Dissociation between the hypotensive effect of thiazides and plasma divalent cations.
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Analysis of Variance↗
Biomedical subjects
D C Batlle
Publications and source records attributed to D C Batlle.
Sodium-dependent urinary acidification in patients with aldosterone deficiency and in adrenalectomized rats: effect of furosemide.
Urinary acidification during metabolic acidosis and in response to stimulation of sodium-dependent hydrogen ion secretion using furosemide administration was evaluated in 12 patients with hyperkalemic hyperchloremic metabolic acidosis associated with mild chronic renal insufficiency and aldosterone deficiency. During spontaneous metabolic acidosis, the urine of all patients was acidic (pH less than 5.5), but ammonium excretion was markedly reduced (6.6 +/- 1.3 mu Eq/min) comprising only about 20% of net acid excretion (30.5 +/- 5.7 mu Eq/min). Furosemide (80 mg orally) resulted in a further fall in urine pH (from 5.29 +/- 0.06 to 4.97 +/- 0.09, P less than 0.02) and a significant increase in net acid excretion (from 30 +/- 5.8 to 38 +/- 5.1 mu Eq/min, P less than 0.02) while plasma aldosterone did not change (from 9.8 +/- 1.7 to 9.7 +/- 1.6 micrograms/dL). To investigate whether the acute stimulatory effect of furosemide on distal acidification requires some degree of mineralocorticoid activity, studies were conducted in adrenalectomized rats. The fall in urine pH and the increase in net acid excretion elicited by furosemide in adrenalectomized rats were comparable to those observed in adrenal-intact animals (5.37 +/- 0.10 v 5.67 +/- 0.11 and 0.43 +/- 0.08 v 0.41 +/- 0.06 mu Eq/min, respectively). In contrast, in adrenalectomized rats given amiloride to inhibit sodium transport in the cortical collecting tubule, furosemide failed to lower urine pH (6.44 +/- 0.23) and to increase net acid excretion (0.07 +/- 0.06 mu Eq/min). These findings demonstrate that furosemide enhances hydrogen ion secretion in the absence of aldosterone provided that sodium-transport in the cortical collecting tubule is not impaired.(ABSTRACT TRUNCATED AT 250 WORDS)
Acidosis↗
Segmental characterization of defects in collecting tubule acidification.
The aim of this study was to investigate cortical collecting tubule (CCT) function in normal individuals and in patients with distal renal tubular acidosis (DRTA) using furosemide (80 mg orally) as a tool to stimulate H+ and K+ secretion by enhancing Na delivery and transport in this nephron segment. In ten normal subjects, furosemide resulted in a fall in urine pH below 5.5 and an increase in net acid and K+ excretion. These effects were obliterated by amiloride, a drug which decreases transtubular epithelial voltage (lumen-negative) in the CCT by blocking Na reabsorption. In 13 patients with DRTA, defined by failure to lower urine pH below 5.5 during acidemia, three distinctive responses to furosemide were found. In six patients with the hyperkalemic variety, furosemide failed to lower urine pH below 5.5 and resulted in a blunted increase in K+ excretion, thereby suggesting that a normal transtubular voltage in the CCT could not be generated in such patients. In five patients with classic RTA, furosemide failed to lower urine pH below 5.5, but K+ excretion increased normally. The increase in K+ excretion indicated that a normal transtubular voltage in the CCT could be generated, while the inability to lower urine pH denotes the presence of a proton pump defect involving the CCT. In two patients with classic RTA, furosemide resulted in both a normal fall in urine pH and an increase in K+ excretion, thereby indicating that the CCT was normal in regards to both proton pump function and in its ability to generate a normal transtubular voltage.(ABSTRACT TRUNCATED AT 250 WORDS)
Acidosis, Renal Tubular↗
Delayed hypotensive response to dialysis in hypertensive patients with end-stage renal disease.
