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PubMed1984

Proximal tubular Na, Cl, and HCO3 reabsorption and renal oxygen consumption.

The majority of the oxygen consumed by the rat kidney appears to occur in the proximal tubule. Therefore changes in metabolically linked ion transport in this segment of the nephron should result in changes in renal oxygen consumption. To study the role of bicarbonate reabsorption in metabolically linked proximal tubular ion transport a series of micropuncture-clearance-extraction experiments were performed comparing the effects of the carbonic anhydrase inhibitor benzolamide and of hypertonic sodium bicarbonate infusion with control conditions in the rat. End-proximal tubular fluid and chloride reabsorption were measured. From these, the rates of sodium and bicarbonate reabsorption were estimated. Simultaneously with the tubular fluids, extraction collections were obtained for determination of renal oxygen consumption. Both benzolamide and hypertonic bicarbonate reduced proximal tubular fluid reabsorption while concomitantly reducing the transepithelial gradient for chloride. The mean rate of renal oxygen consumption did not differ from the control rate in either experimental group and could be dissociated from the calculated net rates of proximal tubular sodium, chloride, and bicarbonate reabsorption. We interpret these data as evidence that proximal tubular hydrogen ion secretion supporting bicarbonate reabsorption requires at most small amounts of oxidative energy, less than detectable by these techniques. The data, in contrast, support the conclusion that the chloride-bicarbonate transepithelial gradient appears to be an important passive driving force in vivo for proximal tubular fluid reabsorption.

Animals↗

PubMed1996

Rapid redistribution and inhibition of renal sodium transporters during acute pressure natriuresis.

Acute arterial hypertension provokes a rapid decrease in proximal tubule (PT) Na+ reabsorption, increasing flow to the macula densa, the signal for tubuloglomerular feedback. We tested the hypothesis, in rats, that Na+ transport is decreased due to rapid redistribution of apical Na+/H+ exchangers and basolateral Na+ pumps to internal membranes. Arterial pressure was increased 50 mmHg by constricting various arteries. We also tested whether transporter internalization occurred when PT Na+ reabsorption was inhibited with the carbonic anhydrase inhibitor benzolamide. Five minutes after initiating either natriuretic stimuli, cortex was removed, and membranes were fractionated by density gradient centrifugation. Urine output and endogenous lithium clearance increased threefold in response to either stimuli. Acute hypertension provoked a redistribution of apical Na+/H+ exchanger NHE3, alkaline phosphatase, and dipeptidyl peptidase IV to higher density membranes enriched in the intracellular membrane markers. Basolateral membrane Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase) activity decreased 50%, 25-30% of the alpha 1-and beta 1-subunits redistributed to higher density membranes, and the remainder is attributed to decreased activity of the transporters. Benzolamide did not alter Na+ transporter activity or distribution, implying that decreasing apical Na+ uptake does not initiate redistribution or inhibition of basolateral Na(+)-K(+)-ATPase. We conclude that PT natriuresis provoked by acute arterial pressure is mediated by both endocytic removal of apical Na+/H+ exchangers and basolateral Na+ pumps as well as decreased total Na+ pump activity.

Acute Disease↗

PubMed1977

Postcapillary changes in blood pH in vivo during carbonic anhydrase inhibition.

A rapidly responding stopped-flow glass pH electrode apparatus was used to investigate pH changes in blood in vivo after it exits from an exchange capillary. Arterial blood was drawn from anesthetized animals through the apparatus. Temperature and pH of the blood in the electrode chamber were continuously recorded, both during withdrawal and after flow was stopped. Blood pH did not change after stopping flow in control experiments. When benzolamide (2 mg/kg) was given to inhibit carbonic anhydrase activity available to plasma (e.g., due to lysis) while having less effect on intracellular activity, pH increased 0.02-0.04 (t1/2 approximately 8 s) after stopping flow. Administration of acetazolamide (50 mg/kg) resulted in pH decreasing 0.07-0.10 (t1/2 approximately 15 s) after stopping flow. Ventilation for 1 min with N2 resulted in an increased rise in pH for the benzolamide-treated animals but a decreased fall in pH for the acetazolamide-treated animals. These shifts in arterial blood pH after gas exchange are largely due to disequilibrium of [H+] between red cells and plasma at the end of the pulmonary capillary.

