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Exposure to hyperoxia (500-600 torr) or low pH (4.5) for 72 h or NaHCO(3) infusion for 48 h were used to create chronic respiratory (RA) or metabolic acidosis (MA) or metabolic alkalosis in freshwater rainbow trout. During alkalosis, urine pH increased, and [titratable acidity (TA) - HCO(-)(3)] and net H(+) excretion became negative (net base excretion) with unchanged NH(+)(4) efflux. During RA, urine pH did not change, but net H(+) excretion increased as a result of a modest rise in NH(+)(4) and substantial elevation in [TA - HCO(-)(3)] efflux accompanied by a large increase in inorganic phosphate excretion. However, during MA, urine pH fell, and net H(+) excretion was 3.3-fold greater than during RA, reflecting a similar increase in [TA - HCO(-)(3)] and a smaller elevation in phosphate but a sevenfold greater increase in NH(+)(4) efflux. In urine samples of the same pH, [TA - HCO(-)(3)] was greater during RA (reflecting phosphate secretion), and [NH(+)(4)] was greater during MA (reflecting renal ammoniagenesis). Renal activities of potential ammoniagenic enzymes (phosphate-dependent glutaminase, glutamate dehydrogenase, alpha-ketoglutarate dehydrogenase, alanine aminotransferase, phosphoenolpyruvate carboxykinase) and plasma levels of cortisol, phosphate, ammonia, and most amino acids (including glutamine and alanine) increased during MA but not during RA, when only alanine aminotransferase increased. The differential responses to RA vs. MA parallel those in mammals; in fish they may be keyed to activation of phosphate secretion by RA and cortisol mobilization by MA.

We have studied the effects of acute respiratory alkalosis (ARALK, hyperventilation) and acidosis (ARA, 8% CO2), chronic respiratory acidosis (CRA; 10% CO2 for 7-10 days), and subsequent recovery from CRA breathing air on loop of Henle (LOH) net bicarbonate flux (JHCO3) by in vivo tubule microperfusion in anesthetized rats. In ARALK blood, pH increased to 7.6, and blood bicarbonate concentration ([HCO3-]) decreased from 29 to 22 mM. Fractional urinary bicarbonate excretion (FEHCO3) increased threefold, but LOH JHCO3 was unchanged. In ARA, blood pH fell to 7.2, and blood [HCO3-] rose from 28 to 34 mM; FEHCO3 was reduced to < 0.1%, but LOH JHCO3 was unaltered. In CRA, blood pH fell to 7.2, and blood [HCO3-] increased to > 50 mM, whereas FEHCO3 decreased to < 0.1%. JHCO3 was reduced by approximately 30%. Bicarbonaturia occurred when CRA rats breathed air, yet LOH JHCO3 increased (by 30%) to normal. These results suggest that LOH JHCO3 is affected by the blood-to-tubule lumen [HCO3-] gradient and HCO3- backflux. When the usual perfusing solution at 20 nl/min was made HCO3- free, mean JHCO3 was -34.5 +/- 4.4 pmol/min compared with 210 +/- 28.1 pmol/min plus HCO3-. When a low-NaCl perfusate (to minimize net fluid absorption) containing mannitol and acetazolamide (2 x 10(-4) M, to abolish H(+)-dependent JHCO3) was used, JHCO3 was -112.8 +/- 5.6 pmol/min. Comparable values for JHCO3 at 10 nl/min were -35.9 +/- 5.8 and -72.5 +/- 8.8 pmol/min, respectively. These data indicate significant backflux of HCO3-along the LOH, which depends on the blood-to-lumen [HCO3-] gradient; in addition to any underlying changes in active acid-base transport mechanisms, HCO3- permeability and backflux are important determinants of LOH JHCO3 in vivo.

It is currently believed that the two chronic acidemic disorders exert disparate effects on urinary calcium excretion: chronic metabolic acidosis induces consistent hypercalciuria, but no appreciable change or even a decrease in calcium excretion is reported to attend chronic respiratory acidosis. Whereas the effect of metabolic acidosis is well documented, little work has been carried out in chronic hypercapnia. In fact, most of the studies on chronic respiratory acidosis were short in duration, had employed only mild hypercapnia, or had failed to control carefully the prevailing metabolic conditions. We have carried out balance observations in nine dogs exposed to a 10% CO2 atmosphere in an environmental chamber for a period of two weeks. Chronic respiratory acidosis led to a significant increase in urinary calcium excretion from a mean control value of 0.4 +/- 0.1 mmol/day to 0.6 +/- 0.1 mmol/day during both week 1 and 2 of hypercapnia (P less than 0.05). Hypercalciuria occurred even though filtered load of calcium fell. Mean fractional excretion of calcium increased significantly during each week of hypercapnia averaging 0.60 +/- 0.12% during control, 1.05 +/- 0.13% during week 1, and 1.26 +/- 0.17% during week 2 of hypercapnic exposure (P less than 0.05). There were no changes in plasma levels of immunoreactive parathyroid hormone or 1,25-dihydroxyvitamin D3. These findings suggest that chronic respiratory acidosis, just like chronic metabolic acidosis, augments urinary calcium excretion by a direct depressive effect on the tubular reabsorption of calcium.