This study was designed to determine the ambulatory arterial blood pressure profile in hypertensive patients with end-stage renal disease during and following hemodialysis. Blood pressure was noninvasively monitored at 15-min intervals for 24 h using a fully automatic portable recorder, while the 10 patients studied followed their customary activities and were not receiving any antihypertensive medications. Prior to dialysis, the blood pressure was 179 +/- 7.0/101 +/- 3.7 mm Hg. After 4 h of dialysis, the systolic blood pressure did not change, while the diastolic blood pressure fell only slightly (178 +/- 4.2/94 +/- 2.4 mm Hg). After dialysis was completed, a progressive fall in both systolic and diastolic blood pressures was observed reaching the lowest value in the 5th h after dialysis (146 +/- 5.5/75 +/- 3.2 mm Hg). Thereafter, the fall in blood pressure was sustained during sleep (147 +/- 1.7/77 +/- 0.9 mm Hg) and during routine daily activities (147 +/- 2.0/78 +/- 1.0 mm Hg). The delayed fall in blood pressure was observed in patients in whom the plasma renin activity was elevated (8.4 +/- 2.4 ng/ml/h) and in patients in whom the plasma renin activity was low or normal (0.9 +/- 0.2 ng/ml/h). Our data suggest that during dialysis vasopressor mechanisms are activated to sustain blood pressure and that following dialysis such mechanisms are attenuated allowing the blood pressure to fall towards normal levels. The delayed fall in blood pressure documented by this study indicates that in many hypertensive patients with end-stage renal disease antihypertensive drug therapy is not required the day after dialysis.
Adult↗
Beta-adrenergic-mediated extrarenal potassium disposal in patients with end-stage renal disease: effect of propranolol.
This study was designed to investigate beta-adrenergic-mediated extrarenal potassium disposal in patients with end-stage renal disease (ESRD). Plasma potassium was measured over a period of 3 months in 20 patients with ESRD who were receiving the nonselective beta-blocker propranolol (n = 10) or not (n = 10). Both groups were virtually anuric and had a comparable plasma BUN, plasma bicarbonate, and red cell Na-K-ATPase activity. Plasma potassium measured before dialysis was higher in propranolol users than in nonusers (5.6 +/- 0.2 and 4.6 +/- 0.1 mEq/l, p less than 0.005). To examine beta-adrenergic-mediated internal potassium disposal more directly, epinephrine and epinephrine plus propranolol were acutely administered to another group of patients with ESRD and to normal subjects. Epinephrine resulted in a similar fall in plasma potassium in both groups (0.69 +/- 0.20 and 0.63 +/- 0.07 mEq/l, respectively), thereby suggesting unimpaired beta-adrenergic-mediated extrarenal potassium handling in patients with ESRD. In patients, however, the response to epinephrine was heterogeneous. In 4 of the 10 patients studied, epinephrine infusion did not result in a decrement in plasma potassium suggesting impaired beta-adrenergic responsiveness and thus blunting of this mechanism of extrarenal potassium disposal. In the remaining 6 patients, epinephrine infusion resulted in a fall in plasma potassium which was greater than that observed in normal subjects (1.13 +/- 0.14 and 0.63 +/- 0.07 mEq/l, respectively, p less than 0.01). In the presence of propranolol, the infusion of epinephrine did not result in a decrement in plasma potassium in these 6 patients or in the 6 normal subjects (0.04 +/- 0.07 and -0.02 +/- 0.06 mEq/l, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic beta-Antagonists↗
Renal and hemodynamic effects of non-diuretic antihypertensive therapy.
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Adrenergic alpha-Antagonists↗
Effect of short-term cyclosporine A administration on urinary acidification.
