Prazosin blunts the antinatriuretic effect of circulating angiotensin II in man.

OBJECTIVE: The present study examines the role of alpha 1-adrenoceptors in determining the renal haemodynamic and sodium excretory responses to a physiological dose of angiotensin II in man. DESIGN: The effects of a low-dose infusion of angiotensin II (1 ng/kg per min) and a non-depressor dose of prazosin (0.25 mg), alone and in combination, on urinary sodium excretion (UNaV), effective renal plasma flow (ERPF), glomerular filtration rate (GFR) and segmental tubular function were studied in eight normal male subjects. METHODS: Subjects were studied undergoing maximal water diuresis. Clearances of inulin and para-aminohippurate were employed to estimate GFR and ERPF, respectively. Segmental tubular handling was assessed by both lithium clearance (CLi) and solute-free water methods. RESULTS: Angiotensin II decreased UNaV without altering ERPF and GFR. Angiotensin II caused a significant fall in fractional CLi, which may indicate a proximal tubular effect of angiotensin II. Angiotensin II alone also increased fractional reabsorption of sodium delivered to the distal nephron, as evaluated by both the CLi method and by estimation of solute-free water clearance. When angiotensin II was given in combination with prazosin, which on its own had no apparent effects on any renal parameters, the antinatriuretic and tubular effects of angiotensin II were significantly blunted. CONCLUSIONS: These findings suggest that low doses of circulating angiotensin II are able to modulate UNaV by increasing sodium reabsorption in the proximal and, to some extent, the distal nephron segment in man. The study also showed that a non-depressor dose of prazosin blunted the renal effects of angiotensin II, thereby providing tentative evidence of a renal interaction between alpha-adrenoceptors and angiotensin II in man.     

Pressure-dependent distal tubular action of atrial natriuretic peptide in healthy humans

OBJECTIVE: To study the influence of blood pressure reduction with sodium nitroprusside on the renal glomerular and tubular actions of atrial natriuretic peptide. DESIGN: Forty-nine healthy subjects were examined in four different groups receiving placebo, sodium nitroprusside alone, atrial natriuretic peptide alone (10 ng/kg per min), or sodium nitroprusside and atrial natriuretic peptide in combination. The infusion rate of sodium nitroprusside was gradually increased until a 10 mmHg decrease in diastolic blood pressure was obtained. METHODS: Lithium clearance was used to evaluate segmental tubular reabsorption. RESULTS: In the placebo group neither renal nor hormonal parameters were changed. Except for a fall in urinary flow, sodium nitroprusside alone had no effect on renal parameters. Urinary excretion of cyclic GMP (cGMP) was slightly increased, whereas the plasma cGMP level was not changed in response to sodium nitroprusside. The plasma aldosterone level was elevated during sodium nitroprusside infusion, although neither the plasma angiotensin II level nor the plasma atrial natriuretic peptide level were changed. Atrial natriuretic peptide alone caused an increase in filtration fraction and a decrease in renal plasma flow. Urinary sodium excretion, fractional sodium excretion, and urinary flow were increased, and distal fractional tubular sodium absorption decreased, whereas lithium clearance and proximal fractional tubular re-absorption were not changed by atrial natriuretic peptide. Atrial natriuretic peptide alone caused a decrease in plasma aldosterone and an increase in plasma and urinary cGMP levels. During blood pressure reduction with sodium nitroprusside, atrial natriuretic peptide caused no changes in the renal parameters except for an increase in filtration fraction. Thus, the increase in urinary sodium excretion (-8 versus +37 micromol/min) and the decrease in distal fractional sodium excretion (0.0 versus -2.4%) caused by atrial natriuretic peptide were attenuated. The atrial natriuretic peptide-induced changes in proximal fractional tubular reabsorption (-0.5 versus +0.6%) and cGMP were not changed by blood pressure reduction. CONCLUSIONS: Blood pressure reduction causes an attenuation of the natriuretic action of atrial natriuretic peptide in normotensive humans that is at least partly caused by attenuation of the distal tubular action of atrial natriuretic peptide. The results support the hypothesis that the action of atrial natriuretic peptide on distal tubular sodium reabsorption is pressure-dependent in humans.     

