Effect Of Acetazolamide Research Articles

Preferential acetazolamide-induced vasodilation based on vessel size and organ: confirmation of peripheral vasodilation with use of colored microspheres.

When carbonic anhydrase activity decreases, the regional blood flow (rBF) in organs increases as hypercapnia develops. However, the effects of acetazolamide (AZ)-induced vasodilation have not been estimated with respect to vessel size and organs. The aim of this study was to determine the diameter of the capillaries in various organs that respond to inhibition of carbonic anhydrase activity by AZ. White rabbits were anesthetized with urethane and ketamine and infused with AZ. While the systolic blood pressure (SBP), pH, hemoglobin concentration, and base excess did not change, the partial pressure of arterial oxygen (PaO2) increased significantly and the partial pressure of arterial carbon dioxide (PaCO2) decreased significantly with AZ. The rBF was calculated by using 3 different sizes (15, 25, and 50 microm) of colored microspheres (CM). The rBF measured with 15 microm CM in the brain, kidneys, and liver increased in response to AZ, and the rBF in these organs was different with the different sizes of CM. However, the rBF calculated by using the different sizes of CM in the stomach and abdominal muscle did not change after the administration of AZ. The AZ-induced vasodilation occurred in all sizes of vessels in the liver, in the small and medium-sized vessels in kidneys, and in the larger capillaries in the brain.

Model of ionic transport for bovine ciliary epithelium: effects of acetazolamide and HCO.

The possible existence of transepithelial bicarbonate transport across the isolated bovine ciliary body was investigated by employing a chamber that allows for the measurement of unidirectional, radiolabeled fluxes of CO2 + HCO. No net flux of HCO was detected. However, acetazolamide (0.1 mM) reduced the simultaneously measured short-circuit current (I(sc)). In other experiments in which (36)Cl- was used, a net Cl- flux of 1.12 microeq. h(-1). cm(-2) (30 microA/cm(2)) in the blood-to-aqueous direction was detected. Acetazolamide, as well as removal of HCO from the aqueous bathing solution, inhibited the net Cl- flux and I(sc). Because such removal should increase HCO diffusion toward the aqueous compartment and increase the I(sc), this paradoxical effect could result from cell acidification and partial closure of Cl- channels. The acetazolamide effect on Cl- fluxes can be explained by a reduction of cellular H+ and HCO (generated from metabolic CO2 production), which exchange with Na+ and Cl- via Na+/H+ and Cl-/HCO exchangers, contributing to the net Cl- transport. The fact that the net Cl- flux is about three times larger than the I(sc) is explained with a vectorial model in which there is a secretion of Na+ and K+ into the aqueous humor that partially subtracts from the net Cl- flux. These transport characteristics of the bovine ciliary epithelium suggest how acetazolamide reduces intraocular pressure in the absence of HCO transport as a driving force for fluid secretion.

The effect of acetazolamide on the kinetics of four newer β-lactams in the aqueous humor

To evaluate whether the effect of acetazolamide on piperacillin's aqueous humor concentrations observed in animals exists also in humans for ceftazidime, cefotaxime, ceftriaxone and aztreonam. One hundred and eighty-eight patients undergoing eye cataract surgery were randomly allocated to receive intravenous ceftazidime, cefotaxime, aztreonam or ceftriaxone with (subgroup A) or without (subgroup B) concomitant oral administration of acetazolamide. Antibiotic concentrations in serum and the aqueous humor, simultaneously sampled during the operation, were measured using an agar well diffusion technique, and the ratios of the concentrations of aqueous humor to serum were calculated and compared. Statistical analysis was performed by using the paired t-test. Mean aqueous humor ceftazidime concentrations at 2, 4 and 6 h were 24.65, 16.4 and 8.6 mg/L (subgroup A), and 4.26, 8.66 and 5.61 mg/L (subgroup B). Corresponding concentrations of cefotaxime were 1.75, 1.0 and 0.77 mg/L (subgroup A), and 1.11, 0.81 and 0.58 mg/L (subgroup B), and of aztreonam 6.9, 5.84 and 3.61 mg/L (subgroup A), and 3.38, 2.57 and 1.48 mg/L (subgroup B). Ceftriaxone concentrations at 2, 4, 6 and 12 h were 1.78, 1.49, 1.57 and 1.41 mg/L (subgroup A), and 1.35, 0.95, 1.08 and 0.85 mg/L (subgroup B). The differences in aqueous humor concentrations when acetazolamide was administered were statistically significant (P < 0.05), with the exception of ceftazidime 6 h, cefotaxime 6 h and ceftriaxone 2 h. Although acetazolamide resulted in statistically significant increases in the aqueous humor concentrations of all the antibiotics tested, this effect was most marked for ceftazidime.

