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PubMed1993

A comparison between the effect of topical and systemic carbonic anhydrase inhibitors on aqueous humor secretion.

We have assessed the onset and duration of decreased intraocular pressure and aqueous humor flow contrasting systemic and topical administration of carbonic anhydrase inhibitors. The relationship between physiological effects and fractional activity of carbonic anhydrase isoenzymes in the eye was also investigated. Experiments were performed in normotensive New Zealand white rabbits. Intraocular pressure was determined manometrically or tonometrically and aqueous humor flow by sulfacetamide clearance. We studied methazolamide (25 mg kg-1), ethoxzolamide (4 mg kg-1), and MK-927 (2% in 0.5% hydroxyethylcellulose, topical, pH 4.8). There is an immediate reduction in intraocular pressure (1.2 and 1.8 mmHg by 2 min) and aqueous flow (33% and 40% by 5 min) following intravenous dosing with either methazolamide or ethoxzolamide. This correlates with rapid appearance of drug in the anterior uvea and very low fractional activity of ocular carbonic anhydrase isoenzymes II (cytosolic) and IV (membrane bound). Peak intraocular pressure reduction averaged 4.2 +/- 0.68 mmHg and 4.5 +/- 0.8 mmHg for methazolamide and ethoxzolamide at 60 and 45 min, respectively. Peak flow reduction was 38% for methazolamide and 40% for ethoxzolamide, at 5 min. Aqueous flow and intraocular pressure returned to baseline at 7 and 4 hr following methazolamide and ethoxzolamide, respectively. This corresponds to decay of drug from ocular tissues and significant increases in fractional activity of carbonic anhydrase isoenzymes. Topical MK-927 resulted in a 1.2 mmHg decrease in pressure by 5 min. This correlated with the early appearance of drug in the anterior uvea prior to its appearance in aqueous humor and very low fractional activity of carbonic anhydrase isoenzymes. Intraocular pressure decreased 3.6 +/- 0.35 mmHg at 1 hr and returned to baseline by 6 hr. Aqueous flow was reduced 12% by 5 min and 35% at 1 hr. The appearance of MK-927 in the anterior uvea prior to detection in aqueous suggests a significant non-corneal route of absorption following topical administration. Topical MK-927 results in a more gradual reduction in intraocular pressure and flow, although peak effects are not statistically different from systemic carbonic anhydrase inhibitors. The time of pressure return to baseline is also comparable to systemic carbonic anhydrase inhibitors. Because the relations between carbonic anhydrase II and carbonic anhydrase IV in the ciliary process are not yet clear and since the drugs have different affinities for the isozymes, the precise degree of fractional inhibition necessary for pharmacological effect is not certain, but based on drug concentration in the anterior uvea, may take 98% inhibition for full intraocular pressure reduction.

Administration, Topical↗
PubMed2002

Non-catalytic role of carbonic anhydrase in rat intestinal absorption.

Carbonic anhydrase (CA) inhibition reduces NaCl absorption in rat distal ileum, a pH-sensitive, low CA activity tissue, and in distal colon, a CO(2)-sensitive, high CA activity tissue. We hypothesized that CA plays a non-catalytic role in NaCl absorption in these segments. Unidirectional fluxes of Na(+) and Cl(-), and total HCO(3)(-) generation (estimated as the sum of radiolabeled HCO(3)(-) and CO(2) produced from glucose) were measured in Ussing chambers in nominally CO(2), HCO(3)(-)-free HEPES Ringer. Measurements were made in the presence and absence of 0.1 mM methazolamide, a membrane-permeant CA inhibitor. Ringer pH reduction from 7.6 to 7.1 stimulated ileal but not colonic Na(+) and Cl(-) absorption. In the ileum, methazolamide reduced J(ms)(Na) and J(ms)(Cl) and caused net Cl(-) secretion at pH 7.6, and prevented the stimulatory effect of lowering pH. In the colon, methazolamide reduced Na(+) and Cl(-) absorption at pH 7.6. Total HCO(3)(-) generation was minimal in HEPES at pH 7.6 and 7.1 in both segments, was minimally affected by methazolamide, and did not account for the changes in Cl(-) absorption caused by pH or methazolamide. We conclude that CA plays a role in ileal and colonic NaCl absorption independent of its catalytic function.