In contrast to chronic metabolic acidosis, chronic respiratory acidosis does not result in an adaptation in either renal ammonia or glucose production. To examine the possibility that this might be explained by a difference in proximal tubule intracellular pH, the response of two pH-sensitive metabolites, citrate and alpha-ketoglutarate, were assessed. Metabolic acidosis of 3 days duration, induced by drinking 1.5% NH4Cl, significantly reduced urinary citrate excretion (172 to 15 mumol/day) and renal cortical citrate (1.33 to 0.88 mumol/g) and alpha-ketoglutarate (0.90 to 0.46 mumol/g) concentrations in comparison with normal rats. Chronic respiratory acidosis, produced by 3 days in a 10% CO2 environment, lowered systemic pH similar to metabolic acidosis but had no effect on either urinary citrate excretion or renal cortical citrate and alpha-ketoglutarate concentrations. By contrast, acute respiratory acidosis (3, 6, or 24 h duration) reduced urinary citrate excretion and renal cortical citrate and alpha-ketoglutarate concentrations in a fashion similar to acute metabolic acidosis. These data suggest that acute acidosis of either respiratory or metabolic origin lowers the intracellular pH of the proximal tubule. However, when the acid-base abnormality enters the chronic phase, proximal tubular intracellular pH remains low with metabolic acidosis but returns to normal values with respiratory acidosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Both acute respiratory acidosis and acute metabolic acidosis stimulate NH3 production by the isolated perfused rat kidney. This stimulatory effect is abolished if the urine is drained back into the recirculating perfusate rather than collected. To determine whether the urinary inhibitor is a cyclooxygenase product, studies were carried out using prostaglandin synthetase inhibitors. Kidneys perfused with 0.5 mmol/L glutamine and urine reinfusion were subjected to acute respiratory acidosis (30% CO2, pH 6.8). With either indomethacin (20 mumol/L) or meclofenamate (20 mumol/L) in the perfusate, NH3 production increased significantly in response to acute respiratory acidosis despite urine reinfusion. The increment in NH3 production was comparable to that in studies with urine collection, indicating that a cyclooxygenase product can account completely for the urinary inhibitor. To further characterize the urinary prostaglandin inhibitor, studies were performed with both the isolated perfused kidney and renal cortical tubules. Prostaglandin E2 (PGE2) did not exhibit an inhibitory effect on NH3 production with either experimental model. Prostaglandin F2 alpha at low doses inhibited NH3 production in response to acute acidosis by the isolated kidney, but an effect was not apparent with higher concentrations. PGF2 alpha inhibited the stimulatory effect of a low pH (7.1) on NH3 production by isolated tubules, and had no effect on ammoniagenesis at pH 7.4. Thus a prostaglandin, which is not PGE2 and may be PGF2 alpha, appears to be the previously unidentified urinary inhibitor of the ammoniagenic response to acute acidosis found with the isolated perfused kidney.