Atrial natriuretic factor modulates proximal glomerulotubular balance in anesthetized rats

The extent to which the natriuretic effect of a prolonged low dose infusion of atrial natriuretic factor (30 ng/kg/min) is dependent on interference with the prevailing intrarenal actions of angiotensin II was examined before and after blockade of angiotensin production with the converting enzyme inhibitor enalaprilat (5 mg/kg). Lithium clearance was used to assess proximal tubular sodium and water reabsorption. Atrial natriuretic factor and enalaprilat caused similar increases in sodium excretion (10-fold and sevenfold, respectively) and glomerular filtration rate (each 34%) and similar decreases in fractional proximal reabsorption of sodium (17% and 13%, respectively) and blood pressure. Each also caused a major disruption in the effectiveness of proximal glomerulotubular balance (30% and 50% of perfect balance). Infusion of atrial natriuretic factor during converting enzyme inhibition increased glomerular filtration rate further by 23%, reaching 63% above control without change in renal blood flow but with a rise in filtration fraction to 0.48. Sodium excretion increased further but fractional proximal sodium reabsorption remained constant and proximal glomerulotubular balance appeared to improve. Atrial natriuretic factor therefore possesses a glomerular action that persists during converting enzyme inhibition and is indeed additive to the removal of angiotensin II when the proximal effect of atrial natriuretic factor is no longer apparent. It is concluded that failure of atrial natriuretic factor to further suppress fractional proximal sodium reabsorption during converting enzyme inhibition is caused by either prior removal of the stimulatory action of angiotensin II on proximal tubular transport or extreme changes in peritubular physical factors consequent on the high filtration fraction.     

Effects of insulin and lipid emulsion on renal haemodynamics and renal sodium handling in IDDM patients

Summary To evaluate the role of insulin and hypertriglyceridaemia in the regulation of renal haemodynamics and sodium handling in insulin-dependent diabetes mellitus (IDDM), 11 IDDM patients without microalbuminuria and 13 weight-, age-, protein intake- and sex-matched healthy control subjects were studied. Clearances of inulin (C_in), para-amino-hippuric acid (C_PAH), sodium (C_Na), and lithium (C_Li) were measured in four 60-min clearance periods (periods I, II, III and IV) during isoinsulinaemia with lipid emulsion infusion (study 1), a hyperinsulinaemic isoglycaemic clamp with Intralipid infusion (study 2), and during time-controlled isoinsulinaemia (study 3). We found that C_in, C_PAH and filtration fraction were comparable in IDDM and control subjects, whereas C_Na was decreased in diabetic subjects (2.01±1.11 vs 3.03±1.32 ml/min; p<0.05) due to elevations of proximal tubular fractional and absolute reabsorptions of sodium (p<0.05). Insulin infusion did not affect C_in, increased C_PAH (p<0.05) and, consequently, lowered the filtration fraction (p<0.01) in both groups. While acute hyperinsulinaemia resulted in increases in distal tubular fractional and absolute reabsorptions of sodium (p<0.01) contributing to a fall in C_Na (p<0.01) in control subjects, in diabetic subjects the sodium-retaining effect of insulin was not significant. The lipid emulsion did not alter any of the estimated parameters. We conclude that IDDM without microalbuminuria is associated with a tendency to sodium retention which is not aggravated by insulin when compared to control subjects. Acutely induced hypertriglyceridaemia does not alter renal haemodynamics or renal sodium handling.Abbreviations IDDM Insulin-dependent diabetes mellitus - GFR glomerular filtration rate - RPF renal plasma flow - C_in clearance of inulin - C_PAH clearance of para-amino-hippuric acid - C_Na clearance of sodium - C_Li clearance of lithium - APR_Na absolute proximal tubular reabsorption of sodium - FPR_Na fractional proximal tubular reabsorption of sodium - ADR_Na absolute distal tubular reabsorption of sodium - FDR_Na fractional distal tubular reabsorption of sodium - FIRI free plasma immunoreactive insulin - TG serum triglycerides - NEFA serum non-esterified fatty acids - MCR metabolic clearance rate of glucose - FF filtration fraction - ANOVA analysis of variance     

Renal sites of action of physiological increases in plasma atrial natriuretic factor concentration in essential hypertension.

