Kinetic properties of the Na+/H+ antiporter of lymphocytes from the spontaneously hypertensive rat: role of intracellular pH.

Enhanced activity of the Na+/H+ antiporter is increasingly reported as a feature of cells from hypertensive subjects but the intracellular pH (ipH) dependency of its activity has not been examined. This study was designed to characterize the kinetic properties of the Na+/H+ antiporter in lymphocytes from adult spontaneously hypertensive rats (SHR) and in those from age-matched normotensive Wistar-Kyoto (WKY) controls. Steady-state ipH, estimated from the measurement of BCECF fluorescence, was significantly lower in lymphocytes from the SHR than in those from WKY rats (7.09 +/- 0.02, n = 17 and 7.17 +/- 0.03, n = 19, respectively, P less than 0.025). The velocity of the antiporter determined from the product of the change in intracellular hydrogen ion concentration (i[H+]) by the buffering power measured concurrently at each starting ipH exhibited similar kinetic parameters in SHR and WKY cells: Vmax, 72 +/- 18 vs. 79 +/- 24 mM H+/30 s; pKH, 10.04 +/- 0.87 vs. 8.49 +/- 0.80; and Hill coefficient, 1.67 +/- 0.12 vs. 1.44 +/- 0.10, respectively. Likewise, no significant differences were observed between SHR and WKY cells in either the Km (29 +/- 5 and 32 +/- 8 mM, respectively) or the Vmax (6.0 +/- 1.0 and 5.53 +/- 1.0 mM H+/30 s, respectively) of the sodium activation curve. We conclude that while the ipH of SHR lymphocytes is reduced, the kinetic properties of the Na+/H+ antiporter are virtually identical in SHR and WKY lymphocytes. Consequently, a primary abnormality in the activity of this antiporter is not an inherent feature of lymphocytes from the SHR model of genetic hypertension. We propose that the activity of the Na+/H+ antiporter in SHR cells is apt to be increased as a result of reduction in ipH which dictates a higher set point in its steady-state activity.

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.

Renal acid excretion and intracellular pH in salt-sensitive genetic hypertension.

Acid-base status and renal acid excretion were studied in the Dahl/Rapp salt-sensitive (S) rat and its genetically salt-resistant counterpart (R). S rats developed hypertension while on a very high salt diet (8%) and while on a more physiological salt diet (1%) and remained normotensive while on a very low salt diet (0.08%). Under the high salt diet, intracellular pH measured in freshly isolated thymic lymphocytes using 2',7'-bis (carboxyethyl)-5 (6)-carboxyfluorescein acetomethyl ester, a pH-sensitive dye, was lower in S than in R rats both when measured in the presence of HCO3/CO2 (7.32 +/- 0.02 vs. 7.38 +/- 0.02, respectively, P < 0.05) and in its absence (7.18 +/- 0.04 vs. 7.27 +/- 0.02, respectively, P < 0.05). Under the high salt diet, net acid excretion was higher in S than R rats (1,777 +/- 111 vs. 1,017 +/- 73 muEq/24 h per 100 g body wt, respectively, P < 0.001), and this difference was due to higher rates of both titratable acid and ammonium excretion. Directionally similar differences in intracellular pH and net acid excretion between S and R rats were also observed in salt-restricted animals. In S and R rats placed on a normal salt intake (1%) and strictly pair-fed to control food intake as a determinant of dietary acid, net acid excretion was also higher in S than in R rats (562 +/- 27 vs. 329 +/- 21 muEq/24 h per 100 g, respectively, P < 0.01). No significant difference in either blood pH or bicarbonate levels were found between S and R rats on either the 0.08%, 1%, or 8% salt diets. We conclude that renal acid excretion is augmented in the salt-sensitive Dahl/Rapp rat. Enhanced renal acid excretion may be a marker of increased acid production by cells from subjects with salt-sensitive hypertension.

Free cytosolic calcium in renal proximal tubules from the spontaneously hypertensive rat.