The Effect of Acetazolamide on Peripheral Pulse Oximetry in Partially Acclimatized Individuals

The Effect of Acetazolamide on Peripheral Pulse Oximetry in Partially Acclimatized Individuals

Quantitative volumetry in patients with carotid disease--effects of acetazolamide.

The intracranial effects of acetazolamide on flow velocities can be monitored noninvasively by transcranial Doppler (TCD) sonography. Extracranial volume flow changes can now reliably be measured with color duplex M-mode systems. The authors tested the volumetric effects of acetazolamide in patients with high-grade unilateral carotid disease to quantify the amount of flow changes. Patients in group 1 had a high-grade > 70% internal carotid artery (ICA) stenosis, without collateral flow through the ophthalmic artery (OA). Patients with occluded ICA were included in group 2 (patent OA collateralization) or group 3 (no OA collateralization) (n = 6 per group). In group 1, common carotid artery (CCA) volume flow in the stenotic (normal contralateral) side increased from 271 (388) ml/min by 52 (54%) with 1 g aceta-zolamide intravenously. Simultaneously, middle cerebral artery (MCA) flow velocities increased from 54 (56) cm/s by 47 (53%). In group 2, extracranial volume flow increased from 166 (444) ml/min by 19 (52)%. MCA flow velocities increased from 43 (65) cm/s by 13 (30)%. In group 3, volume flow increased from 159 (467) ml/min by 2 (46)%. Intracranial flow velocities rose from 49 (54) cm/s by 27 (41)%. Volume flow data showed the expected decline in patients with high-grade ICA stenosis and even more pronounced in patients with occlusion of the vessel. Cerebral reserve capacity was less sufficient in patients with a patent OA, despite an additional supply of 30 ml/min, indicating a hemodynamically critical situation.

Effect of acetazolamide on outward permeability of blood-retina barrier using differential vitreous flyorophotometry

Purpose. To measure fluorescein (F) and fluorescein monoglucuronide (FG) concentrations in the vitreous and evaluate the effect of acetazolamide (AZM) on the outward permeability of the blood-retina barrier (BRB) using differential vitreous fluorophotometry (DVF). Methods. DVF was performed 180 minutes after intravenous injection of AZM (5 mg/kg) and 50 mg of sodium fluorescein in six rabbits (AZM group). DVF also was performed in six rabbits injected intravenously with only 50 mg of sodium fluorescein (control group). The F/FG ratio was calculated based on the concentrations of F and FG obtained by DVF. DVF also was performed 180 minutes after 50 mg of intravenous injection of sodium fluorescein in five rabbits given probenecid (150 mg/kg) intraperitoneally (probenecid group). Results. The average F/FG ratio was 0.36 ± 0.17 (range, 0.22–0.66) in the AZM group, which was significantly smaller than the control value of 0.74 ± 0.22 (range, 0.50–1.60). The average F/FG ratio at 180 minutes after injection was 1.51 ± 0.46 (range, 0.94–2.00) in the probenecid group, which was significant higher (p < 0.05) than that of the AZM or control group. Conclusions. This study showed that the F/FG ratio might be a good indicator of the estimated outward permeability of the BRB using DVF and that AZM may accelerate the outward active transport function of the BRB.

