Renal carbonic anhydrase inhibition by benzolamide (CL 11,366) in man.
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Absorption↗
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Effect of benzolamide on cerebrospinal fluid formation.
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Amides↗
Inhibition of membrane-bound carbonic anhydrase enhances subretinal fluid absorption and retinal adhesiveness.
BACKGROUND: The clinical use of currently available carbonic anhydrase (CA) inhibitors is limited by systemic side-effects, thought to result from the inhibition of intracellular CA isoenzymes. This study investigates how benzolamide, a carbonic anhydrase inhibitor which does not readily penetrate cell membranes, modulates retinal pigment epithelium functions relative to acetazolamide, which diffuses into the cytosol. METHODS: Small retinal detachments were made in Dutch rabbits by injecting saline into the subretinal space. Detachment height was measured using a dual He-Ne beam YAG laser focusing system, and the fluid absorption rate was calculated before and after intravenous injections of saline, acetazolamide or benzolamide. Retinal adhesiveness was determined by peeling the retina from the RPE and measuring the amount of adherent pigment. RESULTS: The baseline fluid absorption rate of 0.04 microl/mm(2)/h was unchanged after injection of 0.9% NaCl or low-dose benzolamide (5 mg/kg). The absorption increased to about 0.14 microl/mm(2)/h after higher benzolamide doses (20-40 mg/kg) and to 0.13 microl/mm(2)/h after acetazolamide (20 mg/kg). Both acetazolamide and benzolamide significantly slowed the post-enucleation failure of retinal adhesiveness. CONCLUSION: Since benzolamide had effects similar to acetazolamide, inhibition of membrane-bound CA appears to be sufficient to enhance subretinal fluid absorption and retinal adhesiveness. Membrane-specific CA inhibitors may therefore be of clinical value if they minimize side-effects from intracellular CA inhibition.
Absorption↗
Role of peritubular capillary forces in the renal action of carbonic anhydrase inhibitor.
Micropuncture study was performed in Munich-Wistar rats to assess peritubular capillary Starling forces in renal superficial cortex during suppression of proximal fluid reabsorption by carbonic anhydrase inhibitor. Administration of benzolamide (2 mg/kg/hr, i.v., Group 1, N = 7 rats) caused not only reduction in absolute rate of proximal fluid reabsorption (APR, from 26.7 +/- 4.0 nl/min to 17.7 +/- 3.6, P less than 0.001), but also an increase in peritubular transcapillary hydraulic-pressure difference (from 10.0 +/- 0.5 mm Hg to 15.2 +/- 0.5, P less than 0.001). In a separate group of seven rats (Group 2), these parameters did not change significantly without benzolamide treatment. In Group 1 rats, an attempt was made to nullify the benzolamide-induced reduction in the peritubular capillary net reabsorptive forces by infusing hyperoncotic high-hematocrit blood. Following this treatment, while benzolamide administration was continued, values for APR returned to levels (25.6 +/- 4.8 nl/min) nearly identical to those measured prior to benzolamide administration, in association with a rise in peritubular transcapillary oncotic pressure difference. A separate group of six rats treated in a fashion identical to that of Group 1 showed continued suppression of carbonic anhydrase activity following blood infusion as indicated by low levels of whole kidney bicarbonate reabsorption rate. Peritubular capillary reabsorption coefficient was calculated based on the measured values for Starling forces in Group 1 and were unaffected throughout the study. Continued benzolamide administration alone without the treatment of hyperoncotic blood did not change APR significantly (Group 3, N = 7 rats).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The efferent limb of the tubuloglomerular feedback system.
