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D Batlle

Publications and source records attributed to D Batlle.

32 records · Page 2Linked to original sources
PubMed1996

Ionic effects of angiotensin II and their role in the activation of the Na+/H+ antiporter.

The possible interdependence of the effects of angiotensin II (Ang II) on intracellular pH (pHi), free cytosolic calcium (Cai2+) and free cytosolic sodium (Nai+) was studied in cultured vascular smooth muscle cells (VSMC) from rat aorta. Cells were loaded with either BCECF/AM, SBFI/AM or Fura-2 for measurement of pHi, Nai+ or Cai2+, respectively. Superfusing with a HEPES solution containing Ang II (1 microM) caused a progressive increase in Nai+. Concurrent pHi changes measured in parallel experiments showed that Ang II caused a brief cell acidification followed by a delayed alkalinization, which is due to activation of the Na+/H+ antiporter. Concurrent Cai2+ changes measured in parallel experiments showed that Ang II caused a prompt rise in Cai2+ with a peak response at approximately 30 seconds followed by a rapid recovery. Obliteration of the Ang II-induced rise in Cai2+ using a Ca2+ chelator (BAPTA), prevented the initial cell acidification but did not prevent the delayed rise in pHi, which reflects stimulation of the Na+/H+ antiporter. Our data thus show that in cultured VSMC neither the rise in Cai2+ nor the fall in pHi caused by Ang II is a total prerequisite for activation of the Na+/H+ antiporter by this agonist.

Angiotensin II↗
PubMed1995

Selected aspects of ACE inhibitor therapy for patients with renal disease: impact on proteinuria, lipids and potassium.

Overt proteinuria is often accompanied by hypercholesterolemia and is associated with increased lipoprotein(a) levels. These lipid abnormalities are probably involved in the high incidence of macrovascular complications associated with diabetic nephropathy and possibly other kinds of non-diabetic proteinuric renal disease. Over the last decade many studies have shown that ACE inhibitors can reduce urinary protein excretion but little attention was paid to the impact of this form of therapeutic intervention on the lipid profile. In this article we review our recent data showing that fosinopril administration was associated with significant decreases in both urinary protein excretion, serum total cholesterol levels, and plasma lp(a) levels. The use of ACE inhibitors in patients with renal impairment can result in the development of hyperkalemia as a result of suppression of angiotensin II-driven aldosterone secretion by the adrenal gland. Inhibition of aldosterone secretion may depend on the degree of inhibition of angiotensin II formation in the circulation and also locally in the adrenal gland. Because the various ACE inhibitors exhibit different degrees of ACE inhibition at the tissue level, we have postulated that angiotensin II-dependent aldosterone production will be inhibited to a lesser degree by agents that have low tissue affinity for the adrenal gland. The implication of this theoretical concept for the development of hyperkalemia in patients with impaired renal function treated with ACE inhibitors is discussed.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Regulation of intracellular pH in the spontaneously hypertensive rat. Role of bicarbonate-dependent transporters.

