Inhibition Of Renal Carbonic Anhydrase Research Articles

Pharmacology of acute mountain sickness: old drugs and newer thinking.

Pharmacotherapy in acute mountain sickness (AMS) for the past half century has largely rested on the use of carbonic anhydrase (CA) inhibitors, such as acetazolamide, and corticosteroids, such as dexamethasone. The benefits of CA inhibitors are thought to arise from their known ventilatory stimulation and resultant greater arterial oxygenation from inhibition of renal CA and generation of a mild metabolic acidosis. The benefits of corticosteroids include their broad-based anti-inflammatory and anti-edemagenic effects. What has emerged from more recent work is the strong likelihood that drugs in both classes act on other pathways and signaling beyond their classical actions to prevent and treat AMS. For the CA inhibitors, these include reduction in aquaporin-mediated transmembrane water transport, anti-oxidant actions, vasodilation, and anti-inflammatory effects. In the case of corticosteroids, these include protection against increases in vascular endothelial and blood-brain barrier permeability, suppression of inflammatory cytokines and reactive oxygen species production, and sympatholysis. The loci of action of both classes of drug include the brain, but may also involve the lung as revealed by benefits that arise with selective administration to the lungs by inhalation. Greater understanding of their pluripotent actions and sites of action in AMS may help guide development of better drugs with more selective action and fewer side effects.

Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness

Acetazolamide, a potent carbonic anhydrase (CA) inhibitor, is the most commonly used and best-studied agent for the amelioration of acute mountain sickness (AMS). The actual mechanisms by which acetazolamide reduces symptoms of AMS, however, remain unclear. Traditionally, acetazolamide's efficacy has been attributed to inhibition of CA in the kidneys, resulting in bicarbonaturia and metabolic acidosis. The result is offsetting hyperventilation-induced respiratory alkalosis and allowance of chemoreceptors to respond more fully to hypoxic stimuli at altitude. Studies performed on both animals and humans, however, have shown that this explanation is unsatisfactory and that the efficacy of acetazolamide in the context of AMS is likely due to a multitude of effects. This review summarizes the known systemic effects of acetazolamide and incorporates them into a model encompassing several factors that are likely to play a key role in the drug's efficacy. Such factors include not only metabolic acidosis resulting from renal CA inhibition but also improvements in ventilation from tissue respiratory acidosis, improvements in sleep quality from carotid body CA inhibition, and effects of diuresis.

Inhibition of renal carbonic anhydrase as a respiratory stimulant-- an obsolete indication?

Inhibition of carbonic anhydrase in general or specific inhibition of one the different isoenzymes results in a significant metabolic acidosis due to renal bicarbonate loss. The increase of arterial pCO2 stimulates central and peripheral chemoreceptors and enhances ventilation. The inhibition of carbonic anhydrase as a respiratory stimulant is an accepted measure for the prevention of acute mountain sickness, has been used for a restricted number of subjects with sleep-disordered breathing or chronic hypoxaemic lung disease. The few indications and the narrow therapeutic index restrict the use of carbonic anhydrase blockers as stimulants for ventilation.

Reduced proximal reabsorption resets tubuloglomerular feedback in euvolemic rats

Inhibition of renal carbonic anhydrase reduces proximal reabsorption and activates tubuloglomerular feedback (TGF). The TGF response is saturable, with highest gain focused near the natural flow rate. Therefore, any large change imposed on ambient tubular flow should reduce the TGF response to subequent flow perturbations. However, TGF tends to align with ambient flow regardless of the rate of ambient flow, suggesting that TGF resets to accommodate changes in flow while maintaining feedback efficiency. We used micropuncture and videometric flow velocitometry to test for TGF resetting in free-flowing nephrons during systemic infusion of the carbonic anhydrase inhibitor benzolamide (BNZ, 5 mg x kg(-1) x h(-1)) in euvolemic rats. Late proximal flow (V(LP)) and the fractional compensation (C) of TGF for perturbations in V(LP) were assessed repeatedly before and during BNZ. Early on, BNZ reduced C, consistent with TGF saturation. Over the next 45-60 min, V(LP) increased gradually by approximately 5 nl/min as C recovered to pre-BNZ levels. BNZ also increased V(LP) by approximately 5 nl/min when TGF was rendered inoperative by intratubular wax block, but this increase occurred rapidly. These data demonstrate rightward resetting of TGF during reduced proximal reabsorption.

Effect of acute hypercapnia on renal and proximal tubular total carbon dioxide reabsorption in the acetazolamide-treated rat.

The present study evaluates the effect of acute hypercapnia on renal total CO2 (tCO2) reabsorption after inhibition of renal carbonic anhydrase. Simultaneous renal clearance studies and free-flow micropuncture studies of the superficial proximal tubule were performed on plasma-repleted Sprague-Dawley rats treated with acetazolamide, 50 mg/kg body weight. Acute hypercapnia (arterial PCO2, 120 mmHg; blood pH, 7.02) was induced by ventilation with a 10% CO2-90% O2 gas mixture. Control rats (PCO2, 49.5 mmHg, pH 7.34) were ventilated with room air. The renal fractional excretion of tCO2 was approximately 20% lower in the hypercapnic group compared with the rats given acetazolamide alone. Acute hypercapnia reduced the fractional delivery of tCO2 to the late proximal tubule by a comparable amount. The absolute proximal reabsorption of tCO2 was increased by hypercapnia to 410 +/- 47 vs. 170 +/- 74 pmol X min-1, P less than 0.05. The single nephron glomerular filtration rate was 32.6 +/- 0.7 nl X min-1 in the hypercapnic group and 43.8 +/- 1.7 nl X min-1 in the rats given acetazolamide only, P less than 0.01. Acute hypercapnia enhances renal sympathetic nerve activity. To eliminate this effect, additional experiments were performed in which the experimental kidney was denervated before study. Denervation prevented the change in the single nephron filtration rate during acute hypercapnia, but absolute and fractional proximal tCO2 reabsorption remained elevated in comparison to denervated controls. The concentration of H2CO3 in the late proximal tubule, calculated from the measured luminal pH and bicarbonate concentration and the estimated cortical PCO2, was higher in the hypercapnic group, which was a finding compatible with H2CO3 cycling from lumen into proximal tubular cell, which provided a source of hydrogen ions for secretion.

