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At least 19 recordsLinked to original sources
PubMed1995

Benzolamide inhibits low-threshold calcium currents in hippocampal pyramidal neurons.

1. Benzolamide is a poorly permeant sulfonamide inhibitor of the enzyme carbonic anhydrase. We studied the effect of benzolamide on low-threshold (LT) Ca currents in neonatal hippocampal CAl neurons. 2. In hippocampal slices, benzolamide (2-10 microM) inhibited the LT current 30-75% in voltage-clamped CAl pyramidal cells (n = 6). In slices bathed in N-2-hydroxypiperazine-N'-2-ethane-sulfonic acid (HEPES)-buffered Ringer, benzolamide also reduced the LT current, indicating that the action of the drug was not bicarbonate dependent. 3. Benzolamide inhibited LT Ca currents 20-75% in acutely dissociated CAl neurons in HEPES (n = 18): inhibition was 36 +/- 8% (mean +/- SE; n = 7) and 50 +/- 8% (n = 7) at 10 and 50 microM benzolamide, respectively. By contrast, high-threshold calcium currents recorded in CAl pyramidal cells (n = 18) and dorsal root ganglion neurons (n = 4) were virtually unaffected by benzolamide. 4. These results indicate that benzolamide inhibits LT Ca channels in central neurons and suggest caution in the use of this agent to inhibit extracellular carbonic anhydrase in excitable tissues.

Animals↗
PubMed1978

Studies on the tubulo-glomerular feedback system in the rat. The mechanism of reduction in filtration rate with benzolamide.

The specific mechanism whereby superficial nephron glomerular filtration rate (sngfr) is reduced after the administration of benzolamide, a carbonic anhydrase inhibitor with a primary inhibitory effect in the proximal tubule, have been examined by measuring pertinent pressures, flows, and glomerular permeabilities in the hydropenic Munich-Wistar rat, a strain with surface glomeruli. Because benzolamide decreases absolute proximal reabsorptive rate, the rate of delivery of tubular fluid to the distal nephron should be at least transiently increased and may reduce sngfr by activating the tubulo-glomerular feedback system. Sngfr fell from 29.2+/2.0 to 2.1+/3.1 nl/min (P less than 0.01) after benzolamide (group 1), a percentage reduction equal to kidney glomerular filtration rate and similar to sngfr obtained in collections from distal tubules. Separate studies (group 2) revealed that if transient increases in distal nephron delivery were prevented by insertion of a long oil block in proximal tubules before control, the decrease in sngfr was prevented (30.3+/1.0 vs. 30.3+/1.8 nl/min, P greater than 0.9). In paired "unblocked" nephrons in the same rats, sngfr fell in group 2 (33.0+/1.0 vs. 25.2+/2.3 nl/min, P less than 0.01). In "blocked" nephrons in which sngfr reduction was prevented, the rate of fluid leaving the proximal tubule increased from 16.9+/ to 23.1+/1.0 nl/min (P less than 0.01). In group 1 studies in which sngfr fell and transient increases in flow out of the last segment of the proximal tubule (distal delivery) (approximately equal to 8 nl/min) were not prevented, steady-state distal delivery was unchanged by benzolamide (13.9+/1.1 vs. 14.2+/2.2 nl/min). Also, sngfr returned toward control, pre-benzolamide values, when a proximal oil block was placed for 15 min and the rate of distal delivery reduced after benzolamide administration, which suggests that this activation was reversible. These data suggest that activation of tubulo-glomerular feedback by transient increases in distal delivery was responsible for decreases in sngfr. Analysis of all determinants of glomerular ultra-filtration revealed that the efferent mechanism leading to reduced sngfr after benzolamide was decreased nephron plasma flow (101+/13 vs. 66+/13 nl/min, P less than 0.01). Hydrostatic pressure and the glomerular permeability coefficient did not contribute to reductions in sngfr with benzolamide. Because the rate of distal delivery remained constant in spite of large changes in both sngfr and absolute proximal reabsorptive rate, it is suggested that the rate of distal delivery may be the physiologic entity that is regulated by the tubulo-glomerular feedback system via alterations in sngfr.

Animals↗
PubMed1972

The influence of the carbonic anhydrase inhibitor, benzolamide (CL-11,366), on the reabsorption of chloride, sodium, and bicarbonate in the proximal tubule of the rat.

