Effect of enalapril on proteinuria, phosphaturia, and calciuria in insulin-dependent diabetes

Elevated urinary calcium and phosphate excretion have been observed in children with insulin-dependent diabetes mellitus (IDDM). This may be related to a defect in tubular reabsorption. It is well known that converting enzyme inhibition decreases microalbuminuria and may prevent or retard diabetic nephropathy. We investigated whether enalapril also improves the defect in calcium and phosphate reabsorption. We studied 16 children and young adults (age 12-21 years) with IDDM and persistent microalbuminuria before and during 12 weeks of enalapril treatment. Before treatment microalbuminuria, urinary calcium excretion, and fractional tubular phosphorus reabsorption (TPR) were 153+/-53 microg/min, 5.5+/-0.9 mg/kg per day, and 71.4+/-3.6%, respectively. At the end of the 12th week, microalbuminuria had decreased to 20.3+/-7.9 microg/min and calcium excretion to 3.3+/-0.4 mg/kg per day (P<0.01), while the TPR increased to 80.1+/-3.8% (NS). The renal threshold phosphate concentration increased from 1.8+/-0.15 to 2.92+/-0.23 mg/dl (P<0.01). The fasting serum glucose and hemoglobin Alc levels did not change significantly during the study. Systolic and diastolic blood pressures were 120.4+/-2.2 / 79.3+/-1.4 mm Hg and 110.5+/-1.8 / 71.3+/-0.9 mm Hg before and after 12 weeks, respectively. We conclude that enalapril treatment improves not only microalbuminuria but also abnormal calcium and phosphate excretion in microalbuminuric children with IDDM.     

Germline mutations of the BRCA1 and BRCA2 genes in a breast and ovarian cancer patient

Nitric oxide (NO) has been implicated as a modulator of the vascular effects of angiotensin II (ANG II) in the kidney. We used a NO-sensitive microelectrode to study the effect of ANG II on NO release, and to determine the effect of selective inhibition of the ANG II subtype I receptor (AT1) with losartan (LOS) and candesartan (CAN). NO release from isolated and perfused renal resistance arteries was measured with a porphyrin-electroplated, carbon fiber. The vessels were microdissected from isolated perfused rat kidneys and perfused at constant flow and pressure in vitro. The NO-electrode was placed inside the glass collection cannula to measure vessel effluent NO concentration. ANG II stimulated NO release in a dose-dependent fashion: 0.1 nM, 10 nM and 1000 nM ANG II increased NO-oxidation current by 85+/-18 pA (n = 11), 148+/-22 pA (n = 11), and 193+/-29 pA (n = 11), respectively. These currents correspond to changes in effluent NO concentration of 3.4+/-0.5 nM, 6.1+/-1.1 nM, and 8.2+/-1.3 nM, respectively. Neither LOS (1 muM) nor CAN (1 nM) significantly affected basal NO production, but both AT1-receptor blockers markedly blunted NO release in response to ANG II (10 nM): 77+/-6% inhibition with LOS (n = 8) and 63+/-9% with CAN (n = 8). These results are the first to demonstrate that ANG II stimulates NO release in isolated renal resistance arteries, and that ANG II-induced NO release is blunted by simultaneous AT1-receptor blockade. Our findings suggest that endothelium-dependent modulation of ANG II-induced vasoconstriction in renal resistance arteries is mediated, at least in part, by AT1-receptor-dependent NO release.     

Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects

This study was designed to evaluate in healthy volunteers the renal hemodynamic and tubular effects of the orally active angiotensin II receptor antagonist losartan (DuP 753 or MK 954). Losartan or a placebo was administered to 23 subjects maintained on a high-sodium (200 mmol/d) or a low-sodium (50 mmol/d) diet in a randomized, double-blind, crossover study. The two 6-day diet periods were separated by a 5-day washout period. On day 6, the subjects were water loaded, and blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 6 hours after a single 100-mg oral dose of losartan (n = 16) or placebo (n = 7). Losartan induced no significant changes in blood pressure, glomerular filtration rate, or renal blood flow in these water-loaded subjects, whatever the sodium diet. In subjects on a low-salt diet, losartan markedly increased urinary sodium excretion from 115 +/- 9 to 207 +/- 21 mumol/min (P < .05). The fractional excretion of endogenous lithium was unchanged, suggesting no effect of losartan on the early proximal tubule in our experimental conditions. Losartan also increased urine flow rate (from 10.5 +/- 0.4 to 13.1 +/- 0.6 mL/min, P < .05); urinary potassium excretion (from 117 +/- 6.9 to 155 +/- 11 mumol/min); and the excretion of chloride, magnesium, calcium, and phosphate. In subjects on a high-salt diet, similar effects of losartan were observed, but the changes induced by the angiotensin II antagonist did not reach statistical significance. In addition, losartan demonstrated significant uricosuric properties with both sodium diets.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypertension development in Dahl S and R rats on high salt-low potassium diet: calcium, magnesium and sympathetic nervous system

