Furosemide dynamics in conscious rabbits: Modulation by arginine vasopressin

Summary The aims of this study were to assess the influence of arginine-vasopressin (AVP) on the pharmacodynamics and kinetics of furosemide. To this purpose, the response and the kinetics of furosemide (5 mg/kg i.v.) were studied in two groups of rabbits, one control and one receiving an infusion of AVP (2.5 ng/kg/min). The infusion of AVP generated mean plasma levels of 35 pg/ml, and in these rabbits osmolal clearance was increased, free water clearance was reduced, and renal plasma flow was reduced by 25% (p<0.05). High AVP plasma levels increased the natriuresis (p<0.01) and the urinary excretion of prostaglandin E₂ (U_PgE2V; p<0.01). The increase in U_PgE2V was associated with AVP plasma concentrations (r=0.8248; p<0.001). AVP reduced the increment in natriuresis and diuresis elicited by furosemide from 163±20 to 87±20 µmol/min (p<0.05) and from 1.22±0.11 to 0.83±0.13 ml/min (p<0.05). The infusion of AVP enhanced furosemide metabolic clearance but diminished its renal clearance, resulting in a decrease in the rate of furosemide urinary secretion. It was concluded that high plasma levels of AVP reduce furosemide natriuresis, presumably because of a decrease in furosemide urinary secretion.     

Furosemide-induced natriuresis is augmented by ultra-low-dose captopril but not by standard doses of captopril in chronic heart failure.

BACKGROUND. Ten chronic heart failure patients were studied on three occasions in randomized double-blind fashion to compare the acute hemodynamic, neurohormonal, and renal sodium-handling responses to 1 mg captopril versus 25 mg captopril, both in the absence of loop diuretic therapy and during furosemide-stimulated natriuresis. METHODS AND RESULTS. Compared with placebo, 1 mg captopril caused nonsignificant decreases in mean arterial pressure and circulating angiotensin II level and had no effect on glomerular filtration rate as determined by 51Cr-EDTA elimination. Captopril (25 mg) produced marked suppression of serum angiotensin II with or without oral furosemide (both p less than 0.002), a marked decrease in mean arterial pressure (p less than 0.001) that was accentuated by furosemide (p less than 0.00001), and a decrease in glomerular filtration rate (p = 0.0007). No difference from placebo in renal sodium excretion was noted with either 1 or 25 mg captopril in the absence of furosemide. In contrast, while 25 mg captopril caused slight attenuation of the natriuretic response to furosemide, 1 mg captopril significantly enhanced furosemide-induced natriuresis (p less than 0.05). No correlation was found in our patients between the natriuretic effect of furosemide and either absolute mean arterial pressure or change in mean arterial pressure during the furosemide phase of each study session. This suggests that blood pressure is not the important factor mediating the divergent renal responses to furosemide of the two captopril dosage regimens. CONCLUSIONS. We propose that in the face of furosemide-induced postglomerular vasodilatation in chronic heart failure, captopril at a starting dose of 1 mg (but not 25 mg) preserves enough circulating angiotensin II to maintain efferent arteriolar tone and thus glomerular filtration, while offsetting the antinatriuretic renal tubular effects of angiotensin II.     

Enalapril attenuates natriuresis of atrial natriuretic factor in humans

We studied the effect of converting enzyme inhibition with enalapril on the natriuresis observed after administration of atrial natriuretic factor (human ANF-[99-126], given as a 100-micrograms bolus i.v. injection) in eight healthy humans consuming a 100 mmol sodium diet. Without enalapril, sodium excretion rose from 127 +/- 19 (mean +/- SE) to 437 +/- 103 mumol/min in the first 20 minutes after ANF was administered. Clearance studies performed during maximal water diuresis indicated a rise in glomerular filtration rate (inulin clearance), free water clearance, phosphate, lithium, uric acid, and magnesium excretion. Four days of enalapril (20 mg b.i.d.) increased effective renal plasma flow (p-aminohippurate clearance) and reduced blood pressure (from 114/71 +/- 2/2 to 105/60 +/- 2/1 mm Hg). Under these conditions baseline sodium excretion was not different from the control study, but it rose less after ANF (from 117 +/- 22 to 242 +/- 63 mumol/min), and the increments in glomerular filtration rate, free water clearance, phosphate, lithium, uric acid, and magnesium were all blunted and nonsignificant. In addition, effective renal plasma flow tended to fall; this effect was not observed when ANF was given without enalapril. These results support the notion that the effects of ANF on renal hemodynamics and on tubular sodium handling depend on renal angiotensin II and that blood pressure reduction may interfere with the ANF-induced natriuresis.     