Benzolamide (CL-11,366), a potent carbonic anhydrase inhibitor, was used to examine the influence of carbonic anhydrase inhibition on the reabsorption of chloride, sodium, and bicarbonate in the rat proximal convoluted tubule. Administration of 2 mg/kg benzolamide was associated with a decrease in the tubular fluid/plasma (TF/P) chloride ratio from 1.19+/-0.10 (SEM) to 1.06+/-0.01, and an increase in the TF/P bicarbonate ratio from 0.181+/-0.02 to 0.584+/-0.02. This dose of benzolamide significantly reduced proximal fractional reabsorption of chloride by 29.14%, of sodium by 34.3%, and of bicarbonate by 35.64%. These results indicate that benzolamide administration inhibits the reabsorption of all three electrolytes in the proximal convoluted tubule. Although 20 mg/kg benzolamide accentuated the changes in fractional reabsorption, the differences between 2 and 20 mg/kg were not statistically significant. Inhibition of proximal tubular cytoplasmic and luminal carbonic anhydrase could well explain the diminished bicarbonate reabsorption and a fraction of the diminished sodium reabsorption noted in these studies. The fall in chloride reabsorption, and a portion of the fall in sodium reabsorption, however, may be a direct or indirect consequence of carbonic anhydrase inhibition or of an influence of benzolamide on a transport mechanism not dependent upon carbonic anhydrase.

Animals↗
PubMed1979

Microelectrode determination of pH and PCO2 in rat proximal tubule after benzolamide: evidence for hydrogen ion secretion.

Previous micropuncture studies supporting hydrogen secretion as the mechanism of bicarbonate reabsorption have relied on the demonstration of an acid disequilibrium pH in the proximal tubule after systemic administration of a carbonic anhydrase inhibitor. Previous calculations of disequilibrium pH, however, have involved the necessary assumption that PCO2 in the proximal convoluted tubule was equal to arterial blood PCO2. This assumption can no longer be supported in view of the recent demonstration that the PCO2 in proximal and distal tubular fluid exceeded arterial blood by approximately 25 mm Hg. The purpose of the present study was to determine directly pH and PCO2 with microelectrodes in both the early and late segments of the accessible proximal tubule of nine Sprague-Dawley rats before and after administration of benzolamide (2.0 mg/kg/hr, i.v.). In the early proximal tubule, pH decreased significantly after benzolamide administration from 6.98 +/- 0.03 to 6.62 +/- 0.03 pH U (P less than 0.001), and PCO2 also decreased from 65.1 +/- 1.2 to 59.3 +/- 1.4 mm Hg (P less than 0.005). In the late proximal convoluted tubule, pH did not change after benzolamide (6.75 +/- 0.02 to 6.77 +/- 0.02), but PCO2 decreased significantly (64.3 +/- 1.5 to 57.7 +/- 1.6) (P less than 0.01). We conclude: (1) the fall in both pH and PCO2 in the early proximal tubule indicates that carbonic acid, not carbon dioxide accumulates after inhibition of luminal carbonic anhydrase; (2) although PCO2 also decreased in the late proximal tubule, unlike the early segment, pH was unchanged after benzolamide administration, perhaps as a result of increased bicarbonate delivery; and (3) PCO2 in vivo was significantly greater than was systemic arterial PCO2 before and after benzolamide administration in both the early and late proximal convoluted tubule. These findings lend support to the view that bicarbonate reabsorption in the proximal convoluted tubule occurs, in part, by hydrogen secretion.

Animals↗
PubMed1980

Effect of benzolamide on pH in the proximal tubules and peritubular capillaries of the rat kidney.

The influence of carbonic anhydrase inhibition with benzolamide on proximal tubular and peritubular capillary pH was evaluated in the rat using a glass-membrane pH microelectrode. Control peritubular capillary pH, 7.38 +/- .02 (N=11), was significantly lower than control arterial pH, 7.44 +/- .01, p < .05. Early proximal tubular pH, 7.20 +/- .02 (N = 17), was more alkaline than late proximal tubular pH, 6.74 +/- .06 (N = 13), p < .001; pH at both sites was more acid than in the peritubular capillary, p < .001. Benzolamide treatment had no detectable effect on arterial or peritubular capillary pH, but reduced early proximal tubular pH by 0.54 pH units, to 6.66 +/- .04 (N = 13), p < .001. Late proximal pH also fell slightly to 6.57 +/- .03 (N = 14), p < .02. The results support previous observations indicating that benzolamide treatment decreases early proximal tubular pH dramatically, and provide further evidence that HCO3- reabsorption is accomplished by hydrogen ion secretion in the proximal tubule.