This study was designed to investigate the short-term effect of cyclosporine A (CyA) at a dose of 25 mg/kg body weight, on urinary acidification and renal potassium handling. Rats treated with CyA for 8 days developed metabolic acidosis (Blood pH 7.34 +/- 0.01, Blood HCO3 20 +/- 0.9 mEq/l) while those treated for 3 days did not (Blood pH 7.39 +/- 0.01, HCO3 24 +/- 1.0 mEq/l). Fractional HCO3 excretion was low in both groups indicating that bicarbonate reabsorption in the proximal nephron was unimpaired. Distal hydrogen ion secretion evaluated by the ability to increase urinary pCO2 in a highly alkaline urine was impaired in both groups (urinary pCO2 61 +/- 2.3 mmHg and 50 +/- 2.5 mmHg in rats treated with CyA for 3 and 8 days, respectively as compared to controls 72 +/- 3.0 mmHg, p less than 0.01). Under basal conditions, renal potassium excretion was lower in CyA treated rats than in controls. This was observed in association with a decrease in GFR in rats treated with CyA for 8 days (GFR 1.3 +/- 0.3 ml/min) but not in those treated for 3 days (GFR 2.2 +/- 0.4 ml/min). Rats treated with CyA for 3 days were able to increase potassium excretion normally in response to both sodium sulfate infusion and to an acute potassium infusion. In rats treated with CyA for 8 days, acute potassium loading failed to elicit an increase in fractional potassium excretion (from 32 +/- 5.3 to 28 +/- 2.3%) despite an increase in plasma K (from 3.0 +/- 0.2 to 8.4 +/- 0.3 mEq/l) and urine flow (from 11 to 36 mu ml/min).(ABSTRACT TRUNCATED AT 250 WORDS)
Ammonium Chloride↗
Amelioration of polyuria by amiloride in patients receiving long-term lithium therapy.
Vasopressin-resistant diabetes insipidus is a common side effect of the treatment of affective disorders with lithium. We studied the effect of amiloride on lithium-induced polyuria in nine such patients receiving maintenance lithium therapy who had a vasopressin-resistant defect in urinary concentrating ability. After a mean (+/- S.E.) of 24 +/- 6 days of amiloride administration, the urine volume fell (from 4.7 +/- 0.6 to 3.1 +/- 0.3 liters per 24 hours; P less than 0.005), and the urine osmolality increased (from 228 +/- 35 to 331 +/- 34 mOsm per kilogram of H2O; P less than 0.001). The decrease in urine output was sustained during six months of observation in the absence of any significant change in plasma levels of lithium, potassium, or bicarbonate; urinary excretion of sodium or lithium; or creatinine clearance. Amiloride administration was also associated with a significant increase in urine osmolality (from 575 +/- 54 to 699 +/- 48 mOsm per kilogram of H2O; P less than 0.005) measured after fluid deprivation and the injection of exogenous vasopressin. We conclude that amiloride mitigates lithium-induced polyuria, at least partly, by blunting the inhibitory effect of lithium on water transport in the renal collecting tubule. Thus, amiloride may provide a specific therapy for polyuria in lithium-treated patients while obviating the need for potassium supplementation in the treatment of this kind of polyuria.
Adult↗
Relationship of urinary and blood carbon dioxide tension during hypercapnia in the rat. Its significance in the evaluation of collecting duct hydrogen ion secretion.
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.
Acidosis, Respiratory↗
Urinary pCO2 as an index of collecting duct hydrogen ion secretion during chronic hypercapnia.
The rise in urinary pCO2 above blood pCO2 which occurs in response to bicarbonate loading (i.e. the urine to blood (U-B) pCO2 gradient), is used with increasing frequency as an index of collecting duct hydrogen ion secretion. We recently proposed, however, that the U-B pCO2 gradient is not an appropriate index of collecting duct hydrogen ion secretion when blood pCO2 is altered acutely. This issue was further investigated by examining the effect of chronic hypercapnia on urinary pCO2 generation. In rats exposed to chronic hypercapnia induced by breathing 10% CO2 for 3 days in an environmental chamber, acute sodium bicarbonate infusion resulted in a U-B pCO2 lower than that of normocapnic control rats (11 +/- 4.6 and 30 +/- 1.8 mm Hg, p less than 0.001). This finding could be interpreted to indicate that collecting duct hydrogen ion secretion is depressed in rats with chronic hypercapnia. The urinary pCO2 of rats with chronic hypercapnia was lower than that of the blood (54 +/- 6.0 and 86 +/- 1.2 mm Hg, p less than 0.005, respectively). In these rats, NaHCO3 infusion, while blood pCO2 was kept constant, elicited a marked rise in urine pCO2 (from 54 +/- 6.0 to 104 +/- 6.0 mm Hg, p less than 0.005) which was not significantly different from that observed in normocapnic control rats. The infusion of carbonic anhydrase resulted in a comparable fall in urine pCO2 in hypercapnic and normocapnic rats (-27 +/- 5 and -30 +/- 3 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)
Amiloride↗
Clinical disorders of aldosterone metabolism.