Acetazolamide↗

PubMed1995

Pharmacological characterization of extracellular pH transients evoked by selective synaptic and exogenous activation of AMPA, NMDA, and GABAA receptors in the rat hippocampal slice.

1. Inhibitors of extracellular carbonic anhydrase (CAo) offer much promise as diagnostic tools in the study of the synaptic basis of activity-induced alkaline transients in the brain. However, most of the present information related to the effects of CAo blockers in nervous tissue comes from experiments that involve simultaneous synaptic activation of various types of postsynaptic receptor channels. In the present work, double-barreled H(+)-selective microelectrodes were used to study alkaline shifts in extracellular pH (pHo) evoked by selective synaptic and pharmacological activation of glutamate and gamma-aminobutyric acid (GABA) receptors in the CA1 cell body layer in rat hippocampal slices. Inhibition of CAo was achieved with the use of the poorly permeant carbonic anhydrase inhibitor, benzolamide (10 microM; applied in the bath solution) or the impermeant macromolecular inhibitor, prontosil-dextran 5000 (PD 5000; applied in microdrops). 2. Alkaline transients that were exclusively attributable to synaptic activation of glutamate receptors were induced by stimulation of Schaffer collaterals in the presence of picrotoxin (PiTX, 100 microM). An enhancement by the CAo inhibitors of these alkaline transients took place at all stimulus frequencies (5-200 Hz) and stimulus train durations (0.5-20 s) examined. 3. Inhibition of CAo enhanced the alkaline transients evoked by selective synaptic activation of alpha-amino-3-hydroxy-5-methyli-oxazolate- 4-propionic acid (AMPA)/kainate receptors in experiments involving stimulation of Schaffer collaterals in the simultaneous presence of PiTX and D-2-amino-5-phosphonopentoate (AP5, 40-80 microM). 4. Alkaline shifts evoked by selective synaptic activation of N-methyl-D-aspartate (NMDA) receptors were enhanced after inhibition of CAo as seen in experiments where Schaffer collaterals were stimulated in the simultaneous presence of PiTX and 6-cyano-2,3-dihydroxy-7-nitroquinoxaline (CNQX, 20-40 microM) in an Mg(2+)-free solution. 5. Benzolamide and PD 5000 also enhanced the alkaline shifts seen upon pressure injection of glutamate, AMPA, or NMDA. The glutamate-induced alkaline shifts were inhibited by AP5+CNQX, suggesting that uptake of glutamate did not significantly contribute to their generation. 6. Stimuli applied at 5-10 Hz in stratum radiatum close (within 0.5 mm) to the recording site evoked alkaline shifts that were blocked by CNQX plus AP5. In the continuous presence of the two glutamate antagonists, PiTX-sensitive alkaline transients were observed in response to brief high-frequency (20-100 Hz) trains consisting of 100 stimuli. Upon application of pentobarbital sodium (100 microM), these apparently monosynaptically evoked GABAA receptor-mediated alkaline transients were evident also at low stimulation frequencies (5-10 Hz).(ABSTRACT TRUNCATED AT 400 WORDS)

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1993

Effects of carbonic anhydrase inhibition on ventilation-perfusion matching in the dog lung.

Lung carbonic anhydrase (CA) permits rapid pH responses when changes in regional ventilation or perfusion alter airway and alveolar PCO2. These pH changes affect airway and vascular resistances and lung compliance to optimize the balance of regional ventilation (VA) and perfusion (Q) in the lung. To test the hypothesis that these or other CA-dependent mechanisms contribute to VA/Q matching, we administered acetazolamide (25 mg/kg intravenously) to six anesthetized and paralyzed dogs and measured VA/Q relationships before and after CA inhibition by the multiple inert gas elimination technique. Four other groups of dogs were studied to control for possible confounding effects of time under anesthesia and nonselective CA inhibition by acetazolamide: (a) saline placebo as a control for duration of anesthesia, (b) 4% CO2 inhalation to mimic systemic CO2 retention, (c) 1 mg/kg benzolamide (a selective renal CA inhibitor) or 0.5 meq/kg HCl to mimic systemic metabolic acidosis, and (d) 500 mg/kg 4,4'-dinitrostilbene-2,2'-disulfonate (an inhibitor of red cell band 3 protein) to mimic the respiratory acidosis arising from an intracapillary block to rapid mobilization of plasma HCO3- in CO2 exchange. Acetazolamide increased VA/Q mismatch and reduced arterial PO2 measured at equilibrium but these did not occur in the control group. There was no deterioration in VA/Q matching when systemic respiratory acidosis produced either by CO2 inhalation or 4,4'-dinitrostilbene-2,2'-disulfonate or metabolic acidosis (benzolamide or HCl) were imposed to mimic the effects of acetazolamide apart from its inhibition of lung CA. These results support the concept that lung CA subserves VA/Q matching in the normal lung.