The effector mechanisms which constitute the efferent limb of the tubuloglomerular feedback system were examined after the administration of benzolamide, a carbonic anhydrase inhibitor, which decreased proximal tubule fluid reabsorption by approximately 8 nl/min and transiently increased delivery of fluid out of the proximal tubule. Since benzolamide administration resulted in a decrease in nephron filtration rate (SNGFR) from 29.2 to 21.1 nl/min, late proximal flow rate returned to control values. If the proximal tubule was blocked after benzolamide by insertion of an oil block, the SGNFR returned towards control values. If a proximal tubule oil block was inserted prior to control measurements, SNGFR did not decrease. These data suggest that benzolamide reduces SNGFR by activating tubulo-glomerular feedback mechanisms secondary to increases in the rate of distal delivery. Analysis of the determinants of glomerular ultrafiltration before and after benzolamide administration revealed that the decrease in SNGFR was solely the result of a decrease in nephron plasma flow secondary to increases in afferent and efferent glomerular arteriolar resistance. No change in either the hydrostatic pressure gradient (delta P) or the glomerular permeability coefficient (LpA) was observed. Continuous infusion in saralasin, an angiotensin II antagonist, prevented the reduction in SNGFR and nephron plasma flow after benzolamide. These studies suggest that changes in nephron plasma flow are involved in a mediating the tubuloglomerular feedback response and that angiotensin II may have a role in the effector mechanism.
Angiotensin II↗
Modulation of spreading depression by changes in extracellular pH.
Spreading depression (SD) and related phenomena have been implicated in hypoxic-ischemic injury. In such settings, SD occurs in the presence of marked extracellular acidosis. SD itself can also generate changes in extracellular pH (pH(o)), including a pronounced early alkaline shift. In a hippocampal slice model, we investigated the effect of interstitial acidosis on the generation and propagation of SD in the CA1 stratum radiatum. In addition, a carbonic anhydrase inhibitor (benzolamide) was used to decrease buffering of the alkaline shift to investigate its role in the modulation of SD. pH(o) was lowered by a decrease in saline HCO(3)(-) (from 26 to 13 to 6.5 mM at 5% CO(2)), or by an increase in the CO(2) content (from 5 to 15% in 26 mM HCO(3)(-)). Recordings with pH microelectrodes revealed respective pHo values of 7.23 +/- 0. 13, 6.95 +/- 0.10, 6.67 +/- 0.09, and 6.97 +/- 0.12. The overall effect of acidosis was an increase in the threshold for SD induction, a decrease in velocity, and a shortened SD duration. This inhibition was most pronounced at the lowest pH(o) (in 6.5 mM HCO(3)(-)) where SD was often blocked. The effects of acidosis were reversible on return to control saline. Benzolamide (10 microM) caused an approximate doubling of the early alkaline shift to an amplitude of 0.3-0.4 U pH. The amplified alkalosis was associated with an increased duration and/or increased velocity of the wave. These effects were most pronounced in acidic media (13 mM HCO(3)(-)/5% CO(2)) where benzolamide increased the SD duration by 55 +/- 32%. The initial velocity (including time for induction) and propagation velocity (measured between distal electrodes) were enhanced by 35 +/- 25 and 26 +/- 16%, respectively. Measurements of [Ca(2+)](o) demonstrated an increase in duration of the Ca(2+) transient when the alkaline shift was amplified by benzolamide. The augmentation of SD caused by benzolamide was blocked in media containing the N-methyl-D-aspartate (NMDA) receptor antagonist DL-2-amino-5-phosphonovaleric acid. These data indicate that the induction and propagation of SD is inhibited by a fall in baseline pH characteristic of ischemic conditions and that the early alkaline shift can remove this inhibition by relieving the proton block on NMDA receptors. Under ischemic conditions, the intrinsic alkalosis may therefore enable SD and thereby contribute to NMDA receptor-mediated injury.
Acidosis↗
Clarification of the site of action of chlorothiazide in the rat nephron.