Renal bicarbonate reabsorption in the new-born dog.

1. Renal bicarbonate reabsorption was measured in thirty new-born dogs 2-27 days of age. Plasma bicarbonate was varied in the puppies by exchanging their blood with blood containing high levels of bicarbonate and low levels of chloride.2. The exchange transfusion resulted in increases of plasma pH, P(CO2) and bicarbonate in the puppies without changing plasma sodium and potassium or glomerular filtration rate (g.f.r.) and body weight.3. There was no tubular reabsorption maximum (T(m)) for bicarbonate and reabsorption values as high as 50 muequiv/ml. g.f.r. could be attained. No animals excreted bicarbonate at plasma levels below 25 mM and some animals had plasma bicarbonate threshold values in excess of 40 mM.4. Bicarbonate reabsorption increased as arterial P(CO2) rose (r = 0.62) but this was due to the rise of filtered bicarbonate since (a) there was no correlation between arterial P(CO2) and bicarbonate reabsorption when factored by filtered bicarbonate and (b) lowering arterial P(CO2) by mechanical hyperventilation did not reduce bicarbonate reabsorption corrected for filtered load.5. Inhibition of renal carbonic anhydrase by acetazolamide (50 mg/kg) resulted in an inhibition of bicarbonate reabsorption of only 4.5 muequiv/ml. g.f.r. (less than 20% of the total). Even with renal carbonic anhydrase inhibited, there was no bicarbonate T(m) and bicarbonate reabsorption values as high as 40 muequiv/ml. g.f.r. could be attained.6. There was good correlation (r = 0.82) between inhibition of sodium and bicarbonate reabsorption during renal carbonic anhydrase inhibition. However, with carbonic anhydrase inhibited, there was no correlation between arterial P(CO2) and bicarbonate reabsorption.7. These results demonstrate that tubular bicarbonate reabsorption mechanisms in the new-born dog are as efficient as those reported for the adult as long as body fluid and plasma sodium and potassium levels are carefully maintained.8. The results are also consistent with a bicarbonate reabsorptive mechanism explained either by direct ionic bicarbonate reabsorption or by hydrogen ion secretion with diffusion of carbonic acid.

Failure of parathyroid hormone and cyclic AMP to inhibit renal carbonic anhydrase.

It has been suggested that the parathyroid hormone and cyclic AMP produce their bicarbonaturic effects through inhibition of renal carbonic anhydrase. In the present study, the incubation of renal carbonic anhydrase with parathyroid hormone or cyclic AMP in presence of ATP, Mg++ and K+ ions, did not produce any inhibition of the enzyme when the pH of the solution was maintained above 7. It is concluded, that parathyroid hormone and cyclic AMP produce urinary bicarbonate excretion by a mechanism independent of carbonic anhydrase inhibition.

Fission products: Sites for the elimination of cesium-137 in the nephrons of dogs

The mechanisms of the renal excretion of 137Cs were studied in the anesthetized dog using classical clearance techniques, stop-flow studies, and pharmacologic agents known to affect potassium transport in the nephron. The clearance of 137Cs was less than that of creatinine. The bulk of the filtered 137Cs was reabsorbed in the proximal tubule, and it was secreted into the lumen of the distal tubule. There was no linear relation between the plasma concentration of 137Cs and the clearance ratio of 137Cs and creatinine. Sodium chloride loading and hypertonic mannitol increased the excretion of 137Cs. Complete inhibition of renal carbonic anhydrase by acetazolamide increased the excretion of 137Cs. About 55% of this increase in 137Cs excretion was blocked by meralluride, indicating that acetazolamide increased a part of 137Cs excretion by increasing its secretion. There was a distinct peak in the stop-flow pattern for the secretion of 137Cs in the distal segment of the nephron under mannitol diuresis. The ratio of 137Cs clearance to glomerular filtration rate was about 2 at the peak, indicating net secretion in the distal segment. The clearance ratio of 137Cs and creatinine was less than unity in the proximal segment, suggesting net reabsorption.

Effect of diamox on plasma and urine acid-base composition during chronic respiratory acidosis.

Diamox, administered during experimental chronic respiratory acidosis in an amount sufficient to inhibit completely renal carbonic anhydrase, resulted in marked increase in plasma pCO2 and bicarbonate concentration. Inhibition of red blood cell carbonic anhydrase was probably responsible for the very high plasma pCO2 observed. The high pCO2, in turn, was capable of so accelerating the uncatalyzed formation of carbonic acid in the renal tubular cell that sufficient secretion of hydrogen ion occurred to accomplish reabsorption of even increased amounts of filtered bicarbonate in the face of complete inhibition of renal carbonic anhydrase. Despite accelerated bicarbonate reabsorption, hyperchloremia and potassium deficiency supervened in blood, ammonia excretion increased, and renal glutaminase was activated.