Animals↗
PubMed1989

Inhibition of carbonic anhydrases in type I muscle fibers influences contractility.

We tested the effects of inhibiting the carbonic anhydrase activity of rat soleus and extensor digitorum longus muscles on the isometric contractile properties and the resistance to fatigue. SOL and EDL muscles from female rats were incubated in vitro in the presence of methazolamide, a specific inhibitor of carbonic anhydrase, before determining their contractile properties. Methazolamide had no effects on the contractile properties of the soleus muscle (10(-5) or 10(-3) M) and extensor digitorum longus (10(-3) M), except for the half-relaxation time of the soleus muscle which increased significantly. Values for half-relaxation time were significantly increased with both concentrations of the inhibitor. Muscles were then submitted to a fatigue protocol lasting 30 min. During the fatigue test, no significant difference was observed between control and 10(-5) M methazolamide soleus muscles. In presence of 10(-3) M methazolamide however, the soleus muscle showed a significantly increased resistance to fatigue compared with control preparations. No significant effect was observed with the extensor digitorum longus muscle exposed to 10(-3) M methazolamide. Results are discussed in terms of the presence of two different isoforms of carbonic anhydrase that may be associated with calcium uptake and energy metabolic processes, respectively.

Animals↗
PubMed2004

Low-dose PGE2 mimics the duodenal secretory response to luminal acid in mice.

Luminal exposure to concentrated acid, the most accepted physiological stimulus for duodenal bicarbonate secretion (DBS), cannot be used with in vitro preparations due to potential tissue damage. We thus examined whether exposure to PGE(2), a well-characterized physiological duodenal secretagogue, could mimic the effects of acid perfusion. DBS was measured in C57/BL mice by pH-stat/back-titration and measurement of total dissolved CO(2) concentration ([CO(2)](t)). Anion transport inhibitor DIDS, anion channel inhibitor 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), carbonic anhydrase inhibitor methazolamide, and nonselective cyclooxygenase inhibitor indomethacin were used to inhibit separate components of HCO(3)(-) secretory pathway. Baseline DBS was not altered by exposure to methazolamide (0.1 mM) but was slightly reduced by DIDS (0.5 mM). DBS and [CO(2)](t) increased after acid and PGE(2) exposure. DIDS (0.5 mM) and NPPB (0.2 mM) abolished acid-induced DBS increase. Methazolamide (0.1 mM) and DIDS inhibited acid-induced [CO(2)](t) increase. DIDS, NPPB, or methazolamide had little effect on DBS in response to high concentration PGE(2) (100 microg/ml). Low concentration PGE(2) (1 microg/ml) increased DBS that was inhibited by DIDS, NPPB, and methazolamide. Pretreatment with indomethacin (5 mg/kg) inhibited DBS induced by acid exposure but not by PGE(2). High-dose PGE(2) substantially increases DBS by a mechanism that appears to be different than secretory response to luminal acid perfusion. Secretory response to low-dose PGE(2), at least in terms of inhibitor profile, closely resembles secretion in response to perfusion of physiological acid concentrations and may be a useful stimulus for in vitro study of DBS in isolated mouse duodenum.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1994

A physiological measure of carbonic anhydrase in Müller cells.