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Acidosis↗
Carbonic anhydrase independent bicarbonate reabsorption in rats with chronic papillary necrosis.
The present study was designed to indirectly localize the tubular sites of carbonic anhydrase independent bicarbonate reabsorption in the rat. Papillary necrosis was induced in rats by intravenous administration of bromoethyleneamine hydrobromide (BEA) 6 weeks prior to the study, in order to assess the role of deep nephrons in this process. Acetazolamide alone, acetazolamide plus amiloride, and acetazolamide, amiloride plus furosemide were infused into rats with intact papillae (groups I, III, V) and rats with BEA-induced papillary necrosis (groups II, IV, VI). Our results show that chronic papillary necrosis does not alter carbonic anhydrase independent bicarbonate reabsorption, since the fractional excretion of bicarbonate (FEHCO3) was not significantly higher when acetazolamide was infused into animals with BEA-induced papillary necrosis as compared to those rats with intact papillae (FEHCO3 group I vs. group II: NS). The addition of amiloride hydrochloride, a blocker of distal acidification at the administered doses, increased FEHCO3 significantly in both, animals with intact papillae and those with papillary necrosis, to a similar degree. The addition of furosemide to acetazolamide and amiloride further induced a significant increase in FEHCO3 only in the group of animals with papillary necrosis (FEHCO3 group V 43.0 +/- 2.9% vs. group VI 52.1 +/- 0.9%; p less than 0.05). It appears from our study that deeper nephrons and papillary structures are not indispensable for carbonic anhydrase independent bicarbonate reabsorption in the rat on a chronic basis. The cortical collecting duct appears to have a significant capacity to reabsorb bicarbonate independent of carbonic anhydrase which can be blocked by amiloride.(ABSTRACT TRUNCATED AT 250 WORDS)
Absorption↗
Syndromes of aldosterone deficiency and excess.
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Aldosterone↗
Suppression of distal urinary acidification after recovery from chronic hypocapnia.
This study examined urinary acidification shortly after recovery from chronic hypocapnia induced by hypoxemia. Distal acidification was evaluated by measuring the urinary PCO2 and urine-blood PCO2 difference (U-B PCO2) when blood PCO2 had returned to normal. In posthypocapnic rats, maximal alkalinization of the urine by acute sodium bicarbonate loading failed to increase urine PCO2 and U-B PCO2 to the level of posthypoxemic control rats and normal control rats with comparable blood pH and urine bicarbonate concentration. To test the hypothesis that decreased distal hydrogen ion secretion in posthypocapnic rats resulted from intracellular alkalosis secondary to protracted hypocarbia, posthypocapnic rats were exposed to hypercapnia of brief duration (30 min) and prolonged duration (120 min) in an attempt to restore distal acidification to normal. In posthypocapnic rats, hypercapnia of brief duration was associated with a significant increase in urine PCO2 and a fall in urine pH. Prolonged hypercapnia resulted in a marked increase in urine PCO2 and a further fall in urine pH. At any urinary bicarbonate concentration, however, the urine PCO2 and U-B PCO2 posthypocapnic rats exposed to hypercapnia were still significantly lower than in normal control rats identically subjected to prolonged hypercapnia and with comparable blood PCO2 and blood pH. Our findings indicate that distal acidification after abrupt recovery from chronic hypocapnia is decreased as if the kidneys were still under the influence of sustained hypocapnia. These findings could not be ascribed to extracellular alkalemia but could be explained by postulating that decreased urinary acidification resulted from persistence of cell alkalinity secondary to the accumulation of non-CO2 buffers generated during protracted hypocarbia. Alternatively, factors other than cell pH could mediate the adaptive decrease in distal hydrogen ion secretion of posthypocapnic rats.