OBJECTIVES: To investigate the renal, haemodynamic and neurohormonal responses to low-dose infusions of atrial natriuretic factor (ANF) in hypertensive humans. DESIGN: Ten patients with mild-to-moderate essential hypertension received incremental infusions of 3 and 6 ng/kg per min ANF or vehicle alone whilst on a constant dietary sodium intake. A 90-min basal clearance period was followed by two 2-h infusion periods, with urine collection in the last 90 min of each period. In each of the three clearance periods, glomerular filtration rate (GFR), renal tubular function, and the activity of the renin-angiotensin and sympathetic nervous systems were determined. METHODS: The renal sites of ANF action were established by simultaneous measurements of 51Cr-ethylenediaminetetraacetate lithium and sodium clearances. Plasma concentrations of neurohormones were measured by radioimmunoassays. RESULTS: Plasma ANF concentrations increased by 1.6- and 2.5-fold during the lower and higher ANF infusion rates, respectively. Plasma cyclic guanosine monophosphate concentrations increased in parallel. ANF caused no changes in supine systolic and diastolic blood pressure or in heart rate. In contrast, haematocrit values increased progressively across the study. The renal effects of ANF administration were characterized by an unaltered GFR and significant increases in the renal clearances of lithium (a marker of end-proximal fluid delivery) and sodium when compared with vehicle infusions, whereas urine flow did not change. Estimated values of fractional proximal and distal tubular sodium reabsorption decreased significantly. Plasma concentration of active renin decreased during ANF infusions, but no significant changes in plasma levels of renin substrate, angiotensin I, angiotensin II or aldosterone were observed. A subtle activation of the sympathetic nervous system was indicated by a moderate increase in plasma noradrenaline during the ANF infusions. CONCLUSIONS: These results indicate that even small increases in plasma ANF, as can be found during physiological conditions, induce natriuresis in patients with essential hypertension by enhancing fluid delivery from the proximal tubules, in addition to impairing distal fractional sodium reabsorption. With minor exceptions, the ANF infusions caused qualitatively and quantitatively similar renal, haemodynamic and endocrine effects in the hypertensive patients as in a previously studied group of normotensive subjects.     

Renal tubular reabsorption of calcium and sodium in primary hyperparathyroidism

Nine patients with primary hyperparathyroidism were studied to investigate the renal tubular reabsorption of calcium and sodium. Fasting serum and urine samples were analysed, and the glomerular filtration rate and the renal plasma clearance of lithium were determined simultaneously. Comparison was made with 9 age- and sex-matched normocalcemic controls. In the proximal tubule, there was a significantly higher absolute reabsorption of calcium in patients than in controls, whereas the fractional reabsorption rate of calcium did not differ between the two groups. In the distal tubule, the absolute calcium reabsorption rate was significantly higher in the patients, whereas the fractional reabsorption rate of calcium was significantly lower than in controls. In the patient group there was a significantly positive linear correlation between the increased tubular capacity for calcium reabsorption and the absolute proximal calcium reabsorption rate, but not between the increased capacity and the absolute distal calcium reabsorption rate. No significant differences were found in the renal tubular handling of sodium between patients and controls. Our results suggest that the increased capacity for tubular calcium reabsorption in primary hyperparathyroidism mainly is localized in the proximal tubule, and that the renal tubular handling of calcium and sodium in this disease differs from that in familial hypocalciuric hypercalcemia.     

Contribution of endogenous oxytocin to sodium excretion in anaesthetized, surgically operated rats

In order to determine the possible role of endogenous oxytocin in controlling electrolyte and water excretion in animals whose renal function is being assessed by invasive techniques, rats were anaesthetized and subjected to micropuncture surgery. Clearance measurements were made in the presence and absence of the potent oxytocin receptor antagonist d(CH(2))(5)[Tyr(Me)(2), Thr(4), Orn(8), Tyr(NH(2))(9)]-vasotocin. In rats infused with vehicle alone, glomerular filtration rate (GFR), sodium excretion and urine flow rate remained stable. In contrast, in antagonist-treated rats GFR was modestly reduced (P<0.05), and there were large falls in both absolute and fractional sodium excretion (P<0.01 in each case) and absolute and fractional water excretion (P<0.05 in each case), indicating effects on both filtered load and fractional tubular reabsorption. The antinatriuresis was not accompanied by a change in the fractional excretion of lithium, suggesting that proximal tubular function is unaffected by oxytocin receptor antagonism; nor was it accompanied by a change in the fractional excretion of potassium, suggesting that the tubular effect is located beyond the potassium secretory site, i.e. downstream of the cortical collecting tubule. We conclude that circulating plasma concentrations of oxytocin during anaesthesia and moderate surgery are sufficient to enhance GFR and reduce fractional tubular sodium and water reabsorption. This has important implications for the interpretation of invasive studies such as micropuncture.     

