol. Pharmacol.1993, 44, 901-906). Indeed, both the very good hCA IV inhibitors (acetazolamide and ethoxzolamide) as well as the quite weak hCA IV inhibitors (methazolamide, dorzolamide, or dichlorophanamide) are effective in lowering IOP when administered either systemically or topically. The membrane-associated isozyme which probably is critical for aqueous humor secretion is hCA XII and not hCA IV.

Animals↗
PubMed2003

Cortisol alters carbonic anhydrase-mediated renal sulfate secretion.

Active transepithelial sulfate secretion rate by winter flounder renal proximal tubule epithelium in primary culture (fPTC) is dependent on intracellular carbonic anhydrase (CA) and enhanced by cortisol. To further evaluate this relationship, a partial cDNA clone (327 bp) of carbonic anhydrase II (CAII) with high sequence similarity to CAII from numerous species including fish, chicken, and human was obtained from fPTCs. The majority of CA activity and CAII protein was present in the cytosol of fPTCs; however, significant amounts of both (in addition to SDS-resistant CA activity, i.e., CAIV-like isoform) were present in concentrated plasma membranes. CAII from concentrated membranes migrated differently than purified CAII on nondenaturing PAGE gels, suggesting that CAII associates with another membrane component. Treatment of fPTCs with the cell-soluble CA inhibitor methazolamide (100 microM) caused a 58% reduction in active transepithelial SO4(2-) secretion. fPTCs that were previously cultured under high-cortisol concentrations, when subjected to 5 days of low physiological levels of cortisol, had decreased CA activity (28%), CAII protein abundance (65%), and net active SO4(2-) secretion (28%), with no effect on epithelial differentiation. Methazolamide and low-cortisol treatment in combination inhibited net active SO4(2-) secretion 56%, which was not different than the effect of methazolamide treatment alone. These data indicate that cortisol directly increases renal CA activity, CAII protein abundance, and CA-dependent SO4(2-) secretion in the marine teleost renal proximal tubule.

Acidosis↗
PubMed2000

Interactions between carbonic anhydrase and its inhibitors revealed by gel electrophoresis and circular dichroism.

Structural properties, and especially the differential stability, of complexes between carbonic anhydrase (CA) and three sulfonamide inhibitors, acetazolamide, dorzolamide and methazolamide, were investigated by spectroscopic and electrophoretic techniques. These included denaturant gradient gel electrophoresis either across a urea or a steady-state transverse sodium dodecyl sulfate (SDS) gradient. Acetazolamide, the smallest and most hydrophilic of the sulfonamides, forms the most stable complex in the presence of urea, whereas dorzolamide, with a bulky and hydrophobic structure, is most stable against the effects of SDS. At pH 7.4, complexes with dorzolamide show minimal changes in mobility across the SDS gradient, as if unaffected by the detergent, both in the presence and in the absence of excess ligand in the gel. When bound to both acetazolamide and methazolamide, on the other hand, CA displays an increase in mobility above 0.05% SDS, lower in the presence than in the absence of excess ligand. The finding of a distinct pattern for the unliganded enzyme, however, suggests the complexes can still retain the ligand, although binding of the surfactant changes their charge density. Under saturating conditions and in the presence of SDS, the surface charge of all complexes is much lower than for unliganded, denatured CA. Circular dichroism (CD) spectra clearly indicate that the increase in secondary structure and the decrease in tertiary structure brought about in CA by the presence of low concentrations of SDS are largely prevented by complexing with the inhibitors. These observations point out peculiar properties of each CA inhibitor, of potential value in the definition of their biological activities and also in the potential development of novel antagonist molecules.

Acetazolamide↗
PubMed1996

A novel system to measure labelled CO2 and HCO3- fluxes across epithelia: corneal epithelium as model tissue.