Free intracellular calcium was measured in renal proximal tubules obtained from spontaneously hypertensive rats (SHR) and from age-matched Wistar-Kyoto rats (WKY) ingesting a normal diet. Experiments were performed on renal proximal tubule suspensions using fura-2 to monitor cytosolic calcium. In 4-week-old rats, when systolic blood pressure was not significantly different between the two groups, renal proximal tubule cytosolic calcium was similar (143 +/- 28 and 144 +/- 15 nM, respectively). By the age of 5 weeks, cytosolic calcium increased significantly in both SHR and WKY (214 +/- 24 and 262 +/- 34 nM, respectively, p less than 0.05). Calcium, however, was not significantly different between the two groups, even though at this age blood pressure was higher in SHR than in WKY. As compared with values in 4-week-old rats, cytosolic calcium was also found increased in tubules from both SHR and WKY aged 10 to 12 weeks (261 +/- 42 and 279 +/- 30 nM, respectively) and 20 to 24 weeks (263 +/- 42 and 308 +/- 28 nM, respectively). However, no significant differences in cytosolic calcium were found between SHR and WKY even though at these ages systolic blood pressure increased markedly in the SHR. Moreover, regression analysis failed to reveal a correlation between cytosolic calcium and blood pressure when data from either group of rats of all ages studied were pooled. Exposure to ouabain (10(-3) M) to inhibit Na+,K+-adenosine triphosphatase and increase intracellular sodium had no significant effect on cytosolic calcium in tubules from either SHR or WKY (260 +/- 69 and 250 +/- 45 nM, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced intracellular pH in lymphocytes from the spontaneously hypertensive rat.

This study was designed to determine the cytoplasmic pH (pHi) profile of lymphocytes from a rat model of genetic hypertension that is well suited for study before and after the development of spontaneous hypertension. For this purpose, pHi was measured in thymic lymphocytes obtained from spontaneously hypertensive rats (SHR) and from age-matched Wistar-Kyoto (WKY) control rats using 2',7'-bis carboxyethyl-5,6-carboxyfluorescein (BCECF), a pH-sensitive fluorescence probe. At the age of 16-20 weeks, pHi of lymphocytes suspended in a HCO3-free HEPES-buffered solution, was markedly lower in the SHR than in the WKY rats (7.07 +/- 0.02, n = 16 and 7.22 +/- 0.01, n = 15, respectively, p less than 0.001), whereas systolic blood pressure was higher in SHR than in WKY rats (175 +/- 5.0 and 105 +/- 3.0 mm Hg, respectively, p less than 0.001). In rats less than 5 weeks of age, pHi was also lower in SHR than in WKY rat lymphocytes (7.12 +/- 0.04, n = 11 and 7.23 +/- 0.04, n = 11, respectively, p less than 0.05), although at this age systolic blood pressure was not different between the two groups (87 +/- 4.0 and 85 +/- 3.0 mm Hg, respectively). In lymphocytes suspended in a more physiological HCO3/CO2-buffered solution, pHi was again lower in the adult SHR than in the WKY rat (7.18 +/- 0.02, n = 16 and 7.31 +/- 0.02, n = 16, respectively, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Altered blood pressure during sleep in normotensive subjects with type I diabetes.

This study was designed to examine the circadian pattern of blood pressure in children and young adults with type I diabetes who were completely normotensive by standard criteria. Forty-five patients and the same number of age- and sex-matched control subjects were studied. In diabetic children of 10-14 years of age, the nocturnal fall in systolic and diastolic blood pressures was intact. In diabetics of 15-20 years of age, the fall in systolic blood pressure was blunted; in diabetics of 21-37 years of age, the fall in both systolic and diastolic blood pressures during sleep was blunted. When data from all diabetic subjects were pooled and analyzed in a multiple linear regression model, mean blood pressure during sleep correlated best with urinary albumin excretion (r = 0.60). On the basis of this finding, we subdivided our patients into two groups: a microalbuminuric group (urinary albumin excretion > 30 mg per 24 hours; mean, 160.3 +/- 29.7; n = 11) and a normoalbuminuric group (urinary albumin excretion < 30 mg per 24 hours; mean, 6.6 +/- 6.5; n = 34). Both systolic and diastolic blood pressures during sleep were higher in microalbuminuric (121.1 +/- 3.3 and 69.3 +/- 2.5 mm Hg, respectively) than in normoalbuminuric diabetics (114.2 +/- 1.8 and 60.1 +/- 1.2 mm Hg, p < 0.05) or control subjects (113.3 +/- 1.2 and 60.1 +/- 1.2 mm Hg, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Metabolic effects of converting enzyme inhibitors: focus on the reduction of cholesterol and lipoprotein(a) by fosinopril.