Dietary combination of high salt with low potassium (HSLK) exacerbates hypertension development in Dahl salt-sensitive (S) rats, and produces a mild degree of hypertension in otherwise salt-resistant (R) rats. Increased blood pressure in both strains is associated with increased urinary excretion of calcium and magnesium. The objective of this study was to determine the effect of blood pressure on body balance of these ions in Dahl rats on HSLK diet. Two groups of S and two groups of R weanlings were all placed on HSLK diet (NaCl=8%, K=0.2%) for eight weeks. One group of each strain was subjected to chemical sympathectomy with 6-hydroxydopamine (6-OHDA) to counteract hypertension development. Urinary norepinephrine was used to determine efficacy of 6-OHDA treatment. Systolic blood pressures of conscious animals were measured daily throughout the study. The last three days on the diet were used to determine total dietary intake and urinary as well as fecal excretion of sodium, calcium and magnesium. At the end of the study, extracellular fluid volume, serum aldosterone and parathyroid hormone were analyzed. Final systolic blood pressures in the 4 groups were as follows: S=235+/-9 mmHg (n=9); R=155+/-3 mmHg (n=8); 6-OHDA S=151+/-6 mm Hg (n=8); 6-OHDA R=117+/-6 mm Hg. Chemical sympathectomy decreased blood pressure in both S and R rats. There was no indication of sodium accumulation in S rats. Associated with reduced parathyroid hormone levels the S strain had significantly less positive balance for calcium than the R strain, primarily due to increased urinary excretion. A less positive balance for magnesium was also observed, due mainly to relatively reduced intestinal absorption of the ion. We conclude that the HSLK diet is associated with inappropriate activation of the sympathetic nervous system and increased arterial pressure in both strains. In addition, since divalent cations may influence blood pressure, we suggest that the observed abnormalities in calcium and magnesium metabolism might independently promote hypertension development in the S strain.     

The role of angiotensin AT1 receptors in the diuretic, natriuretic, kaliuretic and blood pressure responses induced by angiotensin II activation of the median preoptic nucleus in conscious rats

We determined the effects of two classical angiotensin II (ANG II) antagonists, [Sar1, Ala8]-ANG II and [Sar1, Thr8]-ANG II, and losartan (a nonpeptide and selective antagonist for the AT1 angiotensin receptors) on diuresis, natriuresis, kaliuresis and arterial blood pressure induced by ANG II administration into the median preoptic nucleus (MnPO) of male Holtzman rats weighing 250-300 g. Urine was collected in rats submitted to a water load (5% body weight) 1 h later. The volume of the drug solutions injected was 0.5 microliters over 10-15 s. Pre-treatment with [Sar1, Ala8]-ANG II (12 rats) and [Sar1, Thr8]-ANG II (9 rats), at the dose of 60 ng reduced (13.7 +/- 1.0 vs 11.0 +/0 1.0 and 10.7 +/0 1.2, respectively), whereas losartan (14 rats) at the dose of 160 ng totally blocked (13.7 +/- 1.0 vs 7.6 +/- 1.5) the urine excretion induced by injection o 12 ng of ANG II (14 rats). [Sar1, Ala8]-ANG II impaired Na+ excretion (193 +/- 16 vs 120 +/- 19), whereas [Sar1, Thr8]-ANG II and losartan block Na+ excretion (193 +/- 16 vs 77 +/- 15 and 100 +/- 12, respectively) induced by ANG II. Similar effects induced by ANG II on K+ excretion were observed with [Sar1, Ala8]-ANG II, [Sar1, Thr8]- ANG II, and losartan pretreatment (133 +/- 18 vs 108 +/- 11, 80 +/- 12, and 82 +/- 15, respectively). The same doses as above of [Sar1, Ala8]-ANG II (8 rats), [Sar1, Thr8]-ANG II (8 rats), and losartan (9 rats) blocked the increase in the arterial blood pressure induced by 12 ng of ANG II (12 rats) (32 +/- 4 vs 4 +/- 2, 3.5 +/- 1, and 2 +/- 1, respectively. The results indicate that the AT1 receptor subtype participates in the increases of diuresis, natriuresis, kaliuresis and arterial blood pressure induced by the administration of ANG II into the MnPO.     