Acetazolamide↗

PubMed2005

An investigation of the role of carbonic anhydrase in aquatic and aerial gas transfer in the African lungfish Protopterus dolloi.

Experiments were performed on bimodally breathing African lungfish Protopterus dolloi to examine the effects of inhibition of extracellular vs total (extracellular and intracellular) carbonic anhydrase (CA) activity on pulmonary and branchial/cutaneous gas transfer. In contrast to previous studies on Protopterus, which showed that the vast majority of CO(2) is excreted into the water through the gill and/or skin whereas O(2) uptake largely occurs via the lung, P. dolloi appeared to use the lung for the bulk of both O(2) uptake (91.0+/-2.9%) and CO(2) excretion (76.0+/-6.6%). In support of the lung as the more important site of CO(2) transfer, aerial hypercapnia (P(CO(2))=40 mmHg) caused a significant rise in partial pressure of arterial blood CO(2) (Pa(CO(2))) whereas a similar degree of aquatic hypercapnia was without effect on Pa(CO(2)). Intravascular injection of low levels (1.2 mg kg(-1)) of the slowly permanent CA inhibitor, benzolamide, was without effect on red blood cell CA activity after 30 min, thus confirming its suitability as a short-term selective inhibitor of extracellular CA. Benzolamide treatment did not affect CO(2) excretion, blood acid-base status or any other measured variable within the 30 min measurement period. Injection of the permeant CA inhibitor acetazolamide (30 mg kg(-1)) resulted in the complete inhibition of red cell CA activity within 10 min. However, CO(2) excretion (measured for 2 h after injection) and arterial blood acid-base status (assessed for 24 h after injection) were unaffected by acetazolamide treatment. Intra-arterial injection of bovine CA (2 mg kg(-1)) caused a significant increase in overall CO(2) excretion (from 0.41+/-0.03 to 0.58+/-0.03 mmol kg(-1) h(-1)) and an increase in air breathing frequency (from 19.0+/-1.3 to 24.7+/-1.8 breaths min(-1)) that was accompanied by a slight, but significant, reduction in Pa(CO(2)) (from 21.6+/-1.6 to 19.6+/-1.8 mmHg). The findings of this study are significant because they (i) demonstrate that, unlike in other species of African lungfish that have been examined, the gill/skin is not the major route of CO(2) excretion in P. dolloi, and (ii) suggest that CO(2) excretion in Protopterus may be less reliant on carbonic anhydrase than in most other fish species.

Acetazolamide↗

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↗

PubMed1980

Effect of carbonic anhydrase inhibitors and acidosis in choroid plexus epithelial cell sodium and potassium.