Carbonic anhydrase activity was characterized in freshly dissociated Müller cells of the salamander retina. Intracellular pH was monitored using ratio imaging of the indicator dye BCECF as extracellular PCO2 was varied. The extracellular solution was switched rapidly (141 ms rise time) from a HEPES buffered to a CO2-HCO3- buffered solution (both pH 7.4). Introduction of CO2-HCO3- produced a rapid cell acidification. Cell pH dropped from a steady-state pH of 7.02 in HEPES solution to pH 6.81 in CO2-HCO3-. Methazolamide, a carbonic anhydrase inhibitor, dramatically reduced the initial rate of acidification, demonstrating that the acidification was produced by the carbonic anhydrase-catalyzed hydration of CO2. The initial rate of acidification, 52.6 pH units per min (0.88 pH units per s), was reduced approximately 150-fold to 0.36 pH units per min by 10(-3) M methazolamide. Half-maximal inhibition occurred at a methazolamide concentration of 5.6.10(-7) M. The carbonic anhydrase inhibitor acetazolamide (10(-3) M) also greatly reduced the rate of cell acidification. The latency to the onset of carbonic anhydrase inhibition was 660 ms for methazolamide and 7.5 s for acetazolamide. The carbonic anhydrase inhibitor benzolamide (10(-4) M, 4 min exposure), which is poorly membrane permeant, had little effect on the rate of cell acidification, indicating that the site of carbonic anhydrase action was intracellular. The activity of Müller cell carbonic anhydrase may help to buffer extracellular CO2 variations in the retina.

Acetazolamide↗
PubMed2001

Effects of carbonic anhydrase inhibition on the responsiveness of laryngeal receptors in cats to CO2.

The effects of carbonic anhydrase inhibition on the responsiveness to CO2 of pressure-sensitive laryngeal receptors were examined in anaesthetised, paralysed cats. Laryngeal CO2-sensitive receptors from the superior laryngeal nerve were selected by their responsiveness to intralaryngeal pressure and to perfusion of solution equilibrated with 9% CO2. The carbonic anhydrase inhibitor, methazolamide, when given intralaryngeally at 10(-4) M, diminished or abolished the responses to the CO2-equilibrated solution in four of six pressure-sensitive receptors. Histochemical staining for carbonic anhydrase activity showed that the larynges perfused with methazolamide had diminished carbonic anhydrase activity, especially on the superficial layers of surface epithelium. Compared to untreated controls, when given intravenously (50 mg x kg(-1)) methazolamide diminished or abolished the responses to CO2 of five of the six fibres studied. Histochemical staining of these larynges showed no carbonic anhydrase reactivity at the sites of laryngeal receptors. These results suggest that the responses to CO2 of laryngeal pressure-sensitive receptors are dependent on the presence of carbonic anhydrase. Inhibition of laryngeal receptor carbonic anhydrase activity by methazolamide is more reliably achieved by systemic rather than by luminal administration.

Animals↗
PubMed1984

The effects of carbonic anhydrase inhibitors on aqueous humor chemistry and dynamics.

The effects of topical application of the carbonic anhydrase inhibitor trifluormethazolamide (TFM) on intraocular pressure (IOP), ascorbate and CO2 concentrations in aqueous humor, and aqueous humor flow were studied in rabbits. These effects were compared with those produced by systemic treatment with methazolamide. The decrease in IOP observed after TFM was accompanied by changes in the composition of the aqueous humor. Posterior aqueous ascorbate concentration showed a marked increase (up to 1.7-fold), whereas the anterior aqueous ascorbate did not change significantly. Similar changes were found in rabbits after systemic treatment with methazolamide. A small but statistically significant decrease in the CO2 content of both posterior and anterior aqueous was observed after topical TFM application. Methazolamide yielded a more profound lowering in the CO2 content of the aqueous humor, a reflection of the significant decrease in plasma CO2 content. For topical TFM or systemic methazolamide doses yielding complete inhibition of carbonic anhydrase in the eye, a 55-59% reduction of aqueous flow was calculated from the ascorbate data using the Kinsey and Palm equation. However, a 31-42% reduction in aqueous flow was obtained from the same data using an equation based only on posterior chamber data. The reasons for using only posterior aqueous ascorbate data for calculating the changes in aqueous humor flow are discussed.

Administration, Topical↗
PubMed1999

Comparison of intraocular pressure lowering by topical and systemic carbonic anhydrase inhibitors in the rabbit.