The saluretic effect of the thiazide diuretics has been attributed to inhibition of sodium reabsorption in the distal nephron of the kidney. Recent micropuncture studies have shown, however, that chlorothiazide administration can also inhibit sodium reabsorption in the proximal convolution. To clarify the site of the saluretic effect of chlorothiazide, these micropuncture studies examined the effect of chlorothiazide on chloride transport in the nephron. The effect of chlorothiazide on chloride transport was studied because chlorothiazide's effectiveness as a saluretic is largely due to its ability to enhance sodium chloride excretion; if only changes in sodium transport are examined, it would be then difficult to determine if sodium as bicarbonate or as chloride is affected, since chlorothiazide can inhibit carbonic anhydrase. One group of rats was studied before and after 15 mg/kg per h chlorothiazide. For comparison, another group of rats was studied before and after 2 mg/kg per h benzolamide, a carbonic anhydrase inhibitor. Fractional chloride delivery from the proximal tubule was similarly increased in both groups from 59.4 to 71.0% by chlorothiazide administration, Pless than 0.0001, and from 54.3 to 68.2% by benzolamide administration, P less than 0.001. The increased delivery very of chloride from the proximal tubule was largely reabsorbed before the early distal tubule as fractional chloride delivery to this site increased only from 5.08 to 7.40% after chlorothiazide administration, P less than 0.001, and from 4.50 to 6.29% after benzolamide administration, P less than 0.01. Benzolamide had no effect on chloride reabsorption in the distal convoluted tubule. However, chlorothiazide administration resulted in a marked decrease in distal tubular chloride reabsorption, the fraction of filtered chloride present at the late distal tubule incresing from 1.24 to 6.25%, P less than 0.001. Fractional chloride excretion in the urine increased from 0.29 to 3.44%, P less than 0.001, after chlorothiazide, but did not change after benzolamide. The influence of chlorothiazide on proximal chloride transport presumably is related to its ability to inhibit renal carbonic anhydrase. However, it is not the effect of chlorothiazide in the proximal convolution but rather its effect in the distal convoluted tubule which is primarily responsible for its ability to be an effective saliuretic.
Animals↗
Evidence for a bicarbonate leak in the proximal tubule of the rat kidney.
To elucidate the mechanism responsible for the establishment of steady state pH at zero net flux (pH infinity) in proximal convoluted tubules, luminal pH was recorded continuously with antimony microelectrodes under three experimental conditions. First: luminal pH in stationary droplets was allowed to reach pH infinity (6.76 +/- 0.07) and then carbonic anhydrase inhibitor benzolamide (3 x 10(-3) mol/l) was superfused on the kidney surface. Following application of benzolamide, luminal pH decreased within seconds (delta pH = -0.27 +/- 0.03 SEM). Second: tubule segments were perfused continuously with MES-buffer containing solution set to a pH of 6.1. Some 1--2 mm distal to the perfusion pipette luminal pH was recorded and was 6.5 +/- 0.04. After superfusion of benzolamide (3 x 10(-3) mol/l) pH decreased (delta pH = -0.15 +/- 0.03). Third: pH in stationary droplets was again allowed to reach PH infinity (6.69 +/- 0.01) and bicarbonate and CO2- free solution (5 mmol/l phosphate set to a pH of 7.4) was microinfused into the adjacent peritubular capillary. Luminal pH again decreased almost immediately (delta pH = -0.23 +/- 0.02). The data are interpreted as evidence for a bicarbonate leak. In a fourth series of experiments, segments of proximal tubules were perfused under benzolamide (0.4 x 10(-6) mol/min) with solutions initially free of bicarbonate or other buffers. In the collected fluid, bicarbonate was determined by a micro-Astrup method. A significant increase of luminal bicarbonate concentration (r = 0.88) indicates a permeability of 0.98 +/- 0.14 x 10(-6) cm2/s of the tubular wall for bicarbonate. Since bicarbonate eventually increases more than 3-fold the equilibrium concentration, collected bicarbonate could not have been formed by H2CO3 or CO2. Bicarbonate enters the luminal fluid and reacts with secreted hydrogen ions to forms carbonic acid. It, therefore, buffers secreted hydrogen ions and increases luminal pH at or below steady state. Inhibition of carbonic anhydrase and lowering of peritubular bicarbonate thus lower pH infinity.
Animals↗
Hemodynamics of early tubuloglomerular feedback resetting during reduced proximal reabsorption.