Effects of atrial natriuretic peptide on angiotensin II-induced antinatriuresis in anesthetized dogs

Inhibitory effects of atrial natriuretic peptide (ANP) on angiotensin II (ANG II)-induced renal responses were examined in anesthetized dogs. ANG II (5 ng/kg per min) was infused intravenously and changes in renal hemodynamics and urine formation were compared between the ANP (10 ng/kg per min)-infused kidney and the contralateral vehicle-infused (control) kidney. ANG II reduced absolute and fractional urinary sodium excretion in both the ANP-infused kidney and the control kidney. ANG II also reduced glomerular filtration rate in the control kidney but not in the ANP-infused kidney. The ANG II-induced reduction in urinary sodium excretion in the ANP-infused kidney was smaller than the response in the control kidney, whereas ANP did not affect the reduction in fractional sodium excretion. These results suggest that ANP prevents hypofiltration and thereby attenuates the antinatriuresis induced by ANG II.     

Central interaction between atrial natriuretic peptide and angiotensin II in the control of sodium intake and excretion in female rats

We investigated the effects of estrogen on sodium intake and excretion induced by angiotensin II (ANG II), atrial natriuretic peptide (ANP) or ANG II plus ANP injected into the median nucleus (MnPO). Female Holtzman rats weighing 250-300 g were used. Sodium ingestion and excretion 120 min after the injection of 0.5 microliters of 0.15 M NaCl into the MnPO were 0.3 +/- 0.1 ml (N = 12) and 29 +/- 7 microEq in intact rats, 0.5 +/- 0.2 ml (N = 10) and 27 +/- 6 microEq in ovariectomized rats, and 0.2 +/- 0.08 (N = 11) and 36 +/- 8 microEq in estrogen-treated ovariectomized (50 micrograms/day for 21 days) rats, respectively. ANG II (21 microM) injection in intact, ovariectomized, and estrogen-treated ovariectomized rats increased sodium intake (3.8 +/- 0.4, 1.8 +/- 0.3 and 1.2 +/- 0.2 ml/120 min, respectively) (N = 11) and increased sodium excretion (166 +/- 18, 82 +/- 22 and 86 +/- 12 microEq/120 min, respectively) (N = 11). ANP (65 microM) injection in intact (N = 11), ovariectomized (N = 10) and estrogen-treated ovariectomized (N = 10) rats increased sodium intake (1.4 +/- 0.2, 1.8 +/- 0.3, and 1.7 +/- 0.3 ml/120 min, respectively) and sodium excretion (178 +/- 19, 187 +/- 9, and 232 +/- 29 microEq/120 min, respectively). Concomitant injection of ANG II and ANP into the MnPO of intact (N = 12), ovariectomized (N = 10) and estrogen-treated ovariectomized (N = 10) rats caused smaller effects than those produced by each peptide given alone: 1.3 +/- 0.2, 0.9 +/- 0.2 and 0.3 +/- 0.1 ml/120 min for sodium intake, respectively, and 86 +/- 9, 58 +/- 7, and 22 +/- 4 microEq/120 min for sodium excretion, respectively. Taken together, these results demonstrate that there is an antagonistic interaction of ANP and ANG II on sodium intake and excretion, and that reproductive hormones affect this interaction.     

Differential effects of endotoxaemia on pressor and vasoconstrictor actions of angiotensin II and arginine vasopressin in conscious rats