Abnormal renal responses to calcium entry blockade in normotensive offspring of hypertensive parents

In nine young normotensive subjects with no family history of hypertension and nine age-matched normotensive subjects with one parent with essential hypertension, effective renal plasma flow (p-aminohippuric acid clearance), glomerular filtration rate (inulin clearance), and excretion of sodium and exogenously administered lithium were measured for 90 minutes before and after administration of a single 20-mg oral dose of the calcium entry blocker nifedipine. Segmental tubular handling of fluid and sodium was estimated using lithium clearance as a marker of proximal tubular reabsorption. Nifedipine did not cause any change in subjects with no family history of hypertension, but in those with one hypertensive parent there was a marked increase in effective renal plasma flow (from 644 +/- 39 to 847 +/- 42 [SEM] ml/min x 1.73 m2; p less than 0.001) and a decrease in filtration fraction (from 17.6 +/- 1.0 to 12.6 +/- 0.4%; p less than 0.001), while the glomerular filtration rate was unchanged, thus suggesting a prevailing efferent vasodilation. Sodium excretion rate (p less than 0.02) and fractional sodium excretion (p less than 0.025) increased slightly but significantly in subjects with one hypertensive parent, but not in normotensive subjects with no family history of hypertension. Lithium clearance also rose (from 29.0 +/- 2.0 to 32.8 +/- 1.9 ml/min, p less than 0.001), and the derived value of fractional proximal reabsorption diminished (from 75.8 +/- 1.0 to 71.3 +/- 1.2%, p less than 0.001). Estimated distal delivery of sodium and absolute distal sodium reabsorption both increased significantly (p less than 0.005), while fractional distal sodium reabsorption was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Early alteration in glomerular reserve in humans at genetic risk of essential hypertension: mechanisms and consequences

Essential hypertension has a familial predisposition, but the phenotype of elevated blood pressure has delayed penetrance. Because the kidney is a crucial determinant of blood pressure homeostasis, we studied early glomerular alterations in still-normotensive young subjects at genetic risk of hypertension. Thirty-nine normotensive adults (mean age 29 to 31 years), stratified by genetic risk (parental family history [FH]) of hypertension (26 with positive FH [FH+], 13 with negative FH [FH-]), underwent intravenous infusion of mixed amino acids. Before and during amino acid administration, we measured glomerular filtration rate (GFR), putative second messengers of amino acids (nitric oxide [NO.] metabolites and cGMP), serum insulin and amino acid concentrations, and the FE(Li)+ as an index of renal proximal tubular reabsorption. The FH+ group had a blunted GFR rise in response to amino acids (2.43+/-8.16% versus 31.0+/-13.4% rise, P:=0.0126). The amino acid-induced change in GFR correlated (r=0.786, P:<0.01) with the change in urinary NO. metabolite excretion; a diminished rise in urinary NO. metabolite excretion in the FH+ group (P:=0.0105) suggested a biochemical mechanism for the different GFR responses between FH groups: a relative inability to convert arginine to NO. The FH+ group had a far lower initial cGMP excretion at baseline (261+/-21.1 versus 579+/-84.9 nmol. h(-1)/1.73 m(2), P:=0.001), although cGMP did not change during the amino acid infusion (P:=0.703). FH status, baseline GFR, and baseline serum insulin jointly predicted GFR response to amino acids (P:=0.0013), accounting for approximately 45% of the variance in GFR response. Decline in FE(Li)+, an inverse index of proximal tubular reabsorption, paralleled increase in GFR (r=-0.506, P:=0.01), suggesting differences in proximal tubular reabsorption during amino acids between the FH groups. GFR response to amino acid infusion was blunted in the FH+ group despite significantly higher serum concentrations of 6 amino acids (arginine, isoleucine, leucine, methionine, phenylalanine, and valine) in the FH+ group, suggesting a novel form of insulin resistance (to the amino acid-translocating action of insulin) in FH+ subjects. We conclude that blunted glomerular filtration reserve in response to amino acids is an early-penetrance phenotype seen even in still-normotensive subjects at genetic risk of hypertension and is linked to impaired formation of NO. in the kidney. Corresponding changes in GFR and fractional excretion of Li(+) suggest that altered proximal tubular reabsorption after amino acids is an early pathophysiologic mechanism. Resistance to the amino acid-translocating actions of insulin may play a role in the biological response to amino acids in this setting. This glomerular reserve phenotype may be useful in genetic studies of renal traits preceding or predisposing to hypertension.     