Effects of prostaglandin synthesis inhibitors on the renin-angiotensin system and renal function

Equal doses (8 mg/kg) of the nonsteroidal antiinflammatory drugs indomethacin, naproxen, and sulindac and a large dose of sulindac (32 mg/kg) were administered intragastrically to conscious rats after a normal sodium diet, furosemide stimulation, and a low sodium diet for 8 days. Indomethacin, naproxen, and the high dose sulindac (32 mg/kg) decreased urinary prostaglandin E2 excretion significantly under all experimental conditions. Sulindac (8 mg/kg) suppressed prostaglandin E2 excretion after the normal and low sodium diets but not after furosemide stimulation. Indomethacin decreased plasma active renin levels under all three experimental conditions. In rats receiving a normal sodium diet, indomethacin did not affect free water clearance or renal function; however, after furosemide stimulation or a low sodium diet, indomethacin caused a significant reduction of free water clearance and glomerular filtration rate. Naproxen and sulindac (8 mg/kg) did not suppress active renin under any of the experimental conditions. However, naproxen and sulindac caused a significant reduction in free water clearance and glomerular filtration rate after furosemide stimulation and a low sodium diet. Indomethacin, naproxen, and the high dose sulindac suppressed renal prostaglandin E2 excretion under all experimental conditions. Renal prostaglandin E2 does not appear to be necessary for active renin secretion. Indomethacin is the most potent inhibitor of active renin and, therefore, most likely to cause hyporeninemia. Volume depletion appeared to sensitize the kidney to the adverse effects of nonsteroidal antiinflammatory drugs.     

Severe hyperglycemia: a determinant factor for hypofiltration in alloxan diabetic rats

Abstract. The relationships among glomerular filtration rate, renal plasma flow and extracellular fluid volume were investigated in control and severely hyperglycemic (442±33 mg/dl) untreated, alloxan diabetc rats. Most of diabetic animals showed significant lower values of inulin clearance (diabetics, 0.55±0.07 ml/min·100 g; controls, 0.97±0.04) and p-aminohippurate clearance (diabetics, 2.11±0.39 ml/min·100 g; controls, 3.93±0.25). Diabetic rats exhibited reduced efficiency in tubular Na⁺ reabsorption, increased urinary Na⁺ excretion (diabetics, 3.12±0.27 mEq/day; controls, 1.25±0.14) and diminished values of plasma renin activity (diabetics, 3.34±0.44 ng/ml·h; controls, 8.64±0.79). Significant negative correlations were found between glycemia and renal hemodynamic variables. Acute overload with glucose further decreased these variables in both groups: inulin clearance in diabetics vs. controls, 0.26±0.04 vs. 0.44±0.05 ml/min·100 g; p-aminohippuric acid clearance in diabetics vs. controls, 1.09±0.20 vs. 1.55±0.21 ml/min·100 g. We conclude that chronically hyperglycemic alloxan diabetic rats showed diminished glomerular filtration rates (inulin clearance), renal plasma flow (p-aminohippurate clearance) and extracellular fluid volume associated with urinary Na⁺ losses and alterations in the renin-angiotensin system. Decreased reninangiotensin system activity might reduce aldosterone secretion, which in turn could result in (succesively) urinary sodium loss, extracellular fluid volume contraction and reductions in glomerular filtration and renal plasma flow.     