1. Regional haemodynamic responses to arginine vasopressin (AVP; 0.5, 1.0, 5.0 pmol i.v.) and angiotensin II (AII; 5.0, 10.0, 50.0 pmol i.v.) were measured in conscious Long Evans rats at various times (0, 2, 6 and 24 h) during infusion of lipopolysaccharide (LPS, 150 microg kg(-1) h(-1), i.v., n=9) or saline (n=9). Additional experiments were performed in vasopressin-deficient (Brattleboro) rats infused with LPS (n=7) or saline (n=8) to determine whether or not, in the absence of circulating vasopressin, responses to the exogenous peptides differed from those in Long Evans rats. 2. In the Long Evans rats, during the 24 h infusion of LPS, there was a changing haemodynamic profile with renal vasodilatation from 2 h onwards, additional mesenteric vasodilatation at 6 h, and a modest hypotension (reduction in mean arterial blood pressure (MAP) from 103+/-1 to 98+/-2 mmHg) associated with renal and hindquarters vasodilatation at 24 h. 3. In the Brattleboro rats, the changes in regional haemodynamics during LPS infusion were more profound than in the Long Evans rats. At 2 h and 6 h, there was a marked fall in MAP (from 103+/-3 mmHg; to 65+/-3 mmHg at 2 h, and to 82+/-4 mmHg at 6 h) associated with vasodilatation in all three vascular beds. After 24 h infusion of LPS, the hypotension was less although still significant (from 103+/-3 mmHg; to 93+/-4 mmHg, a change of 10+/-4 mmHg), and there was renal and hindquarters vasodilatation, but mesenteric vasoconstriction. 4. During infusion of LPS, at each time point studied, and in both strains of rat, pressor responses to AII and AVP were reduced, but the changes were less marked at 6 h than at 2 h or 24 h. The reduced pressor responses were not accompanied by generalized reductions in the regional vasoconstrictor responses. Thus, in the Long Evans rats, the renal vasoconstrictor responses to both peptides were enhanced (at 6 h and 24 h for AVP; at all times for AII), whereas the mesenteric vasoconstrictor response to AVP was unchanged at 2 h, enhanced at 6 h and reduced at 24 h. The mesenteric vasoconstrictor response to AII was reduced at 2 h, normal at 6 h and reduced at 24 h. The small hindquarters vasoconstrictor responses to both peptides were reduced at 2 h and 6 h, but normal at 24 h. 5. In the Brattleboro rats, the renal vasoconstrictor responses to both peptides were reduced at 2 h and enhanced at 6 h and 24 h, whereas the mesenteric vasoconstrictor response to AVP was normal at 2 h and 6 h, and reduced at 24 h. The response to AII was reduced at 2 h, normal at 6 h and reduced again at 24 h. There were no reproducible hindquarters vasoconstrictions to AVP in the Brattleboro rats. The small hindquarters vasoconstrictor responses to AII were unchanged at 2 h and enhanced at 6 h and 24 h. 6. In isolated perfused mesenteric vascular beds, removed after 24 h of LPS infusion in vivo, there was an increase in the potency of AVP in both strains (Long Evans, ED50 saline: 56.9+/-15.0 pmol, ED50 LPS: 20.4+/-4.8 pmol, Brattleboro, ED50 saline: 38.6+/-4.2, ED50 LPS: 19.6+/-2.9 pmol), but no change in the responses to AII. 7. These findings indicate that a reduced pressor response to a vasoconstrictor challenge during LPS infusion is not necessarily associated with a reduced regional vasoconstriction. The data obtained in the Brattleboro rats indicate a potentially important role for vasopressin in maintaining haemodynamic status during LPS infusion in Long Evans rats. However, it is unlikely that the responses to exogenous AVP (or AII) are influenced by changes in the background level of endogenous vasopressin, since the patterns of change were similar in Long Evans and Brattleboro rats. 8. The results obtained in isolated perfused mesenteric vascular beds differed from those in vivo, possibly due to the conditions pertaining with in vitro perfusion.     

Renal effects of losartan and amlodipine in hypertensive patients with non-diabetic nephropathy

BACKGROUND: The objective of this study was to examine the effects of angiotensin II receptor blocker losartan versus the calcium channel blocker amlodipine on proteinuria, renal haemodynamics, glomerular sieving and tubular function in hypertensive patients with non-diabetic nephropathy. METHODS: The study design was a prospective, double blind, placebo controlled, randomized crossover trial with amlodipine and losartan. Renal parameters were measured at baseline and at the end of each 4-week active treatment period. Fifteen patients with a diagnosis of non-diabetic renal disease and hypertension were included. RESULTS: Mean arterial blood pressure decreased from 123+/-13 mmHg at baseline to 113+/-10 mmHg (P<0.01) on losartan and to 114+/-10 mmHg on amlodipine (P<0.01). Urinary albumin excretion significantly decreased from 3510+/-2586 mg/24 h at baseline to 2684+/-2051 mg/24 h (P<0.01) on losartan and increased non-significantly to 3748+/-3355 mg/24 h on amlodipine. Filtration fraction significantly decreased from a baseline value of 22.8+/-9.3% to 21.2+/-10.2% (P<0.05) on losartan and increased to 23.6+/-8.9% (ns) on amlodipine. Either drug did not significantly alter glomerular sieving of neutral dextrans. CONCLUSION: Our results demonstrate that losartan, but not amlodipine, decreased albumin excretion in hypertensive patients with non-diabetic nephropathy.     