Type I insulin-dependent diabetic patients show an impaired renal hemodynamic response to protein intake

Human kidney responds to a meat meal with an increase in glomerular filtration rate (GFR), but the mechanisms regulating kidney hemodynamics following protein intake are poorly understood in Type I insulin-dependent diabetes. In the present study we investigated GFR response to protein intake (600 gr/1.73 m² meat meal) in nine normal subjects and 21 Type I insulin-dependent diabetic patients with normal albumin excretion rates as well as proximal tubular sodium reabsorption rates and distal sodium delivery (PRNa and DDNa). The same study was reperformed in normal subjects and diabetic patients, with less than a 5 year diabetes duration, following one week of indomethacin treatment. Normal subjects showed a 38% increase in GFR following protein intake, whereas diabetic patients showed a significantly lower response (18%, p < 0.01). the response of GFR to protein challenge was negatively related to diabetes duration but not to baseline glomerular filtration rate. Indomethacin treatment completely prevented the protein induced GFR increase in normal subjects but not in diabetic patients. Sodium reabsorption rate was increased following protein challenge both at the proximal and distal tubular level, as was net natriuresis. These findings demonstrate that 1) Type I diabetic subjects show an impaired GFR response to protein intake that seems to be related to diabetes duration rather than baseline glomerular hyperfiltration; 2) the inhibition of kidney hemodynamic response to proteinby indomethacin in normal, but not diabetic, patients suggests that a prostaglandin mediated GFR increase following protein challenge occurs in normal, but not in diabetic patients; 3) the macula densa feedback system does not seem to play a major role in protein effect of kidney function, as an increased sodium reabsorption at the proximal tubular level was assoclated with concomitant distal sodium delivery.     

Effects of a dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100,240, on endocrine and renal functions in healthy volunteers

OBJECTIVE: To investigate the endocrine and renal effects of the dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100,240. DESIGN: A randomized, placebo-controlled, crossover study was performed in 12 healthy volunteers. METHODS: MDL 100,240 was administered intravenously over 20 min at single doses of 6.25 and 25 mg in subjects with a sodium intake of 280 (n = 6) or 80 (n = 6) mmol/day. Measurements were taken of supine and standing blood pressure, plasma angiotensin converting enzyme activity, angiotensin II, atrial natriuretic peptide, urinary atrial natriuretic peptide and cyclic GMP excretion, effective renal plasma flow and the glomerular filtration rate as p-aminohippurate and inulin clearances, electrolytes and segmental tubular function by endogenous lithium clearance. RESULTS: Supine systolic blood pressure was consistently decreased by MDL 100,240, particularly after the high dose and during the low-salt intake. Diastolic blood pressure and heart rate did not change. Plasma angiotensin converting enzyme activity decreased rapidly and dose-dependently. In both the high- and the low-salt treatment groups, plasma angiotensin II levels fell and renin activity rose accordingly, while plasma atrial natriuretic peptide levels remained unchanged. In contrast, urinary atrial natriuretic peptide excretion increased dose-dependently under both diets, as did urinary cyclic GMP excretion. Effective renal plasma flow and the glomerular filtration rate did not change. The urinary flow rate increased markedly during the first 2 h following administration of either dose of MDL 100,240 (P < 0.001) and, similarly, sodium excretion tended to increase from 0 to 4 h after the dose (P = 0.07). Potassium excretion remained stable. Proximal and distal fractional sodium reabsorption were not significantly altered by the treatment. Uric acid excretion was increased. The safety and clinical tolerance of MDL 100,240 were good. CONCLUSIONS: The increased fall in blood pressure in normal volunteers together with the preservation of renal hemodynamics and the increased urinary volume, atrial natriuretic peptide and cyclic GMP excretion distinguish MDL 100,240 as a double-enzyme inhibitor from inhibitors of the angiotensin converting enzyme alone. The differences appear to be due, at least in part, to increased renal exposure to atrial natriuretic peptide following neutral endopeptidase blockade.     

Renal sodium handling and haemodynamics are equally affected by hyperinsulinaemia in salt-sensitive and salt-resistant hypertensives

OBJECTIVE : It is well-known that insulin induces renal sodium retention. It is not yet known whether insulin's renal effects are involved in the development of salt-sensitive hypertension. We assessed the effects of insulin on renal sodium handling and haemodynamics in 10 salt-sensitive (SS) and 10 salt-resistant (SR) essential hypertensives. DESIGN : After a baseline period of 90 min, all subjects underwent a euglycaemic clamp with sequential infusion of a physiological and supraphysiological dose of insulin (50 and 150 mU/kg per h) during 90 min periods each. Time-control studies were performed in the same subjects. Clearances of 131I-hippuran, 125I-iothalamate, sodium and lithium were used to evaluate renal plasma flow (RPF), CNa/glomerular filtration rate (GFR) and fractional proximal and distal sodium reabsorption. RESULTS : Plasma insulin levels and insulin-mediated glucose uptake did not differ between both groups. RPF and GFR showed similar increases during both insulin infusions in both groups. During physiological hyperinsulinaemia, fractional sodium excretion decreased 38% (P = 0.009) in the SS group and 36% (P = 0.002) in the SR group. During supraphysiological hyperinsulinaemia, fractional sodium excretion decreased 49% (P = 0.01) in the SS group and 19% (P = 0.2) in the SR group, not statistically different between both groups. Fractional proximal sodium reabsorption was unaffected and fractional distal sodium reabsorption increased to a similar magnitude in both groups. CONCLUSION : The comparable renal effects of acute exogenous hyperinsulinaemia in SS and SR hypertensives do not support a role for insulin in the development of salt-sensitive hypertension. However, the results do not yet exclude a role for chronic hyperinsulinaemia.     