Previous studies that have evaluated the Na(+)-H+ antiporter in cells from hypertensive subjects were generally performed under conditions in which HCO3-CO2, the physiological buffer system, was absent from the assay media. The objective of this study was to evaluate the activity of the Na(+)-H+ antiporter and that of the Na(+)-dependent and Na(+)-independent Cl(-)-HCO3- exchangers in cells assayed in the presence of HCO3-CO2 in the media. Lymphocytes from 6- to 8-week-old spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) rats were obtained from the thymus gland and assayed immediately after isolation. The activity of the Na(+)-H+ antiporter after stimulation by cell acidification (pHi approximately 6.4) was similar in SHR and WKY rats (18.67 +/- 1.03 and 16.12 +/- 0.92 mmol H+/L per minute, respectively). Recovery from cell alkalinization was effected by an Na(+)-independent Cl(-)-HCO3- exchanger, with maximal activity at an alkaline pHi (approximately 7.7). The stimulated activity of this Na(+)-independent Cl(-)-HCO3- exchanger was also not different between SHR and WKY cells (2.65 +/- 0.25 and 2.55 +/- 0.32 mmol H+/L per minute, respectively). Acute chloride removal produced a rise in pHi that was Na(+)-dependent and sensitive to 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) but resistant to ethylisopropylamiloride (EIPA), reflecting the activity of an Na(+)-dependent Cl(-)-HCO3- exchanger. Unlike the Na(+)-H+ exchanger and the Na(+)-independent Cl(-)-HCO3- exchanger, which had their highest activities at extremes of pHi (low pHi, Na(+)-H+ exchanger, and high pHi, Na(+)-independent Cl(-)-HCO3- exchanger), the Na(+)-dependent Cl(-)-HCO3- exchanger had its maximal activity near steady-state pHi (approximately 7.1). No significant differences were found in the stimulated activity of this exchanger between cells from SHR and WKY rats (2.23 +/- 0.26 and 2.50 +/- 0.43 mmol H+/L per minute, respectively). The kinetic properties of the Na(+)-dependent and Na(+)-independent Cl(-)-HCO3- exchanger, examined as a function of external Cl-, were also virtually identical in cells from SHR and WKY rats. We conclude that in lymphocytes from SHR and WKY rats, the activity of the two Cl(-)-HCO3- exchangers, like that of the Na(+)-H+ exchanger, is dependent on the prevailing pHi. The Na(+)-dependent Cl(-)-HCO3- exchanger has its highest activity near steady-state pHi, suggesting an important role in the cell defense against intracellular acidosis under physiological conditions.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Acid-base status and intracellular pH regulation in lymphocytes from rats with genetic hypertension.

This article reviews work from this laboratory dealing with acid-base status and intracellular pH (pHi) regulation in rat genetic models of hypertension. With freshly isolated thymic lymphocytes, pHi and its regulation were examined in the spontaneously hypertensive rat (SHR). In this rat model, pHi was found to be reduced as compared with that of lymphocytes from normotensive Wistar-Kyoto (WKY) rats. The activity of the Na+/H+ antiporter assessed after stimulation by acute cell acidification was similar in lymphocytes from SHR and WKY rats both in the nominal absence of HCO3- and in media containing HCO3- (22 mM). The kinetic properties of the Na+/H+ antiporter, examined as a function of pHi with the Hill kinetic model, revealed no significant differences between lymphocytes from SHR and WKY rats. The kinetic properties of the Na(+)-dependent and Na(+)-independent Cl(-)-HCO3- exchangers, examined as a function of external Cl-, were also virtually identical in lymphocytes from SHR and WKY rats. Unlike the Na(+)-H+ exchanger and the Na(+)-independent Cl(-)-HCO3- exchanger, which had their highest activities at extremes of pHi (low pHi, Na(+)-H+ exchanger; high pHi, Na(+)-independent Cl(-)-HCO3- exchanger), the Na(+)-dependent Cl(-)-HCO3- exchanger had its maximal activity near steady-state pHi. In Dahl/Rapp salt-sensitive rats with hypertension, the pHi of thymic lymphocytes was also reduced as compared with that of normotensive salt-resistant animals. In this model, renal net acid excretion in salt-sensitive rats was augmented as compared with that of salt-resistant rats. The increase in renal acid excretion was due to an increase in both ammonium and titratable acid excretion and was observed while animals were placed on high, normal and low salt diets. The findings of intracellular acidosis and enhanced renal acid excretion suggest that cellular acid overproduction is augmented in salt-sensitive hypertension.

Acid-Base Equilibrium↗
PubMed1982

Distal renal tubular acidosis with intact capacity to lower urinary pH.