Fenoldopam improves renal hemodynamics impaired by positive end-expiratory pressure

BACKGROUND: Mechanical ventilation with positive end-expiratory pressure (PEEP) can impair renal hemodynamics. Fenoldopam, a dopamine receptor agonist, has been shown, in animal experiments, to improve renal perfusion. The purpose of the current study was to examine the effects of this agent on altered renal hemodynamics secondary to positive pressure ventilation. METHODS: Twelve patients requiring mechanical ventilation of their lungs and PEEP for the treatment of hypoxemia after multiple trauma or visceral surgery were studied. Hemodynamic variables, renal vascular resistance, urine flow, creatinine, inulin and PAH clearance, and excretion of sodium and potassium (NaE and KE) were measured before and after introduction of a level of PEEP high enough to decrease urine flow rate by 25% or more, and after administration of intravenous fenoldopam. RESULTS: No hemodynamic effect resulted from 0.1 microgram.kg-1.min-1, but 0.2 micrograms.kg-1.min-1 fenoldopam decreased both diastolic and mean arterial blood pressure from 66 +/- 37 (mean +/- SEM) to 57 +/- 21 mmHg, and from 83 +/- 3 to 74 +/- 4 mmHg, respectively. Renal vascular resistance was reduced from 54 +/- 12 to 19 +/- 5 dynes.s.cm-5 at 0.2 micrograms.kg-1.min-1. Fenoldopam produced a dose-related increase in renal blood flow and PAH clearance. With 0.2 micrograms.kg-1.min-1 fenoldopam, urine flow increased from 81 +/- 25 to 116 +/- 29 ml/h, NaE from 28 +/- 7 to 85 +/- 70 microM/min, and KE from 65 +/- 12 to 109 +/- 16 microM/min. CONCLUSIONS: The results of the current study indicate that intravenous fenoldopam at a dose of 0.2 micrograms.kg-1.min-1 improves renal hemodynamics and increases Na and K excretion in patients requiring mechanical ventilation of their lungs and PEEP. These effects are probably caused by an increased kidney perfusion secondary to renal artery vasodilation.     

Losartan attenuates modest but not strong renal vasoconstriction induced by nitric oxide inhibition

Previous studies showed variable success of angiotensin II (ANG II) antagonists to oppose systemic and renal vasoconstriction during long-term nitric oxide synthase (NOS) inhibition. We explored in short-term experiments whether the systemic and renal vasodilatory response to angiotensin II type 1 (AT1)-receptor blockade depends on the extent of NOS blockade. In the first series of experiments, anesthetized rats underwent clearance studies during continuous monitoring of mean arterial pressure (MAP), renal blood flow (RBF, flow probe), and renal vascular resistance (RVR). Compared with control animals, low-dose infusion of the NOS-inhibitor nitro-L-arginine (NLA) increased MAP and RVR, decreased glomerular filtration rate, RBF, and sodium excretion, and had no effect on plasma and kidney ANG II content. High-dose NLA induced stronger effects, did not affect plasma ANG II, and reduced kidney ANG II to approximately 60%. In the second series of experiments, we studied the effect of low- and high-dose NLA on autoregulation of RBF. NLA induced a dose-dependent increase in MAP and decrease in RBF but left autoregulation intact. The AT1-receptor antagonist losartan restored MAP and RBF during low-dose NLA but had no depressor or renal vasodilating effect during high-dose NLA. In summary, short-term NOS blockade causes a dose-dependent pressor and renal vasoconstrictor response, without affecting renal autoregulation, and AT1-receptor blockade restores systemic pressor and renal vasoconstrictive effects of mild NOS inhibition but fails to exert vasorelaxation during strong NOS blockade. Both levels of NOS inhibition did not importantly alter intrarenal ANG II levels. Apparently the functional role of endogenous ANG II as determinant of vascular tone is diminished during strong NOS inhibition.     

Control of renal function and blood pressure by angiotensin II: implications for diabetic glomerular injury

A principal, and unique, renal effector site for angiotensin II (ANG II) is the efferent arteriole, and that has generated considerable interest regarding potential benefits of ANG II inhibition in the treatment and prevention of diabetic renal injury. A hallmark complication of long-standing diabetes is glomerular injury, and there is substantial evidence that lowering glomerular hydrostatic pressure attenuates the injury process. One way that has been accomplished is by lowering arterial pressure, but additional evidence suggests that anti-hypertensive treatment with ANG II inhibition provides even greater protection because of the associated efferent arteriolar dilation. Because of that action, ANG II inhibition in diabetes has been advocated even without diagnosis of hypertension, and the benefits of that treatment have been ascribed largely to the effect of decreased efferent arteriolar resistance to lower glomerular hydrostatic pressure. However, that renal vascular action of ANG II, together with powerful direct effects on tubular sodium reabsorption, underlie its dominant influence on chronic arterial pressure control. Moreover, the influence of ANG II on arterial pressure is not limited to hypertension; it contributes significantly to the maintenance of blood pressure when plasma ANG II levels are normal or even reduced. Thus, while acknowledging that efferent arteriolar dilation is a unique intrarenal benefit associated with ANG II inhibition, this review will focus on how and why inhibition of the multiple intrarenal actions of ANG II also protect the kidneys through systemic mechanisms, even when blood pressure and ANG II are not increased.     