Renal responses to angiotensin II infusion in early type 1 (insulin-dependent) diabetes.

The renal response to infusion of sub-pressor doses of angiotension II was examined in nine euglycaemic Type 1 (insulin-dependent) diabetic patients with diabetes of short duration and nine non-diabetic control subjects. Plasma concentrations of angiotensin II and of free insulin were similar in both groups at baseline and during angiotensin II infusion. Glomerular filtration rate (Inutest clearance) fell to a similar extent during angiotensin II infusion in both groups (diabetic 116(SE 5) to 102(5) ml min-1 1.73-m-2; control 113(6) to 100(5) ml min-1 1.73-m-2). There was a large dose-dependent fall in effective renal plasma flow (p-aminohippurate clearance) during angiotensin II infusion which was of similar magnitude in both groups (diabetic; 694(46) to 521(21) ml min-1 1.73-m-2; control 665(41) to 498(30) ml min-1 1.73-m-2). The absolute and the fractional rates of urinary excretion of sodium were both lower in the diabetic group throughout the study, but there was a comparable antinatriuretic response to angiotensin II. Thus, the renal haemodynamic response to angiotensin II infusion is normal in early well-controlled Type 1 diabetes. Differences were found in the renal handling of sodium, which could not be related to altered renal tubular responses to angiotensin II or to peripheral hyperinsulinaemia.     

Abnormal tubular handling of sodium and water induced by atrial natriuretic peptide in essential hypertension.

Atrial natriuretic peptide (ANP) was given as an intravenous bolus injection (2.0 micrograms kg-1) to 12 essential hypertensive patients (EH) and 13 normotensive control subjects (C) in order to study the effect of ANP on renal glomerular and tubular function using the lithium clearance technique. Urinary sodium excretion (EH, + 370% vs. C, + 120%; P less than 0.001) and urine volume (EH, + 137% vs. C, + 62%; P less than 0.01) increased significantly more in EH than in controls after ANP injection. Glomerular filtration rate, renal plasma flow, and plasma concentrations of angiotensin II, aldosterone and arginine vasopressin remained almost unchanged after ANP injection, whereas the filtration fraction increased to the same extent in both groups. Both proximal (EH, - 15% vs. C, - 5%; P less than 0.01) and distal fractional reabsorption (EH, - 12% vs. C, - 5%; P less than 0.01) of sodium decreased more markedly after ANP in EH than in controls. The increase in plasma cGMP and urinary excretion of cGMP was the same in the two groups. Mean blood pressure decreased and heart rate increased to the same extent in both groups. It is concluded that the increase in urinary sodium excretion and urine volume induced by ANP bolus injection is exaggerated in EH due to a more pronounced reduction in the reabsorption of sodium and water in both the proximal and the distal tubule.     

The mechanism of improved sodium homeostasis of low-dose losartan in preascitic cirrhosis

Renal sodium retention on standing is one aspect of the abnormal renal sodium handling in preascitic, well-compensated patients with cirrhosis. Recently, it has been shown that low doses (7.5 mg) of the angiotensin II (Ang II) receptor antagonist, losartan, can reverse renal sodium retention on high, 200-mmol sodium/d diet in these patients and restore them to sodium balance. Therefore, the effect of 7.5 mg of losartan on sodium excretion, when changing from supine to erect posture for 2 hours, was examined in 10 well-compensated patients with cirrhosis and 9 age- and sex-matched controls on the same sodium diet, under strictly controlled metabolic conditions. In contrast to control subjects, in whom sodium excretion was unaffected, single 7.5-mg doses of losartan again restored the preascitic patients with cirrhosis to sodium balance. In addition, it blunted the fall in erect posture- induced renal sodium excretion by a reduction in proximal and distal tubular reabsorption of sodium. These changes occurred without any significant changes in blood volumes, systemic and renal hemodynamics, or glomerular filtration rate (GFR) and filtered sodium load compared with controls, and despite activation of the systemic renin-angiotensin-aldosterone system, which was still within normal levels. In conclusion, the beneficial natriuretic effects of low-dose losartan on erect posture - induced sodium retention in preascitic cirrhosis supports the suggestion that the pathophysiology of sodium retention in preascites is in part caused by an intrarenal tubular effect of Ang II in that posture.     