To elucidate the mechanism by which carbonic anhydrase inhibitors block fluid production by the choroid plexus (CP), Na-K transport by the rat choroidal epithelium was investigated by measuring acetazolamide- and benzolamide-induced changes in cell [K] and [Na]. Although plasma and cerebrospinal fluid [K] and [Na] were not significantly altered after 1 hr of drug treatment, both acetazolamide (20 mg/kg) and benzolamide (40 mg/kg) decreased in vivo CP cell [Na] by 11 to 18 mmol/kg of cell H2O and substantially increased cell [K] by 25 to 35 mmol. Compensatory artificial respiration to control blood pH blocked the drug-induced effects of cell electrolytes. Furthermore, acetazolamide (5 x 10(-5) and 5 x 10(-4) M) did not significantly alter cell [Na] or [K] in in vitro incubations of CP, although cell [K] tended to decrease in a drug concentration-dependent manner. Thus, carbonic anhydrase inhibitors have no direct effect on the gradient for Na or K between choroid cell fluid and surrounding extracellular fluid. It is proposed that the carbonic anhydrase inhibitors reduced Na entry into the choroid epithelium across the basolateral membrane concurrent with a decrease in the rate of the apical membrane Na-K pump. To investigate whether the drug-induced extracellular acidosis changed cell electrolyte levels directly or indirectly, in vitro CP tissue incubations were performed in which the pH of the artificial cerebrospinal fluid was varied from 7.24 to 7.44. CP cell [K] increased by 20 mmol/kg of H2O and cell [Na] fell by 10 when bathing medium pH was lowered from 7.39 to 7.24. We postulate that the lowered blood pH directly stimulates K uptake and Na efflux from the CP cell, although an indirect effect of acidosis, either through an alteration of levels of circulatory hormones or of autonomic input to the CP, cannot be excluded.

Acetazolamide↗

PubMed2003

Surface carbonic anhydrase activity on astrocytes and neurons facilitates lactate transport.

A number of studies have provided physiological evidence for extracellular carbonic anhydrase (CA) in brain. Association of extracellular CA with glia has been limited to functional studies of gliotic slices and retinal Muller cells. While astrocytes contain intracellular CA, there has been no direct evidence for surface CA on these cells. In fact, some morphological studies suggest that the extracellular CA in brain parenchyma resides on neurons, not glia. There has been no functional demonstration of extracellular CA activity on CNS neurons, however. Here we capitalized on the H(+) dependence of inward lactate transport to reveal functional extracellular CA activity on cultured astrocytes and acutely isolated hippocampal pyramidal neurons. Exposure to 20 mM L-lactate produced a rapid acidification of astrocytes that was reversibly blocked by 10 microM benzolamide. The lactate-induced acidification (LIA) was also blocked by a dextran-conjugated CA inhibitor. In CO(2)/HCO(3) (-)-free, HEPES-buffered media, the LIA was largely unaffected. Acutely dissociated hippocampal pyramidal neurons underwent a similar LIA that was reversibly blocked by benzolamide. Surface CA is likely to facilitate lactate transport by enabling rapid replenishment (i.e., buffering) of surface H(+) required for inward lactate-H(+) cotransport. These results demonstrate functional surface CA for the first time on individual mammalian astrocytes and neurons and suggest that this enzyme may play a role in the utilization of monocarboxylate substrates such as lactate and pyruvate by the brain.

Animals↗

PubMed1993

Interstitial PCO2 and pH in rat hippocampal slices measured by means of a novel fast CO2/H(+)-sensitive microelectrode based on a PVC-gelled membrane.

We describe here the construction and properties of a double-barrelled microelectrode (tip diameter 4-10 microns) which permits simultaneous measurements of PCO2 and pH, and which has a 90% response time of only one or a few seconds for a step change in PCO2. The fast response of the CO2-sensitive barrel is due to (i) the use of a PVC-gelled (tridodecylamine-containing) membrane solution which enables the construction of extremely short (> or = 4 microns), yet mechanically stable, membrane columns, and (ii) the presence of carbonic anhydrase in the filling solution. Recordings made in the pyramidal layer of area CA1 in rat hippocampal slices showed that the deviation in the acid direction of the basal interstitial pH (pH0) from that of the perfusion solution was attributable to a higher PCO2 level within the tissue. Most of the late acid shift evoked by stimulation of the Schaffer collaterals (5- to 20-s trains at 10 Hz) could also be explained on the basis of an accumulation of interstitial CO2 at a constant HCO3- concentration. This conclusion was supported by the finding that inhibition of extracellular carbonic anhydrase activity by 10 microM benzolamide completely abolished the activity-induced fall in pH0, but not the increase in PCO2. The initial stimulus-induced alkalosis was accompanied by a slight decrease in PCO2 only, implying a parallel increase in the interstitial HCO3- concentration. Benzolamide produced a dramatic enhancement of the early alkaline shift as well as of the simultaneous fall in PCO2. The latter effect of the drug unmasks a cellular CO2 sink that is induced by neuronal activity.