Enhanced antinatriuresis in response to angiotensin II in essential hypertension

Angiotensin II regulates sodium homeostasis by modulating aldosterone secretion, renal vascular response, and tubular sodium reabsorption. We hypothesized that the antinatriuretic response to angiotensin II is enhanced in human essential hypertension. We therefore studied 48 white men with essential hypertension (defined by ambulatory blood pressure measurement) and 72 normotensive white control persons, and measured mean arterial pressure, sodium excretion, renal plasma flow, glomerular filtration rate, and aldosterone secretion in response to angiotensin II infusion (0.5 and 3.0 ng/kg/min). Hypertensive subjects exhibited a greater increase of mean arterial pressure (16.7+/-8.2 mm Hg v 13.4+/-7.1 mm Hg in normotensives, P < .05) and a greater decrease of renal plasma flow (-151.5+/-73.9 mL/ min v -112.6+/-68.0 mL/min in controls, P < .01) when 3.0 ng/kg/min angiotensin II was infused. The increase of glomerular filtration rate and serum aldosterone concentration was similar in both groups. Sodium excretion in response to 3.0 ng/kg/min angiotensin II was diminished in both groups (P < .01). However, the decrease in sodium excretion was more pronounced in hypertensives than in normotensives (-0.18+/-0.2 mmol/min v -0.09+/-0.2 mmol/min, P < .05), even if baseline mean arterial pressure and body mass index were taken into account (P < .05). We conclude that increased sodium retention in response to angiotensin II exists in subjects with essential hypertension, which is unrelated to changes in glomerular filtration rate and aldosterone concentration. Our data suggest a hyperresponsiveness to angiotensin II in essential hypertension that could lead to increased sodium retention.     

Acetylsalicylic acid suppresses the renal hemodynamic effect and reduces the diuretic action of furosemide in cirrhosis with ascites

To investigate if lysine acetylsalicylate influences the hemodynamic and diuretic responses to furosemide in cirrhosis, 21 nonazotemic patients with ascites were studied. In 8 patients (group 1), the renal plasma flow and glomerular filtration rate were serially measured before and during three 30-min periods after the i.v. administration of lysine acetylsalicylate (450 mg). In 7 patients (group 2), renal plasma flow, glomerular filtration rate, urine volume, and sodium excretion were measured before and during three 20-min periods after the i.v. administration of furosemide (40 mg). After a 45-min period in which urinary losses were restored, a similar study was performed before and after a second injection of furosemide (40 mg). Six patients (group 3) were studied with an identical protocol as group 2, except that the second injection of furosemide was preceded by the administration of lysine acetylsalicylate (450 mg). In 6 patients of group 1, lysine acetylsalicylate caused a marked and reversible reduction of renal plasma flow and glomerular filtration rate. In groups 2 and 3, the i.v. injections of furosemide alone produced a significant increase in renal plasma flow and glomerular filtration rate, and a marked diuresis and natriuresis. In patients of group 3, pretreatment with lysine acetylsalicylate suppressed the renal hemodynamic effect and markedly reduced the diuretic effect of the second injection of furosemide. Lysine acetylsalicylate did not cause the appearance of renal insufficiency in any of these patients. These results suggest that prostaglandins are involved in the renal response to furosemide in cirrhosis with ascites and that furosemide protects these patients from developing renal insufficiency after acute administration of nonsteroidal antiinflammatory agents.     

Proximal glomerulo-tubular balance in patients with Type 1 (insulin-dependent) diabetes mellitus

Summary To evaluate the glomerulo-tubular balance of sodium and water in the proximal tubules of diabetic patients with elevated glomerular filtration rate, the renal plasma clearance of lithium and the glomerular filtration rate (⁵¹Cr-EDTA plasma clearance) were determined simultaneously in 11 ambulatory Type 1 (insulin-dependent) diabetic patients (aged 25–35 years) with no evidence of diabetic nephropathy and in 10 age-matched healthy subjects. The renal plasma clearance of lithium, which is a measure of flow from the proximal tubule into the thin descending limb of the loop of Henle, did not differ between diabetic and control subjects (28.9±4.0 versus 28.3±5.1 ml/min per 1.73m² surface area, mean±SD), whereas the glomerular filtration rate in the diabetic patients was significantly higher than in the control sub jects (136±10.2 versus 108±13.6 ml/min per 1.73m², p< 0.001). The same held true for the fractional reabsorption rate in the proximal tubules (78.7±3.2 versus 73.6±4.9%, p< 0.02). The results indicate that the elevation of the glomerular filtration rate in diabetic patients is associated with a parallel increase in the proximal reabsorption rate. This type of glomeralo-tubular balance implies that the flow of water and flux of sodium to the segments distal to the proximal tubule are kept constant during variations in the glomerular filtration rate.     