Animals↗
PubMed1978

Effect of benzolamide on luminal pH in proximal convoluted tubules of the rat kidney.

Luminal pH in early and late proximal tubules was recorded continuously with antimony microelectrodes before and during carbonic anhydrase inhibition. Following i.v. application of benzolamide (25 mumol/kg BW), luminal pH decreased almost immediately in early proximal tubules (deltapH--0.42 +/- 0.06SEM), but increased in late proximal tubules (deltapH +0.27 +/- 0.06). Urinary pH increased (deltapH + 1.6 +/- 0.16) after a delay of some 30 s. Similar results, i.e. decrease of pH in early and increase of pH in late proximal tubules, were obtained, when benzolamide containing solutions were microinfused into early proximal tubules or superfused on the nephron surface. In contrast, luminal pH decreased in late proximal tubules, when benzolamide was microinfused into the same nephron segment. The decrease of luminal pH indicates inhibition of luminally active carbonic anhydrase, leading to delayed buffering of secreted hydrogen ions. The increase of luminal pH in late proximal tubules may be attributed to several factors including increased delivery of bicarbonate, impaired bicarbonate exit at the antiluminal membrane and decreased hydrogen ion formation in the tubular cell due to inhibition of cellular carbonic anhydrase.

Animals↗
PubMed2004

Benzolamide is not a membrane-impermeant carbonic anhydrase inhibitor.

Benzolamide, an orphan drug belonging to the pharmacological class of sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) is widely used in many physiological and pharmacological studies, together with the clinically employed classical drugs, acetazolamide, methazolamide, ethoxzolamide or dichlorophenamide, it being frequently stated that benzolamide is a membrane-impermeant inhibitor. We prove here that this is false: in fact benzolamide is rather similar to acetazolamide from the point of view of penetrability through blood red cell membranes. Unlike these neutral drugs, the cationic, positively-charged CAIs incorporating either tetraalkyl ammonium or pyridinium moieties, due to their salt-like character are indeed membrane-impermeant, being the only type of low molecular weight compound possessing such properties. Selective inhibition of membrane-associated CA isozymes is relevant indeed in many physiological studies and also pharmacologically, since the tumor-associated isozymes (CA IX and XII) are both membrane-bound.

Benzolamide↗
PubMed1995

Carbonic anhydrase and control of breathing: different effects of benzolamide and methazolamide in the anaesthetized cat.

1. The effect of inhibition of erythrocyte carbonic anhydrase on the ventilatory response to CO2 was studied by administering benzolamide (70 mg kg-1, i.v.), an inhibitor which does not cross the blood-brain barrier, to carotid body denervated cats which were anaesthetized with chloralose-urethane. 2. In the same animals the effect on the ventilatory response to CO2 of subsequent inhibition of central nervous system (CNS) carbonic anhydrase was studied by infusing methazolamide (20 mg kg-1), an inhibitor which rapidly penetrates into brain tissue. 3. The results show that inhibition of erythrocyte carbonic anhydrase by benzolamide leads to a decrease in the slope of the normoxic CO2 response curve, and a decrease of the extrapolated arterial PCO2 at zero ventilation. 4. Inhibition of CNS carbonic anhydrase by methazolamide results in an increase in slope and alpha-intercept of the ventilatory CO2 response curve. 5. Using a mass balance equation for CO2 of a brain compartment, it is argued that inhibition of erythrocyte carbonic anhydrase results in a decrease in slope of the in vivo CO2 dissociation curve, which can explain the effects of benzolamide. 6. The changes in slope and intercept induced by methazolamide are discussed in relation to effects on neurones containing carbonic anhydrase, which may include central chemoreceptors.

Acidosis↗
PubMed2000

Benzolamide, acetazolamide, and signal transduction in avian intrapulmonary chemoreceptors.

Intrapulmonary chemoreceptors (IPC) are CO(2)-sensitive sensory neurons that innervate the lungs of birds, help control the rate and depth of breathing, and require carbonic anhydrase (CA) for normal function. We tested whether the CA enzyme is located intracellularly or extracellularly in IPC by comparing the effect of a CA inhibitor that is membrane permeable (iv acetazolamide) with one that is relatively membrane impermeable (iv benzolamide). Single cell extracellular recordings were made from vagal filaments in 16 anesthetized, unidirectionally ventilated mallards (Anas platyrhynchos). Without CA inhibition, action potential discharge rate was inversely proportional to inspired PCO(2) (-9.0 +/- 0.8 s(-1). lnTorr(-1); means +/- SE, n = 16) and exhibited phasic responses to rapid PCO(2) changes. Benzolamide (25 mg/kg iv) raised the discharge rate but did not alter tonic IPC PCO(2) response (-9.8 +/- 1.6 s(-1). lnTorr(-1), n = 8), and it modestly attenuated phasic responses. Acetazolamide (10 mg/kg iv) raised IPC discharge, significantly reduced tonic IPC PCO(2) response to -3.5 +/- 3.6 s(-1). lnTorr(-1) (n = 6), and severely attenuated phasic responses. Results were consistent with an intracellular site for CA that is less accessible to benzolamide. A model of IPC CO(2) transduction is proposed.