Animals↗

PubMed1982

Carbonic anhydrase independent bicarbonate reabsorption.

The present study was designed to define the prerequisites of carbonic anhydrase independent bicarbonate reabsorption. In free flow experiments during systemic application of carbonic anhydrase inhibitor benzolamide (50 mg/kg B. W.) bicarbonate recovery in % of filtered load was found to be 74 +/- 8% in late proximal convoluted tubules, 39 +/- 6% in distal convoluted tubules and 32 +/- 4% in urine, indicating that most of carbonic anhydrase independent bicarbonate reabsorption occurs in tubule segments prior to distal convoluted tubules. In vivo continuous microperfusion experiments in proximal convoluted tubules demonstrated that luminal benzolamide (0.5 mmol/l) virtually abolishes net bicarbonate fluxes, when bicarbonate concentration in the luminal perfusate (25 mmol/l) is close to peritubular plasma concentration (24.4 mmol/l). In contrast, a significant downhill reabsorptive flux occurs, when perfusate bicarbonate concentration is 75 mmol/l and a significant downhill secretory flux is observed, when the perfusate is initially free of bicarbonate. The corresponding apparent permeabilities are 1.0 +/- 0.1 X 10(-6) cm2/s for influx and 1.6 +/- 0.4 X 10(-6) cm2/s for efflux of bicarbonate. Clearance studies reveal that carbonic anhydrase dependent and independent bicarbonate reabsorption are not saturable but depend on the rate of volume reabsorption in the kidney. In conclusion, passive movements of bicarbonate do occur in proximal convoluted tubules and most likely contribute to carbonic anhydrase independent bicarbonate reabsorption.

Absorption↗

PubMed1996

Calcium- and barium-dependent extracellular alkaline shifts evoked by electrical activity in rat hippocampal slices.

Synaptic activation of central neurons has been associated with rapid extracellular alkalinization. In this report, we directly activated CA1 pyramidal cells by antidromic invasion, or by field stimulation. Antidromic activation produced no pH change, despite a robust population spike in five of 11 slices. In six slices, antidromic stimulation at 10 Hz evoked a small alkalinization in stratum pyramidale (0.04 +/- 0.01 unit pH) which grew to 0.10-0.20 unit pH at 50-100 Hz, and was blocked in 0 Ca2+ media. Simultaneous pH recordings revealed no alkalinizations in stratum radiatum, despite robust alkaline shifts in stratum pyramidale. When synaptic transmission was blocked by 6-cyano-7-nitroquinoxaline-2,3-dione, DL-2-amino-5-phosphonovalerate and picrotoxin, the Schaffer collateral-induced alkaline shift in stratum radiatum was abolished. With adequate stimulus strength and orientation, however, alkaline shifts in stratum radiatum could still be elicited, presumably by direct activation of the CA1 population. The non-synaptic alkaline shifts ranged from 0.10-0.20 unit pH, were amplified by benzolamide, and blocked by tetrodotoxin, 0 Ca2+ saline, and 300-400 microM Cd2+. Although directly activated alkaline shifts were never observed in 0 Ca2+ saline, large stimulus evoked responses could be elicited upon addition of 5-10 mM Ba2+. The Ba(2+)-dependent responses were also amplified by benzolamide and blocked by tetrodotoxin, Cd2+ or high Mg2+. These data demonstrate that stratum pyramidale can undergo an extracellular alkaline shift independent of stratum radiatum. The ionic dependence and pharmacologic sensitivity of the alkaline shifts suggest that voltage-gated Ca2+ channels are instrumental in triggering the alkalinizing mechanism. However, the ability of Ba2+ to support the alkaline shifts indicates that Ca2+ entry is not an absolute requirement. Implications for the mechanism of these pH changes are discussed.

2-Amino-5-phosphonovalerate↗

PubMed2005

Carbonic anhydrase inhibitors. Inhibition of the human cytosolic isozyme VII with aromatic and heterocyclic sulfonamides.