A periplasmic, α-type carbonic anhydrase from Rhodopseudomonas palustris is essential for bicarbonate uptake

Intact cells of the purple non-sulfur bacterium Rhodopseudomonas palustris growing anaerobically, but not aerobically, contain carbonic anhydrase (CA) activity. The native enzyme was purified >2000-fold to apparent homogeneity and found to be a dimer with an estimated molecular mass of 54 kDa and a subunit molecular mass of 27 kDa. The CA gene (acaP) was cloned and its sequence revealed that it was homologous to alpha-type CAs. The upstream region of acaP was fused to the lacZ gene and beta-galactosidase activity was measured under different growth conditions. Acetazolamide inhibited purified CA with an IC(50) in the range of 10(-8) M, and in the culture media concentrations as low as 30 microM inhibited phototrophic growth under anaerobic, light conditions when bicarbonate was used. An acaP::KAN:(r) mutant strain was constructed by insertion of a kanamycin-resistance cassette and showed a growth pattern similar to wild-type cells grown in the presence of CA inhibitor. CO(2) gas supplied as an inorganic carbon source reversed the effect of mutation or acetazolamide. CA activity measurements, fusion and Western blot experiments confirmed that CA is expressed under different anaerobic conditions independently of bicarbonate or CO(2) and that there is no expression under aerobic conditions.

Acetazolamide opens the muscular K Ca 2+ channel: A novel mechanism of action that may explain the therapeutic effect of the drug in hypokalemic periodic paralysis

Acetazolamide is a thiazide derivative clinically used in skeletal muscle disorders related to altered K+ homeostasis such as the periodic paralyses. The mechanism of action responsible for the therapeutic effects of the drug is still unknown, however. In the present work, we investigated the mechanism of action of acetazolamide in the K-deficient diet rat, an animal model of human hypokalemic periodic paralysis (hypoPP). The in vivo administration of 2.8- and 5.6-mg/kg(-1)/day(-1) concentrations of acetazolamide to K-deficient diet rats prevented paralysis and depolarization of the fibers induced by insulin. In the acetazolamide-treated animals, intense sarcolemma Ca2+-activated K+ channel (KCa2+) activity was recorded. Acetazolamide also restored the serum K+ levels to control values. The concentrations of acetazolamide needed to enhance the KCa2+ current by 50% in vitro were 6.17 and 4.01x10(-6) M at -60 and +30 mV of membrane potentials, respectively. In normokalemic animals, the thiazide derivative enhanced the KCa2+ current with similar efficacy. Our data demonstrate that the therapeutic effects of acetazolamide in the K-deficient diet rats and possibly in human hypokalemic periodic paralysis patients can be mediated by activation of the KCa2+ channel.

Acetazolamide opens the muscular KCa2 channel: A novel mechanism of action that may explain the therapeutic effect of the drug in hypokalemic periodic paralysis

Acetazolamide is a thiazide derivative clinically used in skeletal muscle disorders related to altered K+ homeostasis such as the periodic paralyses. The mechanism of action responsible for the therapeutic effects of the drug is still unknown, however. In the present work, we investigated the mechanism of action of acetazolamide in the K–deficient diet rat, an animal model of human hypokalemic periodic paralysis (hypoPP). The in vivo administration of 2.8- and 5.6-mg/kg−1/day−1 concentrations of acetazolamide to K–deficient diet rats prevented paralysis and depolarization of the fibers induced by insulin. In the acetazolamide-treated animals, intense sarcolemma Ca2+-activated K+ channel (K) activity was recorded. Acetazolamide also restored the serum K+ levels to control values. The concentrations of acetazolamide needed to enhance the K current by 50% in vitro were 6.17 and 4.01 × 10−6 M at −60 and +30 mV of membrane potentials, respectively. In normokalemic animals, the thiazide derivative enhanced the K current with similar efficacy. Our data demonstrate that the therapeutic effects of acetazolamide in the K–deficient diet rats and possibly in human hypokalemic periodic paralysis patients can be mediated by activation of the K channel. Ann Neurol 2000;48:304–312

A comparison of topiramate and acetazolamide on seizure duration and paired-pulse inhibition in the dentate gyrus of the rat

Topiramate is a relatively new antiepileptic drug with several putative anticonvulsant mechanisms. Among them is the ability to inhibit carbonic anhydrase, a property in common with the anticonvulsant acetazolamide. This study examined the effects of topiramate and acetazolamide on the duration of epileptiform activity and on paired-pulse inhibition in the dentate gyrus in urethane anesthetized adult Sprague–Dawley rats. Neither topiramate nor acetazolamide altered excitability in the dentate gyrus, as measured with input–output curves or induction of long-term potentiation. Topiramate increased paired-pulse inhibition, whereas acetazolamide had no effect. Both drugs dose-dependently blocked the lengthening of the duration of epileptiform activity compared to vehicle controls. These results indicate that topiramate has an anticonvulsant-related effect (increase in paired-pulse inhibition), which may contribute to its antiepileptic effect, that is not dependent on its ability to inhibit carbonic anhydrase.