Acetazolamide↗
PubMed1975

CO2 retention as a basis for increased toxicity of salicylate with acetazolamide: avoidance of increased toxicity with benzolamide.

Two carbonic anhydrase inhibitors, acetazolamide and benzolamide, are capable of increasing the toxicity of sodium salicylate in mice. Beginning at about 2 mg/kg, each of the inhibitors, in combination with a fixed (400 mg/kg) dose of salicylate, generates a dose-mortality curve that reaches a plateau at about 60% deaths at 6 to 8 mg/kg. This effect can be duplicated by 8 to 10% inspired CO2. It appears that the respiratory acidosis secondary to the inhibition of red cell carbonic anhydrase is responsible for the increased toxicity; earlier work by others shows that acidosis increases the concentration of salicylate in the brain. In the treatment of salicylate poisoning by carbonic anhydrase inhibitors, the goal is to alkalinize the urine and increase the excretion of salicylate. With the newer inhibitor, benzolamide, it is possible to dissociate the respiratory acidosis from the renal effect. Maximal alkalinization of the urine is possible with a dose (about 1 mg/kg) below that which generates a respiratory acidosis. With this dose, there is no increase in the early toxicity of salicylate.

Acetazolamide↗
PubMed2004

Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides derived from 4-isothiocyanato-benzolamide.

A series of sulfonamides incorporating 4-thioureido-benzolamide moieties have been prepared from aminobenzolamide and thiophosgene followed by the reaction of the thiocyanato intermediate with aliphatic/aromatic amines or hydrazines. The new derivatives have been investigated as inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), and more precisely of the cytosolic isozymes hCA I and II, as well as the tumor-associated isozyme hCA IX (all of human origin). The new compounds showed excellent inhibitory properties against all three isozymes with inhibition constants in the range of 0.6-62 nM against hCA I, 0.5-1.7 nM against hCA II and 3.2-23 nM against hCA IX, respectively. These derivatives are interesting candidates for the development of novel therapies targeting hypoxic tumors.

Benzolamide↗
PubMed1984

Differential effects of acetazolamide, benzolamide and systemic acidosis on hydrogen and bicarbonate gradients across the apical and basolateral membranes of the choroid plexus.

The effect after 1 hr of sulfonamide agents and systemic acidosis on pH (dimethyloxazolidinedione method) and [HCO3-] (calculated from pH and estimated cell pCO2) of choroid plexus epithelium was analyzed in adult Sprague-Dawley rats anesthetized with ether. Acetazolamide (20 mg/kg i.p.) caused a striking increase in choroid cell pH (7.0-7.45) and a substantial elevation in [HCO3-]i, and an alkalinization of cerebrospinal fluid (CSF); effects of benzolamide (3 mg/kg i.v.) were less marked. Acetazolamide-induced augmentation of steady-state pH was found in choroid plexus (0.45 pH unit) but not in submaxillary salivary gland, skeletal muscle, erythrocytes and cerebral cortex. Respiratory acidosis (blood pH 6.94) caused choroid cell pH to decrease less extensively than in the other tissues analyzed; metabolic acidosis (blood pH 7.23) did not significantly alter choroid plexus pH. Both sulfonamide agents and systemic acidoses significantly decreased the pH gradient between arterial blood and cisternal CSF. The sulfonamide-induced increase in choroid cell pH is attributed to suppression of buffering of OH- by CO2, leading to elevated [OH]i; and to a build-up in [HCO3-]i. Acetazolamide caused a reversal of the H+ and HCO3- gradients across the basolateral (plasma-facing) membrane of the choroid plexus. It is postulated that carbonic anhydrase inhibitors decrease CSF formation primarily by reducing Na+-H+ exchange at the basolateral membrane of the choroidal epithelium, and secondarily by slowing down HCO3- and Cl- exit across the CSF-facing membrane.

Acetazolamide↗