BACKGROUND: Carbonic anhydrase inhibition with benzolamide reduces proximal reabsorption and activates tubuloglomerular feedback (TGF). In rats, TGF activation for 30 to 60 minutes locally suppresses renin secretion and resets TGF rightward to accommodate increased late proximal flow. After 24 hours of TGF activation, there is upward resetting of GFR and increased activity of macula densa nitric oxide synthase I (NOS I). METHODS: We studied renal hemodynamics during early TGF resetting with attention to the importance of renin suppression and NOS I activation. Left kidney blood flow (RBF, pulse Doppler) and glomerular filtration rate (GFR; inulin clearance or Fick method) were measured before and during benzolamide infusion (5 mg/kg bolus followed by 5 mg/kg/h IV) in Wistar rats concurrently receiving the converting enzyme inhibitor, enalaprilat (0.3 mg/kg/h IV) or NOS-I blocker S-methyl-thiocitrulline (SMTC; 2.7 mg/kg/h IV). RESULTS: Activating TGF initially reduced RBF and GFR in all groups as expected. During continuous benzolamide, RBF gradually increased toward baseline in control and enalaprilat-treated rats, but not in NOS I-blocked rats. After the initial decline, GFR did not change further during one hour of benzolamide in any group. CONCLUSIONS: During one hour of persistent TGF stimulation, RBF increases toward normal, but GFR does not. This requires an overall decrease in renal vascular resistance and a decrease in the ratio of efferent/afferent arteriolar resistance (RE/RA), implying a major decrease in RE. NOS I, but not angiotensin-converting enzyme (ACE), is required for RBF to increase during TGF resetting. Although the hemodynamic changes during TGF resetting resemble the response to blocking the renin-angiotensin system, these data fail to show that the increase in RBF during early TGF resetting is mediated by renin suppression.
Angiotensins↗
Mode of stimulation by injection of cyclic AMP and external acidification of the sodium efflux in barnacle muscle fibres.
1. A study has been made in single barnacle muscle fibres of the effect of micro-injected pure protein kinase inhibitor (PKI) on the response of the Na efflux to injection of cyclic AMP and external acidification. 2. (i) Injection into fibres of 1.6 x 10(-4) M-pure PKI is without effect on the resting Na efflux. (ii) Injection of 1.6 x 10(4) M-pure PKI before 0.03 M-cyclic AMP causes a marked reduction in the magnitude of the response of the Na efflux to the nucleotide. The same is true when 10(-4) M-cyclic AMP is injected after PKI. (iii) Injection of partially pure catalytic subunits causes a sustained stimulation of the ouabain-insensitive Na efflux, which is almost completely reversed by injecting PKI. (iv) Injection of 100 mM-EGTA before PKI fails to alter the lowered response of the ouabain-insensitive Na efflux to injection of 10(-4) M-cyclic AMP. (v) Ouabain (10(-4) M) when applied following the injection of 10(-4) M-cyclic AMP causes a drastic fall in the stimulated Na efflux. 3. (i) Injection of 1.6 x 10(-4) M-pure PKI before or after external acidification fails to abolish or reduce the stimulatory response to acidification. (ii) Injection of 1.6 x 10(-4) M-pure PKI before acidification practically abolishes the response of the ouabain-insensitive Na efflux to 0.03 M-cyclic AMP in the presence of acidification. (iii) Radioimmunoassay of total cyclic AMP and cyclic GMP content in single fibres before and after acidification shows no appreciable alteration in nucleotide content following acidificiation. (iv) Injection of 100 mM-EGTA before acidification enhances the stimulatory response to acidification. (v) External application of Dantrolene (10(-5) M) fails to alter the size of the stimulatory response to acidification. 4. (i) Prior external application of 5 x 10(-4) M-benzolamide results in a marked reduction in the magnitude of the response of the ouabain-insensitive Na efflux to the injection of 3 x 10(-4) M-cyclic AMP. (ii) Benzolamide totally abolishes the response of the ouabain-insensitive Na efflux to the injection of catalytic subunits. 5. The evidence brought forward is compatible with the view that (a) The mechanism by which cyclic AMP stimulates the Na efflux involves activation by cyclic AMP of the cyclic AMP-dependent protein kinase system, and hence release of the catalytic subunit, and (b) the mechanism by which external acidification leads to stimulation of the Na efflux involves activation of a benzolamide-sensitive system, possibly carbonic anhydrase, rather than the adenyl cyclase system. The actions of cyclic AMP and catalytic subunits on the Na efflux are closely linked to activation of the benzolamide sensitive system.
Animals↗
Studies on the localization of pulmonary carbonic anhydrase in the cat.