A method that allows for an accurate measurement of 14C-labelled fluxes of HCO3- and/or CO2 across epithelia is described. It is based on the principle that in a closed system the specific activities of HCO3- and CO2 are equal to each other. The hemichambers between which the tissue was mounted were modified Ussing-type chambers that included a capacity for recirculation and mixing of the labelled fluid and gas phases within a closed system. The isolated frog corneal epithelium was used as a model system. In solutions containing 25 mM HCO3- and 5% CO2, the unidirectional fluxes from tear to stroma (t-s) and stroma to tear (s-t) were 3.08 +/- 0.12 and 2.33 +/- 0.11 mu eq h-1 cm-2 (means +/- S.E.S), respectively, with a statistically significant t-s net flux. These fluxes were independent of the presence of Cl- in the bathing solutions. The bilateral addition of methazolamide (10(-4) M) reduced both unidirectional fluxes to about 2.0 mu eq h-1 cm-2. This finding was a strong indication of the presence of carbonic anhydrase (CA) in the corneal epithelium as well as its involvement in the production of the net flux of 14C-label. In nominally CO2-free media, unidirectional t-s and s-t fluxes were 0.19 +/- 0.03 and 0.27 +/- 0.05 respectively. These fluxes were not affected by methazolamide. The s-t net HCO3- flux can result from the activity of a basolaterally located Na(+)-(n)HCO3- cotransporter. The CO2-elicited t-s net flux could also be explained by the presence of this transporter and a recirculation of label across the basolateral membrane.

Animals↗
PubMed1995

Mechanisms of fluid and ion secretion by the parotid gland of the kangaroo, Macropus rufus, assessed by administration of transport-inhibiting drugs.

Possible mechanisms of primary fluid formation by macropodine parotid glands were investigated in anaesthetized red kangaroos using ion transport inhibitors. Carotid plasma amiloride concentrations of 0.05-0.5 mmol.l-1 progressively reduced a stable acetylcholine-evoked half-maximal flow rate of 2.0 +/- 0.04 to 0.22 +/- 0.024 ml.min-1 (mean +/- SEM). Concurrently, saliva bicarbonate concentration and secretion fell (135 +/- 1.6 to 67 +/- 1.7 mmol.l-1 and 272 +/- 7.6 to 15 +/- 2.6 mumol.min-1, respectively); [phosphate], [chloride] and [sodium] rose and [potassium] and osmolality were unaltered. High-rate cholinergic stimulation did not increase saliva flow beyond 11 +/- 1.0% of that for equivalent pre-amiloride stimulation. Equipotent levels of amiloride and methazolamide given concurrently were no more effective at blocking flow and bicarbonate secretion than when given separately. Furosemide (up to 2 mmol.l-1), bumetanide (up to 0.2 mmol.l-1) and ethacrynate (1 mmol.l-1) in carotid plasma had no effect on salivary flow or ion concentrations. During methazolamide blockade, furosemide did not curtail the concurrent increase in salivary [chloride]. Chlorothiazide at 0.25-1.0 mmol.l-1 caused progressive depression of saliva flow and [bicarbonate], and elevation of [chloride]. 4-acetamido-4'-isothiocyanatostilbene-2,2'disulphonic acid at 0.1 mmol.l-1 was without effect, whereas at 0.5 mmol.l-1 it stimulated fluid secretion and increased saliva [protein], [sodium], [potassium], [bicarbonate] and osmolality. Concurrently, mean arterial blood pressure and pulse pressure fell and heart rate, haematocrit and carotid artery plasma flow rose. These responses were absent if saliva flow was kept constant by reduction in cholinergic stimulation during 4-acetamido-4-isothiocyanatostilbene-2,2'disulphonic acid administration. It is concluded that secretion of primary fluid by the kangaroo parotid is initiated mainly (> 90%) by secretion of bicarbonate which is formed in the endpiece cells from CO2 delivered by the circulation. No evidence was found for initiation of fluid secretion by chloride transport involving basolateral Na(+)-K(+)-2Cl- symports, Na(+)-Cl- symports or Cl-/HCO3- antiports.

Amiloride↗
PubMed1985

Lack of soluble carbonic anhydrase in aortic smooth muscle of the rabbit.

Rabbit aorta was investigated for the occurrence of soluble, methazolamide-sensitive carbonic anhydrase (CA) by measuring electrometrically the rate of acidification of a weakly alkaline CO2 solution buffered with 12.5 mM veronal/HCl at 0 degree C. For this purpose, aortae of 10 rabbits with the endothelium carefully preserved, were homogenized, centrifuged, and the supernatants pooled. The proteins were fractionated by FPLC, and tested for their CA activity. In control experiments, the pH change resulting from the spontaneous CO2 hydration was found to be -0.92 +/- 0.01 pH units/min (mean +/- SE, n = 10). Aliquots of the 30,000 dalton protein fraction corresponding to 100 mg of aortic tissue wet weight did not alter the hydration rate significantly (-0.94 +/- 0.01 pH units/min, n = 10). Also, in the presence of 10(-4) M of the CA inhibitor, methazolamide, these rates were not altered significantly (-0.94 +/- 0.01 and -0.93 +/- 0.01 pH units/min, respectively, n = 10). No CA activity was found in the other FPLC fractions, either. These results suggest that soluble CA is absent from the myocytes and the endothelium of the rabbit aorta.