Effects of a nitric oxide synthesis inhibitor on renal sodium handling and diluting capacity in humans

BACKGROUND: Inhibition of nitric oxide (NO) synthesis has antinatriuretic and antidiuretic effects. Limited information is available on the role of NO in tubular sodium transport in the human kidney. METHODS: We studied nine healthy, sodium-replete males with clearance techniques during maximal diuresis. NG-monomethyl-L-arginine (L-NMMA, 3 mg/kg priming dose plus 3 mg/kg/h) was infused for 3 h, to achieve steady-state inhibition of NO synthesis. Data were compared with a time control study. RESULTS: The effects of L-NMMA were quickly established and persisted through the entire infusion period. Mean arterial pressure increased slightly from 85+/-3 to 91+/-3 mmHg (P<0.05). Renal plasma flow decreased substantially, and glomerular filtration rate slightly. Large decreases in absolute sodium excretion, from 79+/-10 to 34+/-5 micromol/min (P<0.01), and fractional sodium excretion, from 0.5+/-0.0 to 0.3+/-0.0% (P<0.01), were associated with significant reductions in fractional lithium excretion (P<0.05) and maximum urine flow (P<0.01). Minimal urine sodium concentration decreased from 5.8+/-0.04 to 3.9+/-0.4 mmol/l (P<0.01) whereas minimal urine osmolality increased (P<0.05). Plasma renin activity, aldosterone and atrial natriuretic peptide levels did not change, whereas urinary excretions of guanosine 3'5'-cyclic monophosphate and of nitrite plus nitrate decreased slightly. CONCLUSIONS: Inhibition of endogenous NO synthesis in humans to an extent that raises blood pressure only mildly causes antinatriuresis, that can be attributed to increases in sodium reabsorption both at proximal and distal nephron sites. In addition, renal diluting capacity decreases. The effects in the diluting segment have not been reported before, and may be due to medullary vasoconstriction, similar to that described for angiotensin II.     

Estrogen effects on the renal handling of calcium in the ovariectomized perfused rat

Estrogen deficiency is a major cause of bone loss in women but the mechanism is unclear. The ovariectomized (OVX) rat is a well recognized model for post-menopausal osteoporosis. In this study we have examined the effects of OVX and estrogen replacement in the OVX rat on the renal handling of calcium in response to alterations in the calcium load in the perfused rat. The interaction of estrogen administration and parathyroid hormone (PTH) was also examined in the OVX, parathyroidectomized (PTX) rat. Calcium or EDTA was infused into sham or OVX rats to obtain a range of filtered calcium loads. The excretion of calcium, was compared to the filtered load for the data from both perfusions indicating a lower calcium (P = 0.006) and sodium (P = 0.009) excretion in the OVX rat. A similar result was seen in the OVX rat replaced with 20 micrograms of estrogen valerate 48 and 24 hours prior to perfusion with calcium excretion being greater with estrogen administration (P = 0.005) compared to vehicle alone. This was not observed in the parathyroidectomized rat. Correlations between sodium and water reabsorption and calcium and sodium reabsorption during perfusion indicate that the results of OVX were due primarily to proximal tubule effects. Prior to the perfusion experiment PTH (sham vs. OVX pmol/liter, mean +/- SD; 20 +/- 6 vs. 18 +/- 4) and calcitriol (128 +/- 85 vs. 97 +/- 74) were similar in both groups, indicating that the results were not dependent on calcitropic hormone effects. It is concluded that, in the perfused rat, OVX results in decreased excretion of calcium and sodium as a result of estrogen effects on the renal proximal tubule, an effect dependent on PTH. This effect is opposite to that found in postmenopausal women, perhaps due to the high filtered load of calcium used in the experimental design and species differences in the relative importance of proximal versus distal calcium handling.     

Effects of antihypertensive treatment on vasopressin secretion and on its osmoregulation in moderate hypertension