We compared the effect on intraocular pressure (IOP) of maximal doses of a topical carbonic anhydrase inhibitor (CAI) at acidic and alkaline pH where it is maximally effective with full systemic CA inhibition in ocular normotensive New Zealand Albino rabbits. Tonometric IOP levels were measured hourly during 3 hour control period. Topical MK-417 (pKa 5.8, 8.3), a close congener of MK-507 (Dorzolamide) was given as a 1.4% solution at pH 4.5 (n=6) and pH 9.2 (n=6). MK-417 was instilled to the left eye with the right eye used as an untreated control. One hour later methazolamide was given intravenously at 10 mg/kg, a dose known to give full inhibition of the enzyme. Control IOP (mm Hg) was 19.12+/-0.50. One hour following MK-417, the left eye IOP was 13.40 +/-0.70 (pH 4.5) and 13.25+/-0.70 (pH 9.2). The right eye pressure was unchanged. Methazolamide injection at this time gave no further drop in the left eye IOP at either pH. IOP in the right eye fell to 14.00+/-0.70 so that 2 hours after methazolamide injection, the 2 eyes had the same pressure. In conclusion, topical CAI in sufficient dose and correct pH yields IOP lowering equivalent to a maximally effective dose of systemic CAI in rabbits.

Administration, Topical↗
PubMed2007

Topical inhibition of nasal carbonic anhydrase affects the CO2 detection threshold in rats.

Previous studies indicate that Long-Evans rats can be operantly trained to discriminate inspired CO(2) concentrations as low as 0.5%. This ability has been proposed to be due to the presence of CO(2)-sensitive olfactory receptors that contain the enzyme carbonic anhydrase (CA). The objectives of the present study were as follows: 1) to determine whether Zucker rats could be operantly conditioned to discriminate low concentrations of CO(2) from control air and 2) to determine the rats' CO(2) detection thresholds before and after nasal perfusion of mammalian Ringers or methazolamide, a CA inhibitor. Rats were operantly trained to discriminate between 25% CO(2) and control air (0% CO(2)) and were then subjected to various CO(2) concentrations (0.5-12.5%) to determine their CO(2) detection thresholds. The average (+/-standard error of mean) baseline CO(2) detection threshold of 7 Zucker rats was 0.48 +/- 0.07% CO(2), whereas the average CO(2) detection thresholds after nasal perfusion of either mammalian Ringers or 10(-2) M methazolamide were 1.41 +/- 0.30% and 5.92 +/- 0.70% CO(2), respectively. The average CO(2) detection threshold after methazolamide was significantly greater (P<0.0001) than the baseline detection threshold. These findings demonstrate that like Long-Evans rats, Zucker rats can be trained to discriminate low concentrations of CO(2) and that inhibition of nasal CA reduces the ability of the rats to detect low concentrations (3.5% and below) but not higher concentrations of CO(2) (12.5%). These results add to the growing evidence that olfactory neurons exhibiting CA activity are CO(2) chemoreceptors sensitive to physiological concentrations of CO(2).

Administration, Topical↗
PubMed1991

Carbonic anhydrase and chemoreception in the cat carotid body.

To test the hypothesis that CO2 and O2 chemoreception in the carotid body (CB) may depend on its carbonic anhydrase (CA) activity, we used an in vitro cat CB preparation and studied the effects of methazolamide, a permeable CA inhibitor (pK 7.3), on the chemosensory responses to CO2, O2, and nicotine. The isolated CB was perfused and superfused with Tyrode solution, free of CO2-HCO3-, at 36.0 +/- 0.5 degrees C. The frequency of chemosensory discharges was recorded from the whole carotid sinus nerve. The responses to bolus injections (0.3-0.5 ml) of Tyrode solution equilibrated with PCO2 of 38-110 Torr, switching from HEPES to CO2-HCO3- Tyrode (PCO2 = 25-60 Torr) for about 3 min, hypoxic Tyrode (PO2 = 25-30 Torr) for 2-8 min, perfusate flow interruptions for approximately 4 min, and bolus injections of nicotine (4 nmol) were studied before, during, and after perfusion (30-45 min) with methazolamide (42.4 microM). Methazolamide reversibly inhibited, delayed, and reduced the responses to transient CO2 stimulus, diminished the onset of but not the late response to prolonged CO2 stimulus, and delayed but did not decrease the responses to hypoxia and perfusate interruption. The response to nicotine did not change. The results indicated that CA in the glomus cells played a crucial role primarily in the speed and magnitude of the initial response to CO2 stimulus and indirectly influenced O2 chemoreception. These effects were upstream from the nicotine receptor-mediated sensory response.