Effect of acetazolamide on salivary excretion of inorganic ions in sheep

The salivary excretion of inorganic ions in sheep was studied parallel with infusion of salt solutions of different composition through the temporary isolated rumen cavityin vivo. The amount of Na+ excreted with saliva decreases by 15–55% after an intravenous loading with acetazolamide (50 mg/kg of animal weight) and by 25–55%, of K+, which represents a part of the ion excretion with participation of H+ exchanges. The Na+ excretion that is not inhibited by acetazolamide in sheep is about 40 mmol/10 kg of exchange mass per 1 h in all experiments with loading.

Formulation and evaluation of ophthalmic preparations of acetazolamide

The orally administered acetazolamide has a limited use in glaucoma due to the systemic side effects associated with its use. It has been reported to show little effect on the intraocular pressure (IOP) of human and rabbit eyes upon topical application, probably owing to its poor bioavailability and instability at pH>5.0. In order to enhance the bioavailability of the drug, contact time between the drug molecules and the ocular surface was increased using high viscosity, water soluble polymers (PVA, HPMC), and by incorporating acetazolamide into an in situ-forming ophthalmic drug delivery system. Moreover, a penetration enhancer (EDTA) was also used in these formulations to increase the extent of absorption of the drug. Acetazolamide at a concentration of 10% was used and the formulations (eyedrop suspensions) were evaluated for their in vitro release pattern. The effect of these formulations on the IOP in normotensive conscious rabbits was also investigated. These formulations were found to be therapeutically effective with a peak effect at 2 h. A fall in IOP of up to 46.4% was observed with repeated administration of one of the formulation containing PVA, EDTA and Tween 80 (MK-5). Results indicated that a topical effect of acetazolamide can be observed if the formulation, (a) contains a suitable polymer—to increase the residence time; (b) a penetration enhancer—as acetazolamide has a low permeability coefficient i.e. 4.1×10 −6 cm/s [Duffel, M.W., Ing. I.S., Segarra, T.M., Dixson, J.A., Barfknecht, C.F., Schoenwald, R.D., 1986. J. Med. Chem. 29, 1488–1494]; and (c) pH of the formulation is maintained at the point of maximum stability (pH≤5.0).

Carbonic anhydrase inhibitor suppresses invasion of renal cancer cells in vitro.

Acidification of the extracellular milieu of malignant tumors is reported to increase the invasive behavior of cancer cells. In normal tissues, production of acid is catalyzed by carbonic anhydrases (CAs), some of which are known to be overexpressed in certain cancers. To investigate the functional role of CA activity in such cancer cells, we analyzed the effect of acetazolamide, a potent CA inhibitor, on the invasive capacity of four renal carcinoma cell lines (Caki-1, Caki-2, ACHN, and A-498). We found that 10 microM acetazolamide inhibited the relative invasion rate of these cell lines between 18-74%. The Caki-2 and ACHN cell lines displayed the highest responsiveness, and their responses clearly depended on the acetazolamide concentration in the culture medium. Immunocytochemical and Western blotting results identified the presence of CA isoenzyme II in the cytoplasm of all four cell lines and CA XII on the plasma membrane in three of four cell lines. Because acetazolamide alone reduced invasiveness of these cancer cells in vitro, we conclude that the CAs overexpressed in these renal cancer cells contribute to invasiveness, at least in vitro, and suggest that CA inhibitors may also reduce invasiveness in other tumors that overexpress one or more CAs.

Is the acetazolamide test valid for quantitative assessment of maximal cerebral autoregulatory vasodilation? An experimental study.

