Role of 11beta-hydroxysteroid dehydrogenase 2 renal activity in potassium homeostasis in rats with chronic renal failure.

Aldosterone concentrations vary in advanced chronic renal failure (CRF). The isozyme 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2), which confers aldosterone specificity for mineralocorticoid receptors in distal tubules and collecting ducts, has been reported to be decreased or normal in patients with renal diseases. Our objective was to determine the role of aldosterone and 11beta-HSD2 renal microsome activity, normalized for glomerular filtration rate (GFR), in maintaining K+ homeostasis in 5/6 nephrectomized rats. Male Wistar rats weighing 180-220 g at the beginning of the study were used. Rats with experimental CRF obtained by 5/6 nephrectomy (N = 9) and sham rats (N = 10) were maintained for 4 months. Systolic blood pressure and plasma creatinine (Pcr) concentration were measured at the end of the experiment. Sodium and potassium excretion and GFR were evaluated before and after spironolactone administration (10 mg.kg-1.day-1 for 7 days) and 11beta-HSD2 activity on renal microsomes was determined. Systolic blood pressure (means +/- SEM; Sham = 105 +/- 8 and CRF = 149 +/- 10 mmHg) and Pcr (Sham = 0.42 +/- 0.03 and CRF = 2.53 +/- 0.26 mg/dL) were higher (P < 0.05) while GFR (Sham = 1.46 +/- 0.26 and CRF = 0.61 +/- 0.06 mL/min) was lower (P < 0.05) in CRF, and plasma aldosterone (Pald) was the same in the two groups. Urinary sodium and potassium excretion was similar in the two groups under basal conditions but, after spironolactone treatment, only potassium excretion was decreased in CRF rats (sham = 0.95 +/- 0.090 (before) vs 0.89 +/- 0.09 microEq/min (after) and CRF = 1.05 +/- 0.05 (before) vs 0.37 +/- 0.07 microEq/min (after); P < 0.05). 11beta-HSD2 activity on renal microsomes was lower in CRF rats (sham = 0.807 +/- 0.09 and CRF = 0.217 +/- 0.07 nmol.min-1.mg protein-1; P < 0.05), although when normalized for mL GFR it was similar in both groups. We conclude that K+ homeostasis is maintained during CRF development despite normal Pald levels. This adaptation may be mediated by renal 11beta-HSD2 activity, which, when normalized for GFR, became similar to that of control rats, suggesting that mineralocorticoid receptors maintain their aldosterone selectivity.

Role of 11â-hydroxysteroid dehydrogenase 2 renal activity in potassium homeostasis in rats with chronic renal failure

Aldosterone concentrations vary in advanced chronic renal failure (CRF). The isozyme 11â-hydroxysteroid dehydrogenase 2 (11â-HSD2), which confers aldosterone specificity for mineralocorticoid receptors in distal tubules and collecting ducts, has been reported to be decreased or normal in patients with renal diseases. Our objective was to determine the role of aldosterone and 11â-HSD2 renal microsome activity, normalized for glomerular filtration rate (GFR), in maintaining K+ homeostasis in 5/6 nephrectomized rats. Male Wistar rats weighing 180-220 g at the beginning of the study were used. Rats with experimental CRF obtained by 5/6 nephrectomy (N = 9) and sham rats (N = 10) were maintained for 4 months. Systolic blood pressure and plasma creatinine (Pcr) concentration were measured at the end of the experiment. Sodium and potassium excretion and GFR were evaluated before and after spironolactone administration (10 mg·kg-1·day-1 for 7 days) and 11â-HSD2 activity on renal microsomes was determined. Systolic blood pressure (means ± SEM; Sham = 105 ± 8 and CRF = 149 ± 10 mmHg) and Pcr (Sham = 0.42 ± 0.03 and CRF = 2.53 ± 0.26 mg/dL) were higher (P < 0.05) while GFR (Sham = 1.46 ± 0.26 and CRF = 0.61 ± 0.06 mL/min) was lower (P < 0.05) in CRF, and plasma aldosterone (Pald) was the same in the two groups. Urinary sodium and potassium excretion was similar in the two groups under basal conditions but, after spironolactone treatment, only potassium excretion was decreased in CRF rats (sham = 0.95 ± 0.090 (before) vs 0.89 ± 0.09 µEq/min (after) and CRF = 1.05 ± 0.05 (before) vs 0.37 ± 0.07 µEq/min (after); P < 0.05). 11â-HSD2 activity on renal microsomes was lower in CRF rats (sham = 0.807 ± 0.09 and CRF = 0.217 ± 0.07 nmol·min-1·mg protein-1; P < 0.05), although when normalized for mL GFR it was similar in both groups. We conclude that K+ homeostasis is ...

Inappropriately high plasma renin activity accompanies chronic loss of renal function.

Stimulation of both the systemic and local renin-angiotensin systems participates in the pathogenesis of tissue injury observed in experimental renal disease. However, substantial information demonstrating excessive activation of the renin-angiotensin system in patients with chronic renal disease is not available in spite of the well-established role of this system in the progression of renal damage. This investigation examined the plasma renin activity (PRA) and the ratio of this parameter to the simultaneously measured glomerular filtration rate (PRA/GFR) in normal volunteers (mean values 3.2 ng/ml/h and 3.0 ng/ml/h/100 ml GFR, respectively) and in patients with chronic renal disease (1.6 ng/ml/h and 28.5 ng/ml/h/100 ml GFR, respectively). A mean tenfold increase in the PRA/GFR ratio was observed in patients with chronic renal disease as compared to normal volunteers. The observed augmentation in PRA was not caused by physiologic mechanisms aimed at conserving urinary sodium since a positive correlation was found between PRA/GFR and the fractional excretion of sodium (y = 2.75 + 2.23x; r = 0.781, p < 0.01), as opposed to that of normal controls (y = 5.3 - 1.46x; r = -0.640, p < 0.01). Consequently, our results support the existence of inappropriate activation of the renin-angiotensin system in humans with chronic renal disease. Such stimulation might play a critical role in the pathophysiology of advanced renal injury.