Alkalosis, Respiratory↗
Metabolic and hormonal factors influencing extrarenal buffering of an acute acid load.
This study evaluates metabolic and hormonal factors influencing extrarenal buffering of an acute acid load. Phosphate deprivation of 2 weeks duration was associated with enhanced extrarenal acid buffering. The enhanced extrarenal buffering capacity of phosphate deprivation was not dependent on the presence of parathyroid glands. Parathyroid hormone administration to phosphate-deprived rats promoted a further enhancement of the buffering capacity of an acid load. Blood pH and HCO3 during acid loading were not significantly different between control and diphosphonate-treated rats and between phosphate-deprived rats and phosphate-deprived rats treated with diphosphonate. The mortality rate, however, was significantly higher in diphosphonate-treated rats than in rats not receiving the drug suggesting that diphosphonate blunts the buffering of an acid load in both control and phosphate-deprived rats. Chronic vitamin D administration and acute administration of arginine vasopressin in pharmacologic doses were associated with significant enhancement of buffering capacity as compared to control rats. Thyrocalcitonin administration to intact but not thyroparathyroidectomized rats was associated with diminished capacity to buffer an acid load. These data demonstrate that the buffering of an acute acid load is influenced by a number of dietary and hormonal factors probably acting at the level of the bone.
Acid-Base Equilibrium↗
Hyperkalemic distal renal tubular acidosis associated with obstructive uropathy.
We studied renal function in 13 patients with obstructive uropathy and hyperkalemic metabolic acidosis to characterize the pathogenesis of this disorder. Base-line fractional potassium excretion was lower in all patients than in controls with similar glomerular filtration rates. Acetazolamide was given to 11 patients but failed to increase fractional potassium excretion to normal. In five patients, impaired potassium excretion was associated with decreased ammonium excretion, a urinary pH below 5.5 (5.18 +/- 0.07, mean +/- S.E.M.), and aldosterone deficiency. In the remaining eight patients, the urinary pH did not fall below 5.5 (6.4 +/- 0.2) with acidosis, and we failed to lower the urinary pH and increase fractional potassium excretion to normal by administering a mineralocorticoid and sodium sulfate. A syndrome of hyperkalemic distal renal tubular acidosis may occur in patients with obstructive uropathy. In some patients, this syndrome results from a defect in hydrogen and potassium secretion in the distal nephron rather than from aldosterone deficiency. Obstructive uropathy should be included in the differential diagnosis of hyperkalemic acidosis and renal insufficiency.
Acetazolamide↗
The pathogenesis of hyperchloremic metabolic acidosis associated with kidney transplantation.
The mechanism of persistent hyperchloremic metabolic acidosis developing after kidney transplantation was investigated in six patients. In five patients in whom acidosis failed to lower the urine pH below 5.5, an infusion of sodium sulfate also failed to lower the urine pH. Neutral phosphate infusion failed to increase the urine minus blood (U-B) carbon dioxide tension (pCO2) difference normally in these patients. This abnormal response to both maneuvers indicates the presence of a tubular defect for distal hydrogen ion secretion. In the remaining patient, spontaneous acidosis lowered the urine pH below 5.5 and increased the U-B pCO2 normally with the administration of phosphate, demonstrating that this patient's distal capacity for hydrogen secretion was intact. The plasma aldosterone level was low in this patient, and thus he had the acidification defect characteristic of aldosterone deficiency. Hyperkalemia developed in two patients; both were aldosterone-deficient, and they had a low fractional potassium excretion ion response to stimulation with sodium sulfate or acetazolamide. In all but one patient, who lost his kidney to accelerated rejection, chronic rejection developed. Homogeneous deposition of complement (C3) along the tubular basement membrane was found in three patients. Our data suggest that a secretory type of distal renal tubular acidosis can be an early sign of the immunologic process that leads to chronic rejection.
Acidosis, Renal Tubular↗
Clinical and pathophysiologic spectrum of acquired distal renal tubular acidosis.
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Acidosis, Renal Tubular↗