1. We considered whether some of the carbonic anhydrase of the lung is on the surface of the pulmonary capillaries so that it acts directly on plasma as it traverses the pulmonary capillaries to accelerate CO2/pH equilibration. 2. Experiments were performed on spontaneously breathing cats or saline-perfused cat lungs. 3. In intact cats, Tris buffer injected suddenly into the right atrium transiently lowered end-tidal CO2, FET, CO2. The rate of CO2 uptake came within an order of magnitude of taxing the calculated diffusing capacity of the lungs. The fall in FET, CO2 was much reduced by giving the carbonic anhydrase inhibitors benzolamide or acetazolamide intravenously, or even by adding benzolamide to the injected Tris. The fall in FET, CO2 could be increased by adding carbonic anhydrase to the injected Tris. 4. In saline-perfused lungs ventilated with 5% CO2 in O2, Tris or alkalinized albumin solution injected into the pulmonary artery transiently lowered FET, CO2 and the effect was reduced by the addition of benzolamide or acetazolamide to the injectate. Injecting Tris bubbled with 15% CO2 caused a rise in FET, CO2, also reduced by benzolamide. 5. We conclude that pulmonary carbonic anhydrase is readily accessible to large or small molecular wight buffers in the capillaries and to inhibitors, and we suggest that it is located on the luminal surface of the capillary endothelium.
Acetazolamide↗
Endogenous H+ modulation of NMDA receptor-mediated EPSCs revealed by carbonic anhydrase inhibition in rat hippocampus.
1. The occurrence of extracellular alkaline transients during excitatory synaptic transmission suggests that the NMDA receptor H(+)-modulatory site may have a physiological role. Here we amplify these pH shifts using benzolamide (a carbonic anhydrase inhibitor) and describe concomitant effects on EPSCs in whole-cell clamped CA1 neurones in rat hippocampal slices. 2. In CO2-HCO3(-)-buffered media, benzolamide increased the time to 50% decay (t50) of the EPSCs by 78 +/- 14% (P < 0.01, n = 10). This occurred simultaneously with amplification of the extracellular alkaline shift (154 +/- 14%). 3. In CO2-HCO3(-)-buffered media containing DL-2-amino-5-phosphonovalerate (APV), the EPSC t50 was unaltered by benzolamide, while the extracellular alkaline shifts were increased (111 +/- 23%, n = 8). 4. In Hepes-buffered media, neither the EPSC t50 nor the extracellular alkaline shift was altered by benzolamide (n = 9). 5. These data demonstrate that NMDA receptor activity is dependent on the buffering kinetics of the brain extracellular space. The results suggest that endogenous pH shifts can modulate NMDA receptor function in a physiologically relevant time frame.
2-Amino-5-phosphonovalerate↗
Relative contributions of excitatory and inhibitory neuronal activity to alkaline transients evoked by stimulation of Schaffer collaterals in the rat hippocampal slice.
1. The neuronal basis of alkaline shifts in extracellular pH (pHo) evoked by stimulation of Schaffer collaterals was studied by means of double-barreled H(+)-selective microelectrodes in the area CA1 of rat hippocampal slices. 2. Alkaline transients in stratum pyramidale evoked by stimulation at a low frequency (5-10 Hz) were enhanced by pentobarbital sodium (100 microM). In the absence of the drug, inhibition of extracellular carbonic anhydrase (CAo) by benzolamide or by prontosildextran 5000 (PD 5000) resulted in an increase in the alkaline shifts. In contrast to this, alkaloses evoked by low-frequency stimulation in the presence of pentobarbital were attenuated by a subsequent inhibition of CAo. 3. Blockade of gamma-aminobutyric acid-A (GABAA) receptors with picrotoxin (PiTX; 100 microM) resulted in an enhancement of alkaline transients in s. pyramidale evoked by low-frequency stimulation (10 Hz) but suppressed alkaline shifts evoked by brief high-frequency (1 s, 100 Hz) trains of stimuli. 4. Application of trains of stimuli consisting of a constant number of pulses (50 or 100) revealed a striking dependence of the effect of benzolamide on stimulation frequency (10-200 Hz) in s. pyramidale: the enhancement of the alkaloses seen upon inhibition of CAo became progressively smaller with an increase in frequency, and at 100-200 Hz benzolamide produced a suppression or a complete block of the alkaline transients. However, alkaline transients evoked with the use of a constant train duration (5 s) were enhanced by benzolamide at all stimulation frequencies examined (5-200 Hz).(ABSTRACT TRUNCATED AT 250 WORDS)
Alkalies↗
The effects of the inhibition of the renal carbonic anhydrase on the blood acid-base status in hypercapnic rats.