Animals↗
PubMed2001

Gramicidin-perforated patch analysis on HCO3- secretion through a forskolin-activated anion channel in rat parotid intralobular duct cells.

Forskolin-induced anion currents and depolarization were investigated to clarify the mechanism of HCO3- secretion in the intralobular duct cells of rat parotid glands. Anion currents of the cells were measured at the equilibrium potential of K+, using a gramicidin-perforated patch technique that negligibly affects intracellular anion concentration. The forskolin-induced anion current was sustained and significantly (54%) suppressed by glibenclamide (200 microM), a blocker of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. The anion current was markedly suppressed by addition of 1 mM methazolamide, a carbonic anhydrase inhibitor, and removal of external HCO3-. Forskolin depolarized the cells in the current-clamp mode. Addition of methazolamide and removal of external HCO3- significantly decreased the depolarizing level. These results suggest that activation of anion channels (mainly the CFTR Cl- channel located in luminal membranes) and production of cytosolic HCO3- induce the inward anion current and resulting depolarization. Inhibition of the Na(+)-K(+)-2Cl- cotransporter and the Cl(-)-HCO3- exchanger had no significant effect on the current or depolarization, indicating that the uptake of Cl- via the Na(+)-K(+)-2Cl- cotransporter or the Cl(-)-HCO3- exchanger is not involved in the responses. Taken together, we conclude that forskolin activates the outward movement (probably secretion) of HCO3- produced intracellularly, but not of Cl- due to lack of active Cl- transport in parotid duct cells, and that the gramicidin-perforated patch method is very useful to analyze anion transport.

Amiloride↗
PubMed1978

Patient tolerance to carbonic anhydrase inhibitors.

We evaluated carbonic anhydrase inhibitors in a crossover study with a placebo and random allocation of treatment administration. Drugs evaluated included acetazolamide tablets and Sequels, dichlorphenamide, ethoxzolamide, methazolamide, and an ascorbic acid placebo. The best tolerated drug was acetazolamide Sequels. Methazolamide was next. The least tolerated drugs were ethoxzolamide, acetazolamide tablets, and dichlorphenamide.

Acetazolamide↗
PubMedDate not supplied

The effect of transport-blocking drugs on secretion of fluid and electrolytes by the mandibular gland of red kangaroos, Macropus rufus.

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.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed1991

Calcium metabolism in acidotic patients induced by carbonic anhydrase inhibitors: responses to citrate.

Calcium metabolism and its response to citrate were examined in 51 patients with glaucoma receiving carbonic anhydrase inhibitors (acetazolamide or methazolamide). Metabolic acidosis, hypocitraturia and increased incidence of nephrolithiasis were induced by both drugs. However, the acidosis was milder with methazolamide administration. Normocalciuria was observed in 29 patients and was shown to be a result of low filtered calcium. Renal hypercalciuria in 16 patients was associated with elevated parathyroid hormone but nephrogenic cyclic adenosine monophosphate remained within normal limits. Citrate in the form of potassium citrate (4.3 mmol.) and sodium citrate (4.0 mmol.) did not correct the metabolic acidosis or hypocitraturia but consistently decreased fasting and 24-hour urinary calcium excretion in patients with renal hypercalciuria. This event did not occur in patients with normocalciuria or absorptive hypercalciuria. These results suggest that a small amount of citrate could reverse renal hypercalciuria without correcting the metabolic acidosis.

Acetazolamide↗
PubMed1981

Reducing side effects of carbonic anhydrase inhibitors.

Carbonic anhydrase inhibitor (CAI) side effects are common, but not well understood. Many ideas have surfaced on how to reduce these side effects, even though there is little scientific evidence to support some of the advice. One recommendation involves switching drugs when patients are intolerant of a particular CAI agent. This study included 44 glaucoma patients who needed a CAI drug. All patients were placed on acetazolamide tablets 250 mg qid. Of those who could not tolerate this drug (26 patients), 22 were switched to methazolamide. Half of these 22 (50%) were considered to have "severe" side effects to methazolamide, while 88% of them had "severe" side effects to acetazolamide. Reduction of intraocular pressure was similar on the two drugs. Other than switching drugs to reduce CAI side effects, one can try reduced dosages, a gradual dosage increase, and patience. Administering sodium bicarbonate or potassium, or taking the CAI drug with meals are unproven remedies.