The sine qua non for the diagnosis of distal renal tubular acidosis requires that the urinary pH cannot decrease maximally during systemic acidosis. A defect in distal acidification however, could also result from a decrease in the capacity (or rate) of distal hydrogen ion secretion. In this type of defect, the ability to lower the urinary pH during acidemia could be preserved as long as a certain capacity for hydrogen ion secretion remained. In this report, we describe four patients with deranged distal urinary acidification, in whom urinary pH was able to decrease (4.99 +/- 0.11) during acidemia. One of the patients had hyperchloremic metabolic acidosis whereas the remaining three were not spontaneously acidotic. In these patients, the defect for distal urinary acidification was disclosed by the inability of the urine-blood pCO2 gradient to increase normally (i.e., above 30 mm Hg) during bicarbonate loading. In contrast, a normal increase in the urine-blood pCO2 gradient was observed in each patient in response to neutral sodium phosphate infusion. The reabsorptive capacity of bicarbonate was not depressed in these patients, which indicated that the acidification process in the proximal nephron was intact. We propose that our four patients had a defect in distal urinary acidification caused by a reduction in the rate of distal hydrogen ion secretion rather than an inability to generate a steep pH gradient across the distal nephron. Our data also suggest that the inability to raise urinary pCO2 normally during sodium bicarbonate loading may be the most sensitive index of decreased distal urinary acidification available.

Acidosis, Renal Tubular↗
PubMed1982

Hyperkalemic hyperchloremic metabolic acidosis in sickle cell hemoglobinopathies.

This report describes the occurrence of hyperkalemic hyperchloremic metabolic acidosis in six patients with sickle cell hemoglobinopathies. Three patients had sickle cell anemia, two had sickle cell trait and one had S-C disease. In all patients, decreased renal potassium excretion was demonstrated by the finding of a fractional potassium excretion lower than that of control subjects with comparable glomerular filtration rates. Two patterns of impaired urinary acidification were discerned. Four patients had a urinary pH above 5.5 in the presence of systemic acidosis and, thus, were classified a having distal renal tubular acidosis. The remaining two patients had very low rates of ammonium excretion despite intact capacity to lower urinary pH below 5.5 during systemic acidosis; this pattern was ascribed to selective aldosterone deficiency. Sickle cell hemoglobinopathies should be included in the differential diagnosis of hyperkalemic hyperchloremic metabolic acidosis.

Acidosis, Renal Tubular↗
PubMed1982

Distal renal tubular acidosis: pathogenesis and classification.

Distal renal tubular acidosis results from ineffective addition of hydrogen ions to the lumen of the distal nephron. The syndrome is manifested by hyperchloremic metabolic acidosis often associated with hypokalemia. More recently, it has been recognized that hyperkalemia rather than hypokalemia can be a dominant feature of some cases of distal renal tubular acidosis. It has been generally accepted that all cases of this syndrome ultimately resulted from a similar mechanism. The prevailing view was that the abnormality underlying distal renal tubular acidosis was that of inability to either generate or maintain a steep pH gradient across the distal nephron. Recent advances in our understanding of the process of distal acidification have provided evidence that different mechanisms can alter distal hydrogen ion secretion. In this article, the significance of the various indices of urinary acidification and their use in the characterization of the mechanism underlying distal renal tubular acidosis are revised. A classification of distal renal tubular acidosis on the basis of mechanism is presented. The importance of plasma potassium and renal potassium excretion in the evaluation of patients with distal renal tubular acidosis is emphasized.

Acidosis, Renal Tubular↗
PubMed1982

Parathyroid hormone is not anticalciuric during chronic metabolic acidosis.

The role of parathyroid hormone (PTH) on calcium excretion during chronic metabolic acidosis was investigated in intact and thyroparathyroidectomized (TPTX) acidotic and control dogs. Intact dogs fed NH4Cl for 3 days developed marked hypercalciuria as compared to intact control animals. After thyroparathyroidectomy, calcium excretion corrected per glomerular filtration rate decreased significantly in NH4Cl-treated dogs but not in the controls. This was observed in the face of a TPTX-induced fall in filtered load of calcium in both groups. After restoration of filtered load of calcium to normal by CaCl2 infusion, fractional calcium excretion at any level of fractional sodium excretion was higher in NH4Cl-treated TPTX dogs than that of TPTX controls, indicating a calciuric effect of acidosis independent of PTH. PtH (1 U/min X 60 min) was infused to examine the effect of this hormone on calcium excretion during NH4Cl-induced acidosis. In normal dogs, PTH significantly decreased absolute and fractional calcium excretion. In contrast, PTH infusion to acidotic dogs failed to decrease absolute and fractional calcium excretion. In both groups, phosphate excretion increased significantly. The higher calcium excretion of acidotic dogs during PTH infusion resulted from failure to enhance calcium reabsorption as shown by the fact that, at any level of plasma ionizable calcium, calcium excretion was higher in acidotic dogs than in controls. These findings indicate that during metabolic acidosis PTH does not exert its normal anticalciuric effect. This may contribute to the development of hypercalciuria despite PTH excess in certain clinical conditions associated with chronic metabolic acidosis.