It is generally believed that the use of angiotensin-converting enzyme (ACE) inhibitors has no effect on the lipid profile. Our recent data show that in patients with proteinuric renal disease, serum levels of total cholesterol and lipoprotein(a) [Lp(a)] may be lowered during treatment with an ACE inhibitor, fosinopril sodium. During a 12-week randomized, placebo-controlled, double-blind study involving 26 patients with mild-to-moderate renal impairment, fosinopril administration was associated with significant decreases in both urinary protein excretion and serum total cholesterol levels, whereas placebo was not. During a 6-week washout phase, both parameters returned to baseline in fosinopril-treated patients and remained unchanged in placebo recipients. In addition, fosinopril-treated patients had a decrease in plasma levels of Lp(a), whereas this was not seen in placebo-treated patients. When data from a subset of 13 patients with proteinuric renal disease and hypertension were examined, a significant decrease in serum total cholesterol levels was observed; this decrease reversed after discontinuation of fosinopril. Analysis of the effect of fosinopril on plasma Lp(a) levels in a subset of patients who had type II diabetes mellitus and overt proteinuria revealed a significant decrease in plasma Lp(a) after administration of fosinopril. Moreover, fosinopril lowered plasma Lp(a) levels in blacks, whose pretreatment levels were higher than those of whites with comparable degrees of proteinuria and levels of serum total cholesterol. Thus, the reduction in serum Lp(a) levels may be related not only to amelioration of proteinuria, but also to another direct action of fosinopril on the metabolism of Lp(a).

Renal effects of antihypertensive drugs.

Antihypertensive drugs have disparate effects on renal haemodynamics, tubular function, plasma electrolytes, and hormonal responses. Calcium entry blockers and angiotensin-converting enzyme (ACE) inhibitors are unique in that they may increase glomerular filtration rate (GFR) and renal blood flow in patients with hypertension. Both classes of drugs are distinctive in that they prevent salt retention because of their inhibitory effect on tubular sodium reabsorption. In addition to these attributes, which are desirable in terms of lowering systemic blood pressure, these 2 classes of drugs exert important intrarenal effects which may participate in limiting the progression of renal disease. ACE inhibitors have been shown to protect against the development of glomerulosclerosis in various experimental models of renal insufficiency. Importantly, there is emerging evidence from human studies supporting a distinctive beneficial effect of these agents on renal function in patients with hypertension, mild chronic renal insufficiency and diabetes mellitus. Calcium entry blockers have also been shown to exert some beneficial effect in limiting the progression of experimental kidney disease but neither an improvement in glomerular sclerosis nor a decrease in proteinuria have been clearly documented. At present ACE inhibitors appear the most attractive agents in terms of arresting the progression of renal disease. Acute deterioration in renal function may occur following the administration of ACE inhibitors, calcium entry blockers, and beta-blockers. This complication should be considered in every patient on antihypertensive therapy who suffers an unexplained deterioration in renal function. In particular, the sudden deterioration in renal function following initiation of therapy with an ACE inhibitor is a clue to the possible presence of bilateral renal artery stenosis or stenosis of a solitary functioning kidney. Renal damage may also occur in patients with unilateral renal artery stenosis even though total (2-kidney) GFR may not be appreciably reduced. In this setting, a captopril renal scan with hippuran and diethylenetriamine pentaacetic acid (DTPA) provides physiological information regarding the renal blood flow and GFR of each kidney. In patients with unilateral renal artery stenosis the impact of ACE inhibitor therapy on GFR may be discerned by the use of the DTPA scan, which may demonstrate a reduction in GFR in the stenotic kidney that is not apparent by evaluation of total kidney GFR. This suggests that despite adequate control of systemic blood pressure and unchanged plasma creatinine progressive kidney damage in the stenotic kidney ensues.

Cytosolic calcium in T lymphocytes from the spontaneously hypertensive rat.

To gain further insight into the possible generalized nature of intracellular calcium-related alterations in hypertension we measured free cytosolic calcium (iCa2+) in lymphocytes obtained from the spleen and the blood of the spontaneously hypertensive rat (SHR) and age-matched normotensive Wistar-Kyoto (WKY) rats. By monitoring Fura-2 fluorescence at an excitation wavelength of 340 nm and an emission wavelength of 510 nm we estimated; Ca2+. In peripheral lymphocytes from the SHR iCa2+ was increased as compared to those from WKY rats (146 +/- 14 and 112 +/- 6.0 nm, respectively, P less than .025). In contrast, in lymphocytes obtained from the spleen, iCa2+ was not different between SHR and WKY rats (93 +/- 7.0 and 96 +/- 8.0 nm, respectively). When spleen cells were subjected to selective B lymphocyte depletion to generate a preparation of predominantly T lymphocytes, iCa2+ was found to be higher in SHR than in WKY rats (149 +/- 23 and 89 +/- 12 nm, respectively, P less than .05). The finding that iCa2+ is elevated in peripheral lymphocytes and spleen cells subjected to B cell depletion but not in untreated spleen cells indicates that T, but not B, lymphocytes have increased iCa2+ in the SHR. This observation may be related to existing evidence that T lymphocyte function is impaired in the SHR. An increase in iCa2+ is not a phenomenon generalized to all cells of this model of genetic hypertension.