The inhibition of a newly cloned human carbonic anhydrase (CA, EC 4.2.1.1), isozyme VII (hCA VII), has been investigated with a series of aromatic and heterocyclic sulfonamides, including some of the clinically used derivatives (acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide and benzolamide), as well as the sulfamate antiepileptic drug topiramate. Inhibition data for the the other physiologically relevant cytosolic isoforms hCA I, hCA II and mCA XIII are also provided for comparison. hCA VII shows a high catalytic activity for the CO(2) hydration reaction, with a k(cat) of 9.5 x 10(5)s(-1) and k(cat)/K(m) of 8.3 x 10(7)M(-1)s(-1) at pH7.5 and 20 degrees C. A very interesting inhibition profile against hCA VII with this series of 32 sulfonamides/sulfamates was observed. hCA VII shows high affinity for all the investigated compounds, with inhibition constants in the range of 0.45-210 nM. Topiramate, ethoxzolamide and benzolamide showed subnanomolar hCA VII inhibitory activity, whereas acetazolamide, methazolamide, dorzolamide and brinzolamide showed K(I)-s in the range of 2.1-3.5 nM. Dichlorophenamide was slightly less active (K(I) of 26.5 nM). A number of heterocyclic or bicyclic aromatic sulfonamides also showed excellent hCA VII inhibitory properties (K(I)-s in the range of 4.3-7.0 nM) whereas many monosubstituted or disubstituted benzenesulfonamides were less active (K(I)-s in the range of 45-89 nM). The least active hCA VII inhibitors were some substituted benzene-1,3-disulfonamides as well as some halogenated sulfanilamides (K(I)-s in the range of 100-210 nM). The inhibition profile of hCA VII is rather different of that of the other cytosolic isozymes, providing thus a possibility for the design of more selective, hCA VII-specific inhibitors. In addition, these data furnish further evidence that hCA VII is the isozyme responsible for the anticonvulsant/antiepileptic activity of sulfonamides and sulfamates.

Anticonvulsants↗

PubMed2005

Carbonic anhydrase inhibitors: inhibition of the transmembrane isozyme XIV with sulfonamides.

The inhibition of the last human carbonic anhydrase (CA, EC 4.2.1.1) isozyme (hCA XIV) discovered has been investigated with a series of sulfonamides, including some clinically used derivatives (acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, benzolamide, and zonisamide), as well as the sulfamate antiepileptic drug topiramate. The full-length hCA XIV is an enzyme showing a medium-low catalytic activity, quite similar to that of hCA XII, with the following kinetic parameters at 20 degrees C and pH 7.5, for the CO2 hydration reaction: k(cat) = 3.12 x 10(5) s(-1) and k(cat)/K(M) = 3.9 x 10(7) M(-1) s(-1). All types of activities have been detected for the investigated compounds, with several micromolar inhibitors, including zonisamide, topiramate, and simple sulfanilamide derivatives (K(I)-s in the range of 1.46-6.50 microM). In addition, topiramate and zonisamide were observed to behave as weak hCA XII inhibitors, while zonisamide was an effective hCA IX inhibitor (K(I) of 5.1 nM). Some benzene-1,3-disulfonamide derivatives or simple five-membered heteroaromatic sulfonamides showed K(I)-s in the range of 180-680 nM against hCA XIV, whereas the most effective of such inhibitors, including 3-chloro-/bromo-sulfanilamide, benzolamide-like, ethoxzolamide-like, and acetazolamide/methazolamide-like derivatives, showed inhibition constant in the range of 13-48 nM. The best hCA XIV inhibitor was aminobenzolamide (K(I) of 13 nM), but no CA XIV-selective derivatives were evidenced. There are important differences of affinity of these sulfonamides/sulfamates for the three transmembrane CA isozymes, with CA XII showing the highest affinity, followed by CA IX, whereas CA XIV usually showed the lowest affinity for these inhibitors.

Carbonic Anhydrase Inhibitors↗

PubMed1995

Addition of carbonic anhydrase augments extracellular pH buffering in rat cerebral cortex.

1. The ability of the extracellular space to buffer rapid alkaline shifts was studied in rat cortex in vitro and in vivo. Alkaline shifts were generated by iontophoresis of OH- or were evoked by pressure ejection of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). 2. In cortical slices, alkaline shifts induced by OH- were enhanced by the carbonic anhydrase (CA) inhibitor benzolamide (83 +/- 16%, mean +/- SE), and were decreased by superfusion of 10 mg/l CA (-59 +/- 4%). CA had no effect at 1 mg/l, and no additional effect at 100 mg/l. 3. In slices, and in vivo, alkaline shifts induced by AMPA were similarly enhanced by benzolamide and decreased by superfusion of CA. 4. These data indicate that extracellular CA activity is less than that required for maximum buffering. This suggests that equilibrium between CO2 and bicarbonate may not be attained during rapid extracellular pH shifts.