Arterial blood acid-base status was measured in unanesthetized rats treated with benzolamide (a selective renal carbonic anhydrase inhibitor). These measurements were carried out in rats exposed to different levels of CO2 in air (0-10% CO2) for periods of up to 6 hr. In untreated rats the whole body buffer value showed a continuous increase and after 6 hr of exposure to hypercapnia its value was twice that measured initially. On the other hand, the whole body buffer value of benzolamide treated rats did not change during the 6 hr of exposure to hypercapnia. The whole body buffer value of normal rats, measured after 6 hr of hypercapnia is similar to that reported for chronic (3-5 days) hypercapnia in the normal dog. The whole body buffer value in benzolamide treated rats was similar to that reported for the normal dog and man, during acute CO2 exposures. It is suggested that mechanisms involving the renal carbonic anhydrase are responsible for the significant, rapid changes in the whole body buffer value that take place during the initial phase of acute exposure to CO2 in the rat. This may represent a mechanism of adaptation to burrow hypercapnic conditions.
Acid-Base Equilibrium↗
Activity-evoked extracellular pH shifts in slices of rat dorsal lateral geniculate nucleus.
Activity-dependent extracellular pH shifts were studied in slices of the rat dorsal lateral geniculate nucleus (dLGN) using double-barreled pH-sensitive microelectrodes. In 26 mM HCO3--buffered media, afferent activation (10 Hz, 5 s) elicited an early alkaline shift of 0.04+/-0.02 pH units associated with a later, slow acid shift of 0.05+/-0.03 pH units. Extracellular pH shifts in the ventral lateral geniculate nucleus were rare, and limited to acidifications of approximately 0.02 pH units. The alkaline shift in the dLGN increased in the presence of benzolamide (1-2 microM), an extracellular carbonic anhydrase inhibitor. The mean alkaline shift in benzolamide was 0.10+/-0.05 pH units. In 26 mM HEPES-buffered saline, the alkaline response averaged 0.09+/-0.03 pH units. The alkaline shifts persisted in 100 microM picrotoxin (PiTX) but were blocked by 25 microM CNQX/50 microM APV. If stimulation intensity was raised in the presence of CNQX/APV, a second alkalinization arose, presumably due to direct activation of dLGN neurons. The direct responses were amplified by benzolamide, and blocked by either 0 Ca2+/EGTA, Cd2+ or TTX. In 0 Ca2+, addition of 500 microM-5 mM Ba2+ restored the alkalosis. Alkaline shifts evoked with extracellular Ba2+ were larger and faster than those elicited by equimolar Ca2+. In summary, synchronous activation in the dLGN results in an extracellular H+ sink, via a Ca2+-dependent mechanism, similar to activity-dependent alkaline shifts in hippocampus.
2-Amino-5-phosphonovalerate↗
Inhibition of membrane-bound carbonic anhydrase decreases subretinal pH and volume.
PURPOSE: The lipophilic carbonic anhydrase (CA) inhibitor acetazolamide has been shown to enhance subretinal fluid resorption, reduce subretinal pH, and can improve cystoid macular edema, but its clinical use is limited by systemic side effects. While these are most likely a result of inhibiting intracellular CA isoenzymes, retinal pigment epithelial (RPE) transport is thought to be modulated via membrane-bound CA. This study investigates whether benzolamide, a hydrophilic CA inhibitor that does not readily penetrate cell membranes, is sufficient to modulate subretinal volume and pH. METHODS: Volume and pH were assessed in the subretinal space (SRS) of the perfused chick retina-RPE-choroid preparation by calculating these variables from data obtained with two different double-barreled, ion-selective electrodes (H+ for pH and the extracellular space marker tetramethylammonium (TMA+) for SRS volume). Light induced variations and changes in baseline measurements were recorded before and after addition of 10(-4) M acetazolamide or benzolamide to the basal perfusion. RESULTS: Basal perfusion with either drug induced both an acidification of the SRS by 0.02-0.04 pH units, which occurred within 60 s, as well as an increase in the amplitude of the light-induced alkalinisation of the SRS. TMA+ concentration in the SRS increased steadily over a period of several minutes after basal perfusion with either of the CA inhibitors, and the calculated SRS volume was reduced by 40% within 8-10 min. CONCLUSION: The observation that benzolamide had effects equal to acetazolamide suggests that inhibition of membrane-bound CA at the basolateral membrane of the RPE is sufficient to decrease subretinal pH and volume. This may represent a clinically important mechanism for the resorption of sub- and intraretinal fluid.