The cerebral vasodilating effect of acetazolamide (ACZ) injection has been used as an index of the autoregulatory vasodilation (or cerebral perfusion reserve). The question of whether the ACZ test assesses the maximal autoregulatory vasodilating capacity is not definitely resolved. The effects of ACZ injection on this reserve at a dose producing maximal vasodilation have never been evaluated and may help to resolve this problem. The effect of ACZ injection on cerebral blood flow (CBF) autoregulation was tested in anesthetized rats. A pilot experiment evaluated the dose-effect relationship of injected ACZ, cumulative doses (n=4, group 1), and independent bolus doses (n=6, group 2). CBF was estimated by laser-Doppler flowmetry, and cerebrovascular resistance (CVR) was calculated from mean arterial blood pressure (MABP) and from CBF (expressed as a percentage of baseline CBF). A bolus of ACZ of 21 mg/kg produced the maximal cerebral vasodilation that could be obtained by ACZ administration. In the main experiment, MABP was lowered from 110 to 20 mm Hg by stepwise bleeding in 3 groups of 6 animals treated 10 minutes before bleeding by injection of saline (group 3), 7 mg/kg ACZ (group 4), or 21 mg/kg ACZ (group 5). The CVR-MABP relationship was linear in all groups, indicating that CBF autoregulation was still effective after ACZ administration. These results indicate that maximal ACZ-induced cerebral vasodilation is not quantitatively equivalent to maximal autoregulatory vasodilating capacity in anesthetized rats.

Noninvasive magnetic resonance imaging evaluation of cerebral blood flow with acetazolamide challenge in patients with cerebrovascular stenosis.

To evaluate the utility of using magnetic resonance imaging (MRI) of cerebral blood flow (CBF) in conjunction with pharmacologic flow augmentation, the authors imaged 14 patients with ischemic symptoms referable to large artery cerebrovascular stenosis of the anterior circulation. CBF was measured by using continuous arterial spin labeling (CASL) both at rest and 10 minutes after 1 g intravenous acetazolamide on a commercial 1.5 Tesla scanner. Quantitative CBF images were calculated along with augmentation images showing the effects of acetazolamide. Interpretable studies were obtained from all patients. Based on the image data as well as a region of interest analysis of CBF changes in middle cerebral artery distributions, varying patterns of augmentation were observed that suggested differing mechanisms of ischemic symptomatology. The ability to obtain this information in conjunction with a structural MRI examination extends the diagnostic potential for MRI in cerebrovascular disease and allows the value of augmentation testing in clinical management to be assessed more widely. J. Magn. Reson. Imaging 1999;10:870-875.

INTRAOPERATIVE ACETAZOLAMIDE IN THE PREVENTION OF INTRAOCULAR PRESSURE RISE AFTER PARS PLANA VITRECTOMY WITH FLUID-GAS EXCHANGE

Purpose: To assess the effect of intraoperative acetazolamide (Diamox) on postoperative intraocular pressure (IOP) in gas-filled, vitrectomized eyes. Methods: We conducted a prospective randomized clinical trial of 63 consecutive patients undergoing pars plana vitrectomy with total fluid-gas exchange and long-acting intraocular gas tamponade. Patients were randomized by a blind draw to receive either intravenous 500 mg acetazolamide (Diamox) (Group 1) or no treatment (Group 2) at the conclusion of the operative procedure. Intraocular pressures at the conclusion of surgery (IOP-1), 4-8 hours following surgery (IOP-2), and on the first postoperative day (IOP-3) were measured using an Oculab Tono-Pen. Results: Patients in Groups 1 and 2 showed similar mean IOP on postoperative day 1 (20.48 ± 7.84 mmHg versus 19.89 ± 7.89 mmHg). A similar incidence of IOP-2 greater than 30 mmHg (1 versus 3 patients with high IOP) and IOP-3 greater than 30 mmHg (4 versus 3 patients with high IOP) was seen. Patients in Group 1 had a lower mean IOP at 4-8 hours postoperatively (16.25 ± 6.47 mmHg) than those in Group 2 (20.13 ± 6.33 mmHg). No correlation could be demonstrated between IOP-1 and subsequent IOP. However, IOP on the first postoperative day (IOP-3) was strongly correlated with IOP 4-8 hours after surgery (IOP-2) (P = 0.0001). No protective effect of Diamox could be demonstrated on either IOP-2 or IOP-3. Conclusions: No protective effect against pressure rise could be demonstrated for intraoperative acetazolamide (Diamox) in the prophylaxis of IOP rise following pars plana vitrectomy and total fluid-gas exchange with long-acting intraocular gas.