Acetazolamide↗
PubMed1998

Anion exchanger and chloride channel in cat carotid body chemotransduction.

In order to test the hypothesis that carotid body (CB) chemoreception depends on the functions of anion channels and HCO3-/Cl- exchangers, we studied the effects of the anion channel blocker anthracene-9-carboxylic acid (9-ANC), the carbonic anhydrase inhibitor methazolamide, and the HCO3-/Cl- exchanger blocker 4,4 diisothiocyanatostilbene-2-2'disulfonic acid (DIDS) on the chemosensory discharges of cat CB, perfused-superfused in vitro at 36.5 +/- 0.5 degrees C, with a modified Tyrode solution. The chemosensory responses to hypoxia (PO2 approximately 50 Torr), hypercapnia (PCO2 approximately 60 Torr, pH = 7.10), nicotine (2-4 nmol) and NaCN (20-40 nmol) were recorded. 9-ANC (2 microM) and DIDS (10 microM) decreased the chemosensory baseline activity, and eliminated the initial peak responses to hypercapnia and hypoxia and increased the time to achieve it. Methazolamide (0.13 mM) did not alter the effect of 9-ANC. The steady state responses to hypoxia and hypercapnia were not diminished after 9-ANC but DIDS lowered the responses. Responses to NaCN effects were all diminished but those to nicotine were not affected. The results suggest that the functions of anion channels and HCO3-/Cl- exchangers are important for the resting dischargers and for the fast responses to hypoxia and hypercapnia.

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

Thermodynamics of binding of the CO2-competitive inhibitor imidazole and related compounds to human carbonic anhydrase I: an isothermal titration calorimetry approach to studying weak binding by displacement with strong inhibitors.

The visible spectrum of Co(II)-substituted human carbonic anhydrase I (HCA I) complexed with the unique CO2-competitive inhibitor imidazole undergoes a marked alkaline intensification, with a midpoint near pH 8 [Bauer, R., Limkilde, P., & Johansen, J. T. (1977) Carlsberg Res. Commun. 42, 325-339]. This change was first attributed to the ionization of a nondisplaced water ligand of the active-site metal in a five-coordinate complex. Later proposals favored assigning it to the deprotonation of the bound imidazole itself to give a tetrahedrally coordinated imidazolate anion at high pH. We have determined by isothermal titration calorimetry the pH dependence of the enthalpy of binding of imidazole and its analogues to HCA I and Co(II)HCA I. We devised an indirect strategy whereby the enthalpy of binding of the strong sulfonamide inhibitor methazolamide was determined in the absence and presence of a constant high concentration of the competing imidazole or its analogues. The standard enthalpy of binding of deprotonated methazolamide to the "acid" form of HCA I and Co(II)HCA I was found to be pH independent over the pH range of 6.5-9.5, as expected. It was also identical for both the zinc (-13.5 +/- 1.1 kcal M-1) and the cobalt (-13.7 +/- 0.4 kcal M-1) forms. The standard enthalpy of binding of neutral imidazole (average value -6.1 +/- 0.8 kcal M-1) surprisingly did not show any marked pH dependence, varying by about 1.1 and 2.6 kcal M-1 for the zinc and cobalt enzymes, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding, Competitive↗
PubMed2002

Inhibition of aquaporin-mediated CO2 diffusion and voltage-gated H+ channels by zinc does not alter rabbit lung CO2 and NO excretion.