Mechanism of acetazolamide-induced rise in renal vascular resistance assessed in the dog whole kidney.

The reduction in renal blood flow (RBF) and glomerular filtration rate (GFR) observed after the administration of the carbonic anhydrase inhibitors acetazolamide and benzolamide had been explained as due to activation of the tubuloglomerular feedback mechanism. If correct, pharmacologic blockade of this pathway should prevent the development of renal vasoconstriction with the carbonic anhydrase inhibitors. Thus, the current study evaluates in the dog whole kidney the effect of acetazolamide (20 mg/kg body weight) in the presence or absence of furosemide (5 mg/kg body weight), a drug which blocks the tubuloglomerular feedback. Acetazolamide resulted in a large increase in urinary bicarbonate excretion accompanied by a significant reduction in GFR (16%) and RBF (18%). By contrast with the effects of acetazolamide, furosemide did not alter GFR and increased RBF. In addition, the loop diuretic induced a large chloruresis without changes in urinary bicarbonate excretion. The infusion of acetazolamide in furosemide-treated dogs resulted in a significant increment in renal bicarbonate excretion and in a significant reduction in the levels of both GFR (28%) and RBF (13%). Therefore, furosemide pretreatment did not block the effects of acetazolamide on renal hemodynamic parameters. Consequently, the acetazolamide-induced reduction in both GFR and RBF cannot be accounted for by changes in chloride levels in the juxtaglomerular region due to enhanced salt transport in the macula densa/distal nephron. The increased renal vascular resistance observed with acetazolamide might occur by either a direct effect of this agent on the renal circulation or as a result of changes in intrarenal pressure secondary to the inhibition of proximal fluid reabsorption.

Kaliuretic response to potassium loading in amiloride-treated dogs.

To assess whether an intact mechanism of sodium transport in the distal nephron is a prerequisite for the development of a kaliuresis in response to an acute potassium load (0.4 M KCl, 1 ml/min), the effects of a simultaneous infusion of KCl and amiloride (1 mg/kg/h) were evaluated in anesthetized dogs. A major reduction in potassium excretion mainly due to a sharp decrease in urine K+ concentration to one tenth of control levels was found after amiloride. The simultaneous infusion of KCl and amiloride resulted in a rapid and major increase in kaliuresis that was accounted for mostly by the rise in urine K+ concentration. The increased kaliuresis after the acute potassium infusion was of similar magnitude when expressed as percent value of control to that previously reported in dogs not receiving amiloride; the absolute rates of K+ excretion, however, were only 2.7 and 7.3% (before and after KCl infusion, respectively) of the values in dogs not receiving amiloride. Our observations suggest that potassium infusion in the intact dog increases kaliuresis primarily as a result of a more favorable chemical gradient of this cation between blood and/or distal tubular cells and urine. Yet, when a chemical gradient is the only driving force of potassium secretion, as was the case in our amiloride-treated dogs, the absolute rate of kaliuresis is very modest. The presence of an unimpaired electrical profile and sodium transport mechanisms in the distal nephron, although not critical for the development of kaliuresis in response to a K+ load, accounts for a severalfold rise in renal potassium excretion above basal levels.

Reversal by indomethacin of renal effects of dopamine in subjects with normal renal function.

In five subjects with normal renal function, intravenous dopamine, at a rate of 6 ug/kg/min, produces a renal vasodilation, increase in Na excretion and reduction in urinary osmolality, without modification in glomerular filtration rate. These effects were reversed by intravenous indomethacin (2 mg/kg), suggesting that the renal effects of dopamine might depend on normal prostaglandins production.

Acute effect of amiloride on urinary magnesium excretion in dogs.

Under the effect of amiloride Na excretion increased and K excretion decreased. These urinary changes were mainly due to alterations in urinary concentration of Na and K with little or no change in urinary volume. Neither plasma Mg concentration nor urinary Mg excretion were modified by the drug. From these results we conclude that, in dogs without Mg loading, Mg transport at distal sites, where amiloride effects take place, is not altered by this diuretic; thus, the change of transepithelial potential difference produced by amiloride would not affect Mg transport.

Reversal by indomethacin of renal effects of dopamine in subjects with normal renal function.

In five subjects with normal renal function, intravenous dopamine, at a rate of 6 ug/kg/min, produces a renal vasodilation, increase in Na excretion and reduction in urinary osmolality, without modification in glomerular filtration rate. These effects were reversed by intravenous indomethacin (2 mg/kg), suggesting that the renal effects of dopamine might depend on normal prostaglandins production.

Acute effect of amiloride on urinary magnesium excretion in dogs.

Under the effect of amiloride Na excretion increased and K excretion decreased. These urinary changes were mainly due to alterations in urinary concentration of Na and K with little or no change in urinary volume. Neither plasma Mg concentration nor urinary Mg excretion were modified by the drug. From these results we conclude that, in dogs without Mg loading, Mg transport at distal sites, where amiloride effects take place, is not altered by this diuretic; thus, the change of transepithelial potential difference produced by amiloride would not affect Mg transport.