Acetazolamide↗
Study of factors which modify the development of norepinephrine-induced acute renal failure in the dog.
Previous studies have demonstrated that the fall in inulin clearance which occurs 3 hours after the intrarenal administration of norepinephrine can be markedly attenuated by the prior administration of intrarenal prostaglandin E2 (PGE). Since in the previous studies PGE led to a marked increase in both renal blood flow and solute excretion, we designed the present series of experiments to investigate whether an increase in renal blood flow, solute excretion, or other factors were responsible for the protective effect in the norepinephrine model. Two renal vasodilators, bradykinin and secretin, were evaluated initially. Bradykinin administration prior to norepinephrine administration had a protective effect similar to that previously found with PGE, whereas secretin did not. Both of these vasocilators increased renal blood flow to the same degree, but only bradykinin increased urine flow and solute excretion. The fall in inulin clearance 3 hours after the administration of norepinephrine was also attenuated by two diuretics (mannitol and furosemide) which tended to increase renal blood flow. In contrast, two natriuretic agents, which are also renal vasoconstrictors (chlorothiazide and benzolamide), had no protective effect. Further, chlorothiazide and benzolamide obviated the protective effect of bradykinin. These studies demonstrate that there are several types of pharmacologic agents which can modify the magnitude of renal functional impairment resulting from extreme renal ischemia. Although the mechanism of the protective effects remain unclear, the findings are compatible with the view that the protective effect noted with PGE, bradykinin, mannitol, and furosemide may be related to an increase in osmolar excretion which occurred with administration of each of these agents. This potentially salutory effect (increased osmolar excretion), however, could be overcome by an agent (e.g., chlorothiazide or benzolamide) which also increased renal resistance prior to the administration of norepinephrine.
Acute Kidney Injury↗
Carbonic anhydrase inhibitor sulthiame reduces intracellular pH and epileptiform activity of hippocampal CA3 neurons.
PURPOSE: Sulthiame is a carbonic anhydrase (CA) inhibitor with an anticonvulsant effect in the treatment of benign and symptomatic focal epilepsy in children. The aim of the study was to elucidate the mode of action of sulthiame with respect to possible changes of intracellular pH (pHi) that might develop along with sulthiame's anticonvulsant properties. METHODS: The effects of sulthiame (a) on pHi of 2',7-bis(2-carboxyethyl)-5(6)-carboxyfluorescein-acetoxymetyl ester (BCECF-AM) loaded CA3 neurones as well as (b) on epileptiform activity (induced by 50 microM 4-aminopyridine) were compared with those of the CA inhibitors acetazolamide and benzolamide. RESULTS: In the majority of neurons, sulthiame (1.0-1.5 mM; n = 8) as well as the membrane permeant acetazolamide (0.5-1.0 mM; n = 6) reversibly decreased pHi by 0.18 +/- 0.05 (SD) and 0.17 +/- 0.10 (SD) pH units, respectively, within 10 min. The poor membrane permeant benzolamide (1.0-2.0 mM) had no influence on pHi (n = 8). Sulthiame (1.0-2.5 mM) and acetazolamide (1.0-2.0 mM) reversibly reduced the frequency of action potentials and epileptiform bursts after 10-15 min (n = 9, n = 7), whereas benzolamide (1.0-2.0 mM) had no effect (n = 6). CONCLUSIONS: The results suggest that sulthiame acts as a membrane-permeant CA inhibitor whose beneficial effect on epileptiform activity results at least in part from a modest intracellular acidosis of central neurons.
Acetazolamide↗