Animals↗
PubMed1991

Fatigue and recovery of rat soleus muscle are influenced by inhibition of an intracellular carbonic anhydrase isoform.

Carbonic anhydrase III (CA III; EC 4.2.1.1) is the most abundant cytosolic enzyme in type I skeletal muscle fibers. Methazolamide, a specific CA inhibitor, was used to characterize the effects of inhibiting CA III on the resistance to fatigue and recovery of the rat soleus muscle using a 60-min fatigue protocol performed in vitro at 25 degrees C. Incubation with 10(-3) M methazolamide resulted in a smaller decrease in tension production during the fatigue protocol, thereby increasing the total tension-time integral for the fatigue test. However, the rate and extent of recovery after the test were lower in the experimental group compared with the control group. A similar effect was observed at physiological temperature (35 degrees C). The results indicate that inhibition of CA III significantly influences tension production as early as 30 s into the stimulation protocol. Inhibition of CA III only during the recovery period did not influence the recovery profile, thereby indicating that the impaired recovery was related to the presence of methazolamide during the stimulation period.

Acetazolamide↗
PubMed1988

Electroretinal changes in the presence of a carbonic anhydrase inhibitor.

A specific carbonic anhydrase activity inhibitor (methazolamide) was injected into one vitreous body each of 4 New Zealand White rabbits. Electroretinograms (ERG) were recorded before and several times after the methazolamide injection. The stimulus levels maximized the rod and cone response characteristics of the rabbit ERG. The effects of methazolamide were followed over 5 h. During this time, the electroretinograms showed a decline in amplitude of both a and b waves at both stimulus levels. The data support the involvement of carbonic anhydrase in the excitatory physiological events in the retina. Preliminary evidence indicates a slow recovery of the carbonic-anhydrase-inhibited ERG.

Animals↗
PubMed2000

Localization of diuretic effects along the loop of Henle: an in vivo microperfusion study in rats.

In order to clarify the effects on sodium reabsorption in the loop of Henle of methazolamide (a carbonic anhydrase inhibitor), chlorothiazide and the loop diuretics frusemide and bumetanide, superficial loops were perfused in vivo in anaesthetized rats and the individual diuretics were included in the perfusate. Differentiation between effects in the pars recta and in the thick ascending limb of Henle (TALH) was achieved by comparing responses to the diuretics when using a standard perfusate, designed to mimic native late proximal tubular fluid, and a low-sodium perfusate, designed to block net sodium reabsorption in the pars recta. With the standard perfusate, methazolamide caused decreases in sodium reabsorption (J(Na)) and water reabsorption (J(V)); with the low-sodium perfusate, a modest effect on J(Na) persisted, suggesting that carbonic anhydrase inhibition reduces sodium reabsorption in both the pars recta and the TALH. The effects of chlorothiazide were very similar to those of methazolamide with both the standard and low-sodium perfusates, suggesting that chlorothiazide also inhibits sodium reabsorption in the pars recta and TALH, perhaps through inhibition of carbonic anhydrase. With the standard perfusate, both frusemide and bumetanide produced the expected large decreases in J(Na), but J(V) was also lowered. With the low-sodium perfusate, the inhibitory effects of the loop diuretics, particularly those of frusemide, were substantially reduced, while net potassium secretion was found. These observations indicate that a significant component of the effect of frusemide (and possibly of bumetanide) on overall sodium reabsorption is located in the pars recta, and that loop diuretics induce potassium secretion in the TALH.

Absorption↗