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)

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)

Na+/H+ exchange and vascular smooth muscle proliferation.

Abnormal growth of vascular smooth muscle (VSM) is seen in various pathologic conditions such as hypertension and atherosclerosis. Many classic vasoconstrictors have now been shown to be mitogenic, either by themselves or in conjunction with other cofactors, such as insulin. The mitogenic effects of vasoconstrictors may be due, in part, to activation of similar second messenger pathways, including stimulation of the Na+/H+ antiporter. It has been suggested, therefore, that an enhanced proliferation rate may be, in part, the consequence of elevated Na+/H+ exchange. This hypothesis is supported by several observations of the close association between Na+/H+ exchange activity and DNA synthesis in some cell types including fibroblasts and VSM. Stimulation of Na+/H+ exchange may play a permissive role in optimal growth by preventing H+ accumulation (a fall in intracellular pH [pHi]) due to the increased metabolic activity during cell stimulation. Enhancement of Na+/H+ exchange activity increases Na+ influx into the cell, and secondarily increases K+ entry through activation of Na+/K+ ATPase activity. Although the Na+/H+ antiporter may influence cell proliferation through various ionic mechanisms, it is not clear that enhanced proliferation is the consequence of overactivity of this antiporter. In VSM, there are also differences in the pattern of activation of the Na+/H+ antiporter by hyperplastic and hypertrophic agents. Although pHi is increased in response to both acute and chronic stimulation by hyperplastic factors, such as platelet-derived growth factor, a hypertrophic agonist such as angiotensin II increases pHi acutely but lowers it chronically. Likewise, hyperplastic factors increase the Na+/H+ antiporter (NHE-1) mRNA levels, whereas angiotensin II does not.(ABSTRACT TRUNCATED AT 250 WORDS)

Tissue renin angiotensin systems: theoretical implications for the development of hyperkalemia using angiotensin-converting enzyme inhibitors.

In patients with renal insufficiency, as the number of functioning nephrons is reduced, potassium balance is maintained by an increase in potassium excretion in the remaining nephrons. This adaptive response is, in part, mediated by an increase in aldosterone production by the adrenal gland. Use of angiotensin-converting enzyme (ACE) inhibitors in these patients can result in hyperkalemia by suppressing aldosterone production by the adrenal gland. Inhibition of aldosterone production depends on the degree of inhibition of angiotensin II formation in the circulation as well as the degree of inhibition of angiotensin II formed locally in the adrenal gland. Recent experimental evidence suggests that the latter process may be important for the tonic regulation of aldosterone production. Because the various ACE inhibitors exhibit different degrees of ACE inhibition at the tissue level, it is reasonable to postulate that angiotensin II-dependent aldosterone production will be inhibited to a lesser degree by agents that have low tissue specificity for the adrenal gland. This feature would be most advantageous in treating patients with chronic renal insufficiency and congestive heart failure who are at risk for hyperkalemia. Therefore, the ideal ACE inhibitor should not suppress aldosterone secretion in such patients.

Patterns of metabolic acidosis in patients with chronic renal failure: impact of hemodialysis.

The type of metabolic acidosis in patients with chronic renal failure was studied prospectively over a three-month period in 32 stable patients on chronic hemodialysis using acetate. All patients had pre-dialysis metabolic acidosis (mean TCO2 = 16.6 +/- 0.4 mEq/l, range 10 to 23 mEq/l). The patterns of metabolic acidosis were defined using the ratio: delta AG/delta TCO2 where delta AG is the increment in plasma anion gap above normal and delta TCO2 the decrement in plasma bicarbonate below normal. The group as a whole showed a mixed hyperchloremic and high anion gap pattern with a mean delta AG/delta TCO2 ratio of 53.3 +/- 7.1%. The individual distribution of patterns ranged from a pure hyperchloremic acidosis (24%) to a pure high anion gap acidosis (30%) with the mixed pattern being the most frequent (46%). An inverse correlation between the TCO2 change (y) during the dialysis procedure and the TCO2 (x) prevailing at the start of dialysis was found by linear regression analysis: y = -0.51x + 11, r = -0.54, p less than 0.01. Thus, before acetate conversion to bicarbonate was fully completed, patients gained bicarbonate during dialysis if TCO2 was less than 21 mEq/l and lost it when the pre-dialysis TCO2 was above this level. On average, the delta AG was reduced to a greater extent than the delta TCO2 so that the delta AG/delta TCO2 ratio fell significantly (from 53 +/- 7.1 to 11 +/- 8.8%, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)