Mechanisms of the impaired diuretic and natriuretic responses to a sustained and moderate saline infusion in rats with experimental cirrhosis

Kidney function and tubular handling of water and sodium by superficial nephrons, packed cell volume, total plasma proteins and albumin distribution space were studied in control and cirrhotic rats before and after a moderate and sustained saline infusion (3% body weight per 30 min + reposition of urinary losses). Tubular fluid samples were obtained from late proximal, early distal and late distal convolutions of superficial nephrons using micropuncture. Protein distribution was assessed by intravenous injection of 0.5 muCi of (125I)-albumin. In basal conditions, both groups of rats showed similar glomerular filtration rate and renal plasma flow, but cirrhotic animals had lower sodium excretion (fractional excretion of sodium = 0.04 +/- 0.01% vs. 0.22 +/- 0.02%, p less than 0.05) and urinary volume (4.31 +/- 0.41 vs. 7.57 +/- 0.53 microliter per min; p less than 0.05). After saline infusion, total plasma proteins decreased more in cirrhotic than in control rats (-18.5 +/- 2.7 vs. -12.9 +/- 2.2%, p less than 0.05). The opposite was observed for albumin distribution space (34.5 +/- 6.1 vs. 22.1 +/- 3.5%, p less than 0.05). Fractional sodium excretion increased to 2.98 +/- 0.15% in control rats but only to 0.61 +/- 0.080% in cirrhotic rats. The ratio single nephron glomerular filtration rate/glomerular filtration rate increased from 19.6 +/- 0.7 to 21.2 +/- 1.0 (X10(-6), p less than 0.005) in control animals but did not change in cirrhotic rats. These animals were unable to decrease adequately fractional fluid reabsorption in the proximal tubule and the loop of Henle.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal tubular reabsorption of calcium in familial hypocalciuric hypercalcaemia

To investigate the nephron site of the enhanced tubular calcium reabsorption in familial hypocalciuric hypercalcaemia (FHH), the renal plasma clearance of lithium and calcium and the glomerular filtration rate were determined simultaneously after an overnight fast in nine FHH patients and ten healthy controls. As the renal plasma clearance of lithium equals the rate of the proximal tubular fluid delivered into the thin descending loop of Henle's loop, the reabsorption of calcium in the proximal and distal tubule, respectively, could be calculated. We found that the FHH patients had a significantly higher fractional calcium reabsorption in the proximal tubule (77.6 +/- 4.7 (%) vs 73.3 +/- 3.1, P less than 0.05). The same held true for the absolute proximal calcium reabsorption (1.49 +/- 0.12 (mmol/l) vs 1.07 +/- 0.05, P less than 0.001). There was a significant linear correlation between the increased tubular capacity for calcium reabsorption and the absolute proximal calcium reabsorption (r = 0.70, P less than 0.05). The distal tubular calcium reabsorption did not differ in the two groups. Our results therefore suggest that the enhanced tubular calcium reabsorption in FHH takes place exclusively in the proximal renal tubule.     

Pressure-dependent,enhanced natriuretic response to low-dose,atrial natriuretic peptide infusion in essential hypertension