BACKGROUND: Changes in plasma osmolality and arterial pressure can affect the secretion of vasopressin (AVP). OBJECTIVE: To investigate the effect of a drug-induced lowering of the arterial pressure on the plasma concentration of AVP and on its osmoregulation in moderately severe uncomplicated hypertensives. DESIGN AND METHODS: A group of 33 moderate uncomplicated and untreated essential hypertensives of both sexes (mean age 48 +/- 1 years, average arterial pressure 171 +/- 3/108 +/- 2 mmHg) was studied. We measured AVP and other plasma and urine variables in 21 of them before and after administration of a hypertonic NaCl solution (100 mmol NaCl in 50 ml). Antihypertensive treatment with a single drug or, if necessary, with a combination of drugs was initiated for eight of these subjects and hypertonic saline administration was repeated after 1 month of treatment. The hypertonic stimulus was administered to the other 12 subjects after acute lowering of the arterial pressure by continuous intravenous infusion either of 0.3 mg clonidine in 100 ml (n = 6) or of 50 mg sodium nitroprusside in 250 ml (n = 6). RESULTS: Administration of hypertonic saline to untreated hypertensives increased their AVP level from 1.6 +/- 0.28 to 5.4 +/- 0.7 pg/ml (n = 21, P < 0.01). Their mean arterial pressure was lowered after pharmacological treatment for 1 month (n = 8) from 125 +/- 2 to 101 +/- 2 mmHg; their baseline AVP level remained unchanged (1.2 +/- 0.21 versus 0.9 +/- 0.25 pg/ml); after hypertonic saline had been administered to hypertensives with lowered arterial pressures, their AVP level increased to 6.0 +/- 1.03 pg/ml (P < 0.01). The AVP level in subjects whose MAP had been lowered acutely by administration of clonidine (n = 6) or of sodium nitroprusside (n = 6; on the average, from 132 +/- 3 to 110 +/- 4 mmHg) increased concurrently from 1.6 +/- 0.63 to 3.4 +/- 0.7 pg/ml (P < 0.05); after administration of the hypertonic saline the AVP level increased to 10.8 +/- 2.22 pg/ml (P < 0.01). This stimulated value was significantly (P < 0.01) higher than that observed after hypertonic saline had been administered to untreated hypertensives (5.4 +/- 0.7 pg/ml). CONCLUSIONS: Acute lowering of the arterial pressure in moderate essential hypertension appears to facilitate the secretion and osmoregulation of AVP. On the other hand, during prolonged antihypertensive treatment, baroreflex regulation of the secretion of AVP appears to be set at a lower operating point, thus exerting the same influence on the release of AVP as it did before antihypertensive treatment.     

Acute glucosuria after continuous glucocorticoid loading in the rat in vivo

We investigated the effects of the continuous infusion of various steroids in rats on renal tubular reabsorption of glucose in vivo to elucidate the pathogenesis of steroid-induced glucosuria. Urinary glucose excretion increased 60 min after administration of dexamethasone (2.38 mM). By 120 min, urinary excretion of glucose was three times higher in the dexamethasone group than in the control group (24.1 +/- 4.6 versus 72.4 +/- 16.7 micromol); the plasma level of glucose did not increase. Dexamethasone had no effect on the resorption of 1,5-anhydro-D-glucitol, which is a glucose-resembling polyol that is actively absorbed by the renal tubules as glucose. Neither estradiol nor progesterone increased urinary excretion of glucose. These findings suggest that continuous administration of a high-dose glucocorticoid selectively influences the glucose reabsorption system in the kidney.     

Single dose fetal betamethasone administration stabilizes postnatal glomerular filtration rate and alters endocrine function in premature lambs

These studies determined the effects of fetal treatment with betamethasone alone, or in combination with thyroid hormone (thyroxine; T4), on postnatal renal and endocrine adaptations in preterm newborn lambs. Ovine fetuses (126 d of gestation; term = 150 d) received single, ultrasound-guided intramuscular injections of saline, 0.5 mg/kg betamethasone (Celestone Soluspan, or 0.5 mg/kg betamethasone plus 60 micrograms/kg T4. After 48 h, lambs were delivered, treated with surfactant (Survanta, 100 mg/kg), and ventilated for 3 h. Due to maintained urine flow in the betamethasone-treated animals and a significant decrease in the saline group, betamethasone versus saline urine flow values (0.11 +/- 0.03 versus 0.03 +/- 0.004 mL.min-1.kg-1) were significantly elevated by the end of studies. GFR (1.5 +/- 0.3 versus 0.8 +/- 0.2 mL.min-1.kg-1) and mean blood pressure (61 +/- 4 versus 42 +/- 3 mm Hg) values also were higher in the betamethasone-treated animals. Although renal blood flow, renal plasma flow, and fractional sodium excretion rates did not differ, betamethasone versus saline values for the filtration fraction (11.9 +/- 1.5 versus 7.4 +/- 1.5%) and total sodium reabsorption (196 +/- 38 versus 81 +/- 16 microEq.min-1.kg-1) were increased. Betamethasone versus saline treatment also was associated with significant reductions in plasma angiotensin II (125 +/- 23 versus 550 +/- 140 pg/mL) and AVP (116 +/- 19 versus 230 +/- 77 pg/mL) levels. Overall, the effects of combined betamethasone + T4 treatment were similar to the effects of betamethasone alone. Conclusions: 1) fetal betamethasone injection 48 h before delivery stabilizes GFR and significantly alters endocrine function in preterm newborn lambs, and 2) the addition of T4 does not augment betamethasone-induced renal and endocrine responses.     