Acidosis↗
PubMed1982

Distal nephron function in patients receiving chronic lithium therapy.

Renal tubular function was studied in 14 patients chronically treated with lithium for affective disorders. Patients were separated into two groups according to the duration of lithium therapy: long-term (35 +/- 7.0 months) and short-term (4.8 +/- 0.8 months). At comparable urine lithium concentrations, patients on long-term therapy had a lower maximal urine osmolality (Umax) and free water reabsorption (TcH2O) than did patients on short-term therapy. The latter group achieved a Umax above 800 mOsm kg H2O. In contrast, both groups of patients failed to increase the urine-blood (U-B) Pco2 gradient normally during acute sodium bicarbonate loading. This low U-B Pco2 was observed at comparable urine bicarbonate concentrations between both groups of patients and controls, and thus was associated with a higher urine pH in patients. These findings indicate that the inability of these patients to achieve a normal U-B Pco2 in a maximally alkaline urine was the result of decreased distal hydrogen ion secretion rather than inability to raise urine bicarbonate concentrations as a result of a concentrating defect. Bicarbonate reabsorptive capacity was normal in our lithium-treated subjects. Both groups of patients achieved a normal U-B Pco2 gradient in response to sodium phosphate loading. They also were able to achieve a minimal urine pH and a maximal acid excretion similar to those of controls in response to a 3-day ammonium chloride loading test. Our data demonstrate that chronic lithium therapy is associated with a mild distal acidification defect disclosed only by the finding of a low U-B Pco2 gradient during sodium bicarbonate loading. This peculiar defect can be found in short-term lithium-treated patients in whom the concentrating capacity is relatively well preserved.

Ammonium Chloride↗
PubMed1982

Distal acidification in the rabbit: role of diet and blood pH.

A distal acidification defect is said to exist in rabbits because this species does not achieve a normal urine minus blood (U-B) PCO2 gradient in response to sodium bicarbonate infusion. This observation contrasts with data derived from studies in isolated rabbit cortical collecting tubules that have shown an acidifying capacity when the tubules were obtained from acidotic animals. The present study was designed to examine the role of diet and blood pH on distal acidification in the rabbit. Maximal alkalinization of the urine by acute sodium bicarbonate infusion was associated with a low U-B PCO2 gradient (0.7 +/- 2.1 mmHg). Rabbits made acidotic by ammonium chloride administration for 1 wk achieved a substantial U-B PCO2 gradient (29 +/- 5 mmHg) in response to neutral sodium phosphate infusion. To further evaluate the role of blood pH on the ability to raise U-B PCO2 gradient, rabbits and rats made acidotic by chronic ammonium chloride administration were studied. Neutral sodium phosphate was then infused to stimulate distal acidification. At comparable levels of urinary phosphate concentration and blood pH, acidotic rabbits were able to achieve a U-B PCO2 (50 +/- 7 mmHg) comparable with that of acidotic rats (48 +/- 8.3 mmHg). These data show that the failure of rabbits to raise U-B PCO2 gradient can be partially corrected by prior exposure to acid in the diet and further corrected by maintaining the blood pH within the acidotic range.

Acidosis↗
PubMedDate not supplied

Aquaporin-2 as a biomarker of distal renal tubular function using lithium as an experimental model.

Aquaporin-2 protein levels can be detected in the urine of normal of subjects if measured after fluid deprivation. By contrast, in patients with nephrogenic diabetes insipidus caused by mutations in the aquaporin-2 gene, urine aquaporin-2 protein excretion cannot be detected. We propose that properly standardized measurements of urinary aquaporin-2 protein may provide a useful biomarker of distal tubular function in a variety of acquired conditions that impair concentrating ability including some nephrotoxic agents.

Aquaporin 2↗