Abstract. Objective. To examine whether the effect of atrial natriuretic peptide (ANP) on renal glomerular and tubular segmental handling of sodium in patients with essential hypertension is pressure dependent. Design. Part 1. The renal effects of a low-dose continuous infusion (10 ng kg^?1 min^?1) with ANP for 1 h were compared in 10 untreated essential hypertensives (EH) and 13 normotensive control subjects (CS). Part 2. The hypertensives were studied on another day with ANP infusion during preceding acute BP reduction with sodium nitroprusside infusion (NP). The results were compared with those obtained during infusion with ANP + placebo (Part 1). Methods. Lithium clearance was used to estimate the proximal tubular reabsorption of sodium. Results. Part 1. Atrial natriuretic peptide caused an exaggerated increase in urinary sodium excretion (+ 102 vs. + 38%; P < 0.05), fractional excretion of sodium (+ 80 vs. + 37%; P < 0.05), and urinary output (+ 56 vs. + 8.3%; P < 0.05) in EH compared with CS. Glomerular filtration rate and filtration fraction increased to the same degree in both groups. Absolute lithium clearance (C_L1) increased and FE_L1 tended to increase (P = 0.061) in EH, but these were unchanged in CS. The increase in plasma cyclic guanosine 5′-phosphate (cGMP) and urinary excretion of cGMP and the decrease in plasma aldosterone during ANP infusion were the same in the two groups. Part 2. During NP infusion the natriuresis caused by ANP in EH was reduced (+ 51 vs. +99%; P <0.05). The relative changes in GFR, C_L1, and FE_L1 during ANP infusion were not affected by the preceding BP reduction with NP. Mean arterial pressure was reduced from 122 to 101 mmHg during NP infusion. The relative increase in sodium excretion in EH was significantly correlated to mean arterial pressure. Conclusions. Low-dose ANP infusion causes an exaggerated natriuresis in untreated essential hypertensives due to a more pronounced reduction in tubular reabsorption. After BP reduction, the natriuresis induced by ANP in essential hypertensives is decreased, probably due to a less pronounced reduction in tubular reabsorption beyond the proximal tubules. We suggest that the enhanced natriuretic response to ANP in EH is secondary in some degree to the elevated systemic pressure.     

Effects of norepinephrine and angiotensin II on the determinants of glomerular ultrafiltration and proximal tubule fluid reabsorption in the rat.

In 26 Wistar rats with surface glomeruli, the determinants of glomerular ultrafiltration and peritubular capillary uptake of proximal reabsorbate were studied before and during intravenous infusions of norepinephrine or angiotensin II. Regardless of whether renal perfusion pressure (AP) was permitted to increase, both hormones produced elevations in single nephron filtration fraction due to declines in glomerular plasma flow with little change in nephron glomerular filtration rate. The resulting large increases in the efferent arteriolar oncotic pressure, piE, were accompanied by equivalent increases in the mean glomerular transcapillary hydraulic pressure difference, deltaP. Equality of piE and deltaP, denoting filtration pressure equilibrium, obtained before and during infusion of either hormone. Por both hormones, when elevations in AP were allowed, marked and roughly proportional increases in the resistance to blood flow through single afferent and efferent arterioles occurred, whereas when increases in AP were prevented by partial aortic constriction increases in resistance were confined primarily to the efferent arteriole. Tespite the marked increases in piE, absolute rates of proximal tubule fluid reabsorption, on the average, were unchanged by these hormones due to the opposing effects of marked decreases in efferent arteriolar plasma flow rate and, to a lesser extent, increases in peritubular capillary hydraulic pressure.     

Renal studies in the hypothyroid rat

Whole kidney clearance studies were performed on 27 hypothyroid rats (H) and 25 euthyroid littermate rats (C). Absolute glomerular filtration rate (GFR) was less in hypothyroid rats (1.02 versus 1.39 ml/min), but when factored by body surface area (BSA) the two groups were comparable ($\text{GFR}\text{BSA}\text{= 2.26 versus 2.24 μl}\text{/min/sq/cm}$). Absolute and fractional (per GFR) sodium clearance was greater in the hypothyroid animals ($\text{C}{}_{\mathrm{Na}}\text{GFR:H}\text{= 0.36, C = 0.11, p < 0.001}$), but total electrolyte (Na⁺ + K⁺) excretion and clearance were comparable. End proximal tubular fluid (TF) micropuncture collections in 20 animals revealed no change in fractional reabsorption ($\text{TF}\text{P}$ inulin) in hypothyroid rats ($\text{TF}\text{P}$ insulin, 2.5 versus 2.7), but showed a decrease in single nephron GFR (Vo, 17 versus 36 nl/min) and absolute reabsorption (11 versus 20 nl/min). Hypothyroidism is associated with a decrease of sodium reabsorption at nephron sites distal to the convoluted proximal tubule. With ad libitum electrolyte and water intake most rats can maintain themselves in volume-sodium balance, but an occasional animal may display this distal leak syndrome in the extreme. One such rat had a urinary sodium concentration U_Na of 147 mEq/liter and a urinary flow rate of 56.0 μl/min (H = 3.33, C = 1.39). In addition, its hydropenic normal end proximal $\text{TF}\text{P}$ inulin mean of 2.7 confirmed the inability of the proximal nephron to compensate for this late leak. This rat's plasma sodium was 128 mEq/liter (H = 147, C = 148), dilutional hyponatremia. These renal problems are similar to those reported in man and suggest that the rat is an appropriate model for the study of human hypothyroidism.