Role of the renin-angiotensin-aldosterone system in the progression of renal disease: a critical review

Interruption of the renin-angiotensin-aldosterone system (RAAS) by converting enzyme inhibition or angiotensin II (ANG II) receptor antagonism dramatically reduces injury in the remnant kidney model. Furthermore, converting enzyme inhibition reduces proteinuria and slows the decline in renal function in clinical disease. Hemodynamic actions of ANG II in the kidney in conjunction with a more poorly defined effect of the RAAS on systemic hypertension have been posited as the major mechanisms for maintenance of elevated glomerular pressure. Reductions in glomerular pressure have been attributed, at least in part, to removal of intrarenal effects of ANG II. Growth and fibrotic actions of ANG II may also contribute to progressive renal injury and relief from them reduce injury. The participation of circulating aldosterone in the remnant kidney model has been recently raised. Hyperaldosteronism and adrenal hypertrophy attend the hypertension, proteinuria, and glomerulosclerosis of this model. Although the hemodynamic actions of aldosterone probably account for some of the adverse effects it has in this model, other direct cellular actions may participate in its renal, as well as cardiac and fibrotic consequences. Thus, the RAAS, working through both ANG II and aldosterone, contributes to chronic progressive renal injury.     

Long-term nephrotoxicity of cisplatin, ifosfamide, and methotrexate in osteosarcoma

The acute renal effects of chemotherapy are known, but long-term nephrotoxicity has rarely been investigated. The aim of the present study was to assess long-term renal function in children and adolescents who received at-risk chemotherapy, including cisplatin, ifosfamide, and methotrexate, to treat an osteosarcoma. Renal function tests [creatinine clearance, microalbuminuria, and renal excretion of sodium, potassium, chloride, calcium, magnesium (Mg), phosphorus (P), and uric acid] were prospectively performed 5.4+/-2.2 (+/-SD) years after chemotherapy (total cumulative dose: methotrexate 41+/-31 g/m2, ifosfamide 39+/-14 g/m2, cisplatin 674+/-188 mg/m2) in 18 children and adolescents. The results were compared with 13 normal volunteers matched for age and sex. Creatinine clearance, which was greater than 80 ml/min per 1.73 m2 in all patients, correlated with the total dose of ifosfamide (r=0.55, P<0.05) and cisplatin (r=0.48, P<0.05). Microalbuminuria was noted in 4 patients. Hypomagnesemia was present in 4 and hypercalciuria in 3 patients; renal excretion of P, Mg, and uric acid was higher in patients than in controls. Glomerular function was not significantly altered and only mild tubular dysfunction was present. Since renal excretion of P and Mg were increased in patients compared with normal volunteers and hypercalciuria was occasionally seen, divalent ion disorders are the most-likely potential complications.     

The influence of hyperinsulinaemia on calcium-phosphate metabolism in renal failure

BACKGROUND: Patients with renal failure are characterized by impaired insulin-mediated glucose uptake. Insulin plays a major role in the maintenance of phosphate homeostasis but it remains to be determined whether in uraemia insulin-dependent renal and extrarenal phosphate disposal is also affected. METHODS: The effect of hyperinsulinaemia on serum concentrations of phosphate, ionized calcium and intact PTH as well as renal excretion of calcium and phosphate was studied under euglycaemic conditions (glucose clamp technique) in patients with advanced renal failure and in healthy subjects. Fifteen patients with renal failure (mean serum creatinine 917 micromol/l) and 12 control subjects were included. All subjects underwent a 3-h euglycaemic clamp with constant infusion of insulin (50 mU/m2/min) following a priming bolus. The urine was collected for 3 h before and throughout the clamp. RESULTS: The tissue insulin sensitivity (M/I) was lower in patients with renal failure than in control subjects (5.3+/-2.4 vs 6.7+/-1.8mg/kg/min per mU/ml, P= 0.001) but the phosphate lowering action of insulin was larger in patients with renal failure than in control subjects. Urinary calcium excretion increased (P < 0.05) and phosphate excretion did not change during the clamp in both groups. Despite a decrease of serum ionized calcium in the group of patients with renal failure and no change in the control group, plasma PTH fell significantly in both groups but this effect was still significant after 180 min only in the renal failure group. A significant correlation was observed between changes in serum phosphate and PTH induced by hyperinsulinaemia (r = 0.48, P < 0.01 ) CONCLUSIONS: Phosphate-lowering effect of insulin is well preserved in severe renal failure despite the resistance to insulin-stimulated glucose uptake. The decrease of serum PTH observed during hyperinsulinaemia appears to be independent of serum ionized calcium.