This study was designed to establish the relationship between urinary pCO2 and systemic blood pCO2 during acute hypercapnia and to investigate the significance of this relationship to collecting duct hydrogen ion (H+) secretion when the urine is acid and when it is highly alkaline. In rats excreting a highly alkaline urine, an acute increase in blood pCO2 (from 42 +/- 0.8 to 87 +/- 0.8 mmHg) resulted in a significant fall in urine minus blood (U-B) pCO2 (from 31 +/- 2.0 to 16 +/- 4.2 mmHg, P less than 0.005), a finding which could be interpreted to indicate inhibition of collecting duct H+ secretion by hypercapnia. The urinary pCO2 of rats with hypercapnia, unlike that of normocapnic controls, was significantly lower than that of blood when the urine was acid (58 +/- 6.3 and 86 +/- 1.7 mmHg, P less than 0.001) and when it was alkalinized in the face of accelerated carbonic acid dehydration by infusion of carbonic anhydrase (78 +/- 2.7 and 87 +/- 1.8 mmHg, P less than 0.02). The finding of a urinary pCO2 lower than systemic blood pCO2 during hypercapnia suggested that the urine pCO2 prevailing before bicarbonate loading should be known and the blood pCO2 kept constant to evaluate collecting duct H+ secretion using the urinary pCO2 technique. In experiments performed under these conditions, sodium bicarbonate infusion resulted in an increment in urinary pCO2 (i.e., a delta pCO2) which was comparable in hypercapnic and normocapnic rats (40 +/- 7.2 and 42 +/- 4.6 mmHg, respectively) that were alkalemic (blood pH 7.53 +/- 0.02 and 7.69 +/- 0.01, respectively). The U-B pCO2, however, was again lower in hypercapnic than in normocapnic rats (15 +/- 4.0 and 39 +/- 2.5 mmHg, respectively, P less than 0.001). In hypercapnic rats in which blood pH during bicarbonate infusion was not allowed to become alkalemic (7.38 +/- 0.01), the delta pCO2 was higher than that of normocapnic rats which were alkalemic (70 +/- 5.6 and 42 +/- 4.6 mmHg, respectively, P less than 0.005) while the U-B pCO2 was about the same (39 +/- 3.7 and 39 +/- 2.5 mmHg). We further examined urine pCO2 generation by measuring the difference between the urine pCO2 of a highly alkaline urine not containing carbonic anhydrase and that of an equally alkaline urine containing this enzyme. Carbonic anhydrase infusion to hypercapnic rats that were not alkalemic resulted in a fall in urine pCO(2) (from 122+/-5.7 to 77+/-2.2 mmHg) which was greater (P <0.02) than that seen in alkalemic normocapnic controls (from 73+/- 1.9 to 43+/-1.3 mmHg) with a comparable urine bicarbonate concentration and urine nonbicarbonate buffer capacity. CO(2) generation, therefore, from collecting dust H(+) secretion and titration of bicarbonate, was higher in hypercapnic rats that in normocapnic controls. We conclude that in rats with actue hypercapnia, the U-B p(CO(2)) achieved during bicarbonate loading greatly underestimates collecting duct H(+) secretion because it is artificially influenced by systemic blood pCO(2). the deltapCO(2) is a better qualitative index of collecting duct H+ secretion that the U-B pCO(2), because it is not artificially influenced by systemic blood pCO(2) and it takes into account the urine PCO(2) prevailing before bicarbonate loading.

The effects of acute hypercapnic acidosis (PaCO2 = 52 +/- 2 mm Hg, pH = 7.23 +/- 0.01) of 40-80 min duration on renal water excretion and circulating vasopressin were examined in conscious dogs during stable diuresis in protocols either with hypotonic water loading (n = 6) or in the euvolemic state (n = 7). The mean arterial pressure increased (p less than 0.05) during acute hypercapnic acidosis in euvolemic dogs, but was unchanged in the dogs given a water load. However, the free water clearance decreased (p less than 0.05), and urine osmolality increased during acute hypercapnic acidosis in both water-loaded and euvolemic dogs despite stable renal hemodynamic function and osmolar clearance. Plasma vasopressin concentrations increased (p less than 0.05) during hypercapnic acidosis in euvolemic but not in water-loaded dogs. The plasma renin activity increased with hypercapnic acidosis in both water loaded and euvolemic dogs. These observations indicate that acute hypercapnic acidosis results in diminished renal water excretion and increased urine osmolality in conscious dogs.

Although metabolic acidosis produces calciuric, phosphaturic, and magnesiuric effects, the consequences of chronic respiratory acidosis are unclear. To examine the role of systemic pH on renal divalent metabolism, 4-day balance studies were performed in rats with both metabolic acidosis induced by adding 1.5% NH4Cl to the drinking water, and respiratory acidosis produced by exposure to 10% atmospheric CO2 in an environmental chamber, and in controls pair-fed with each group. By the fourth day, blood pH had decreased to an identical degree with both chronic metabolic and respiratory acidosis and averaged 7.28. As anticipated, chronic metabolic acidosis resulted in significant calciuria, magnesiuria, and phosphaturia. However, despite the similar decrement in blood pH, calcium, phosphorus, and magnesium excretion was similar to that in the pair-fed controls with chronic respiratory acidosis. These findings indicate that a low systemic pH, per se, does not account for the modifications in urinary divalent ion handling that accompany chronic metabolic acidosis. However, additional observations suggest that differences in the intracellular pH of the proximal tubular epithelium may be an important regulatory variable.

The renal net acid excretion (NAE), the blood pH (pHe), the total body intracellular pH (pHi) and the urinary pH (pHu) were calculated in 10 patients with chronic obstructive lung disease and hypercapnia and in 5 normocapnic subjects. The mean value of NAE was significantly higher in hypercapnic subjects than in normocapnic ones. pHe was significantly lower in hypercapnic than in normocapnic subjects. The differences of pHi and pHu between normo and hypercapnic subjects were not significant. NAE is significantly correlated with PaCO2, pHe, pHu and pHi in all the subjects considered together. H+-secretion probably depends on the H+-availability and pHi of tubular cells, but from our results it is not possible to confirm this relationship, because the method used for pHi is fundamentally a measure of muscle-pHi.