Aquaporins (AQs) increase cell membrane CO(2) diffusivity, and it has been proposed that they may serve as transmembrane channels for CO(2) and other small gas molecules. In addition, it has been hypothesized that voltage-gated H(+) channels located on the apical membrane of the alveolar epithelium contribute to CO(2) elimination by the lung. To test whether these membrane proteins contribute to CO(2) elimination in vivo, we measured CO(2) exchange in buffer- and blood-perfused rabbit lungs before and after addition of 0.5 mM ZnCl(2), an inhibitor of both AQ-mediated CO(2) diffusion and voltage-gated H(+) channels. For comparison, red cell and lung carbonic anhydrases (CAs) were inhibited by 0.1 mM methazolamide. ZnCl(2) had no effect on CO(2) exchange when inspired CO(2) was altered between 2% and 5% in 5-min intervals. Pulmonary vascular and airway resistances were not altered by ZnCl(2). In contrast, methazolamide inhibited CO(2) exchange by 30% in buffer-perfused lungs and by 65% in blood-perfused lungs. Exhaled NO concentrations were unaffected by ZnCl(2) or by CA inhibition. Lung capillary gas exchange modelling shows that under normal resting conditions it would be necessary to reduce the alveolar-capillary membrane CO(2) diffusion capacity by >90% to lower CO(2) elimination by 10%. Therefore we conclude that red cell and lung AQs and voltage-gated H(+) channels in the alveolar epithelium contribute minimally to normal physiological CO(2) elimination.

Animals↗
PubMed2006

Carbonic anhydrases and mucosal vanilloid receptors help mediate the hyperemic response to luminal CO2 in rat duodenum.

BACKGROUND & AIMS: The duodenal mucosa is exposed to PCO(2) >200 mm Hg due to the luminal mixture of gastric acid with secreted bicarbonate, which augments mucosal protective mechanisms. We examined the hyperemic response to elevated luminal PCO(2) in the duodenum of anesthetized rats luminally exposed to high CO(2) saline to help elucidate luminal acid-sensing mechanisms. METHODS: Blood flow was measured by laser Doppler, and intracellular pH of epithelial cells by measured by ratio microimaging. The permeant carbonic anhydrase (CA) inhibitor methazolamide, relatively impermeant CA inhibitor benzolamide, vanilloid receptor antagonist capsazepine, or sodium-hydrogen exchanger 1 (NHE-1) inhibitor dimethyl amiloride were perfused with or without the high CO(2) solution. RESULTS: The high CO(2) solution increased duodenal blood flow, which was abolished by pretreatment with methazolamide or capsazepine or by dimethyl amiloride coperfusion. Sensory denervation with capsaicin also abolished the CO(2) effects. Benzolamide dose-dependently inhibited CO(2)-induced hyperemia and at 100 nmol/L inhibited CO(2)-induced intracellular acidification. The membrane-bound CA isoforms IV, IX, XII, and XIV and cytosolic CA II and the vanilloid receptor 1 (TRPV1) were expressed in duodenum and stomach. Dorsal root ganglion and nodose ganglion expressed all isoforms except for CA IX. CONCLUSIONS: The duodenal hyperemic response to luminal CO(2) is dependent on cytosolic and membrane-bound CA isoforms, NHE-1, and TRPV1. CO(2)-induced intracellular acidification was inhibited by selective extracellular CA inhibition, suggesting that CO(2) diffusion across the epithelial apical membrane is mediated by extracellular CA. NHE-1 activation preceding TRPV1 stimulation suggests that luminal CO(2) is sensed as H(+) in the subepithelium.

Amiloride↗
PubMed1995

A Na(+)-dependent mechanism is involved in mucosal uptake of cinnamic acid across the jejunal brush border in rats.

Phenolic acids are present in all plant-derived foods and in most diets. Indirect evidence indicates substantial absorption of phenolic monomers from the gastrointestinal tract. However, the mechanisms involved in the absorptive process are unknown. The present study investigates mucosal uptake of radioactively labeled cinnamic acid as a model substance for monomeric cinnamic acid derivatives (e.g., cinnamic, ferulic or caffeic acid) in the rat jejunum using an in vitro mucosal uptake technique. The results indicate the existence of a Na(+)-dependent saturable transport mechanism for uptake of cinnamic acid across the jejunal brush border membrane. The observed Na+ dependence of jejunal cinnamate uptake seems not to be related to the activity of the Na+,H+ exchanger. Lowering the pH of the incubation medium resulted in a pronounced increase in mucosal cinnamate uptake that can be only partially explained by an increase in nonionic diffusion of cinnamic acid. Furthermore, jejunal uptake of cinnamate seems to be influenced by intracellular HCO3- and/or pH, since the addition of methazolamide to a HCO3(-)- and CO2-free incubation medium significantly inhibited mucosal cinnamate uptake, whereas methazolamide was without an effect in the presence of HCO3- and CO2 in the incubation medium. Unlabeled cinnamic and ferulic acid as well as short-chain fatty acids (acetic, propionic and butyric acid) significantly inhibited Na(+)-dependent uptake of radioactivity labeled cinnamic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