Homeostatic indications for the administration of diuretics

The authors monitored the effects of the different diuretics upon the natrium and water homeostasis and acid-base balance. The aim of the study was to clarify the exact mechanisms of their action and possible ways of monitoring of their homeostatic effects. The effects of furosemide (18 patients), hydrochlorothiazide (eight patients), spironolactone (14 patients), acetazolamide (10 patients), amiloride (four patients) and manitol (eight patients) were monitored in critically ill patients using computer programme utilizing 17 routinely monitored input values and calculating creatinine clearance, tubular resorbtion excretion fractions of sodium, potassium, water and osmotically active substances, clearance of the osmotically active substances, clearance of solute free water, electrolyte clearance, electrolyte free water clearance, urine outputs of sodium, potassium and urea, urea concentration index and serum and urine anion gaps. The development of parameters typical for each diuretic was evaluated using Student's t-test comparing the values before and during the treatment with the agent.

Effect of low-dose acetazolamide on the ventilatory CO2 response during hypoxia in the anaesthetized cat.

Acetazolamide, a carbonic anhydrase inhibitor, is used in patients with chronic obstructive pulmonary diseases and central sleep apnoea syndrome and in the prevention and treatment of the symptoms of acute mountain sickness. In these patients, the drug increases minute ventilation (V'E), resulting in an improvement in arterial oxygen saturation. However, the mechanism by which it stimulates ventilation is still under debate. Since hypoxaemia is a frequently observed phenomenon in these patients, the effect of 4 mg x kg(-1) acetazolamide (i.v.) on the ventilatory response to hypercapnia during hypoxaemia (arterial oxygen tension (Pa,O2)=6.8+/-0.8 kPa, mean+/-SD) was investigated in seven anaesthetized cats. The dynamic end-tidal forcing (DEF) technique was used, enabling the relative contributions of the peripheral and central chemoreflex loops to the ventilatory response to a step change in end-tidal carbon dioxide tension, (PET,CO2) to be separated. Acetazolamide reduced the CO2 sensitivities of the peripheral (Sp) and central (Sc) chemoreflex loops from 0.22+/-0.08 to 0.11+/-0.03 L x min(-1) x kPa(-1) (mean+/-SD) (p<0.01) and from 0.74+/-0.32 to 0.40+/-0.10 L x min(-1) x kPa(-1) (p<0.01), respectively. The apnoeic threshold B (x-intercept of the ventilatory CO2 response curve) decreased from 2.88+/-0.97 to 0.95+/-0.92 kPa (p<0.01). The net result was a stimulation of ventilation at PET,CO2 <5 kPa. The effect of acetazolamide is possibly due to a direct effect on the peripheral chemoreceptors as well as to an effect on the cerebral blood flow regulation. Possible clinical implications of these results are discussed.

Effect of Acetazolamide on Cation Concentration in the Endolymph of the Endolymphatic Sac

Effect of Acetazolamide on Cation Concentration in the Endolymph of the Endolymphatic Sac

O-15]H2O Positron Emission Tomography Determination of Cerebral Blood Flow Reserve after Intravenous Acetazolamide during Balloon Test Occlusion of the Internal Carotid Artery

The purpose of this paper was to evaluate the effects of acetazolamide on cerebral blood flow (CBF) measured by [O-15]H2O positron emission tomography (PET) during balloon test occlusion (BTO) of the internal carotid artery (ICA). [O-15]H2O PET cerebral blood flow studies were completed in 20 patients undergoing BTO CBF determinations were obtained without carotid occlusion as a baseline, following balloon occlusion, and as a third scan with balloon occlusion after an intravenous acetazolamide bolus. The balloon was left deflated between scans, and was only inflated immediately before and during the 90 second period of time needed for CBF determination. Significance was determined at the P < 0.05 level. Two of twenty studies were technical failures. Prior to acetazolamide there was a significant decrease in CBF (P < 0.0007) ipsilateral to the occlusion. After acetazolamide administration there was no statistically significant change in flow on the occluded side (P < 0.3047); however, there was a significant increase in cerebral blood flow (P < 0.0002) on the non-occluded side. In this patient population, there was no acetazolamide-induced CBF decompensation (steal) phenomenon or haemodynamically significant risk in CBF ipsilateral to the occlusion.