Aging↗

PubMed2001

Downstream shift in sodium pump activity along the nephron during acute hypertension.

Acute hypertension rapidly inhibits proximal tubule (PT) Na,K-ATPase activity and sodium reabsorption 30 to 40%, increasing sodium and volume delivery to the thick ascending loop of Henle (TALH) and macula densa, providing the error signal for tubuloglomerular feedback. The hypothesis was tested in rats that an acute increase in sodium and volume delivery to the TALH would acutely increase outer medulla Na,K-ATPase activity. Flow to the TALH was increased by either (1) elevating BP (102 to 160 mmHg) for 5 min by constricting arteries (hypertension) or (2) inhibiting PT sodium and volume reabsorption with the carbonic anhydrase inhibitor benzolamide: 2 mg/kg in 300 mM NaHCO(3) at 50 microl/min for 5 to 7 min. Both stimuli increased urine output and lithium clearance three- to four-fold and increased basolateral Na,K-ATPase activity about 40%. In homogenates, acute hypertension increased medullary Na,K-ATPase activity from 20 +/- 3.5 to 27 +/- 6.4 micromol Pi/mg protein per h while decreasing renal cortex activity from 10.9 +/- 0.9 to 6.5 +/- 0.7. Hypertension and benzolamide also doubled medullary alkaline phosphatase activity. As chronic hypertension develops in the young spontaneously hypertensive rat, medullary Na,K-ATPase activity similarly increases. In conclusion, there is a rapid activation of medullary Na,K-ATPase activity during acute hypertension that can be explained by the increase in sodium and volume flow to the region independent of hypertension. That is, the glomerulotubular balance response in the loop of Henle is accompanied by increased Na,K-ATPase activity. The rapid, downstream shift in Na,K-ATPase activity during acute hypertension contributes the driving force for activating TGF (by inhibition in the PT) and minimizes changes in distal sodium delivery (by activation in the TALH).

Acute Disease↗

PubMed1975

Effect of ouabain on cerebrospinal fluid formation after carbonic anhydrase inhibition.

The effect of ventriculo-cisternal perfusion of ouabain was determined on CSF production after inhibition of carbonic anhydrase by benzolamide in cats. An additional decrease in CSF formation was observed by combination of i.v. benzolamide and intraventricular ouabain. However, the effect of the combined drugs was less than the sum of the effects of the drugs given individually. It is concluded that the reduction of the CSF production by ouabain is probably partly due to its effect on Na-K exchange (through inhibition of Na-K-activated ATPase) and partly due to its effects on Na+ transport coupled to anion transport mediated by carbonic anhydrase.

Animals↗

PubMed1983

Procainamide uptake by rabbit proximal tubules.

Procainamide is an organic cation and commonly prescribed drug that is actively secreted into the urine by renal proximal tubules. In order to elucidate further the mechanisms involved in this secretion, [3H]procainamide uptake into dissected S2 segments of superficial proximal tubule cells was studied. Uptake of [3H]procainamide was reduced by hypothermia and in a dose-related manner by the organic cations nonradiolabeled procainamide, cimetidine and quinidine and also by the carbonic anhydrase inhibitors acetazolamide and benzolamide, but not by ouabain. All these drugs were shown previously to inhibit transtubular secretion of [3H]procainamide in isolated perfused proximal tubules. The results of these and our previous studies suggest that 1) organic cations reduce the tubular secretion of each other, in part, by competing for uptake across the basolateral membrane of renal tubule cells, 2) acetazolamide and benzolamide reduce urinary excretion of organic cations, in part, by inhibiting proximal tubular secretion and 3) the potential difference across the basolateral cell membrane (due to activity of Na+-K+-dependent adenosine triphosphatase) is not the only driving force for uptake of organic cations into intact renal tubule cells.

Animals↗