The effect of intravenous insulin infusion on kidney function in insulin-dependent diabetes mellitus

Summary Glomerular filtration rate, renal plasma flow, urinary excretion of -2-microglobulin and albumin, heart rate and blood pressure were studied in eight young male insulin-dependent diabetics. Measurements were performed before and during insulin infusion at 2 mU/kg/min. No patient had discernible insulin antibodies. Two studies were performed at random in each patient. In series A blood glucose concentration was allowed to decline, while in series B it was maintained at a constant level. Ten 20 min clearance periods were performed, four before and six during insulin infusion. Results are given as mean±SEM of values from the first four (control) and last four (test) clearance periods. Blood glucose declined in series A experiments from 10.8±0.8 mmol/l in the control period to 5.8±0.5 mmol/l during the test period, but remained constant during experiment B (9.8±1.1 and 9.5±1.1 mmol/l). Plasma insulin levels were comparable in the two series. Glomerular filtration rate fell from 141±7 ml/ min X 1.73m₂ to 132±7ml/min X 1.73m₂ (p< 0.01) in series A but did not change significantly during series B. Similarily renal plasma flow declined with declining glucose but remained constant when glucose was maintained at a constant level. In series A the magnitude of decrease in renal plasma flow was correlated with the magnitude of decrease in glomerular filtration rate (r=0.95, p< 0.001). -2-microglobulin excretion decreased significantly (p < 0.05) in both series (A: 89±17 to 60±13 ng/min, B: 117±46 to 62±17ng/min). Albumin excretion increased in five out of six patients with normal control values (not significant) in series A and in four out of six in series B. No significant changes in heart rate or blood pressure were observed. Thus insulin infusion reduced renal plasma flow and glomerular filtration rate, but this effect could be completely abolished by keeping blood glucose constant. This suggests that it is not the lack of insulin but the associated hyperglycaemia which contributes to the elevated renal plasma flow and glomerular filtration rate in insulin-dependent diabetics.     

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.     

Effect of metabolic regulation on renal leakiness to Dextran molecules in short-term insulin-dependent diabetics

Summary Renal clearance of dextran of two ranges of molecular size and glomerular filtration rate (GFR,⁵¹Cr-EDTA) were measured in seven short-term insulin-dependent diabetics (mean age 25 years). Measurements were carried out in the same patient during good and poor metabolic regulation (plasma glucose, mean±SEM, 6.5±0.9 and 14.8±1.5 ] mmol/l, respectively). GFR was elevated in all patients during poor metabolic regulation (119±6 ml/min/1.73 m², versus 99±2 ml/min/1.73 m² during good control, p<0.01). The average renal clearance of dextran with molecular weights ranging from 25,000 to 35,000 and 35,000 to 45,000 increased during poor metabolic regulation from 14.8±0.8 to 19.8±1.8 ml/min/1.73 m², and 5.2±0.3 to 6.8±0.6 ml/min/1.73 m², respectively (p< 0.05). The elevated GFR and renal dextran clearance found during poor metabolic regulation were normalized within one to three weeks of effective insulin treatment. This rapid reversibility can hardly be explained by the previously demonstrated enlargement in glomerular size and filtration surface area, since these alterations remain unchanged after more than one month of insulin treatment. The metabolic regulation did not influence the size-selective properties of the glomerular wall. Therefore, we suggest that the dominating mechanism involved in the GFR and renal dextran clearance alterations is functional, viz. increased filtration pressure.     

Prostaglandin I2 versus prostaglandin E2 in dogs with and without low cardiac output. Differential effects on renal function.

Exogenous prostaglandin (PG) administration has been proposed as a vasodilator therapy for heart failure patients. The effects of this therapy on renal function have not been well studied in this disorder. Therefore, we investigated the renal effects of the PGI2 analog iloprost in comparison to PGE2 in 12 conscious dogs before and after induction of a low cardiac output state by rapid right ventricular pacing (250 beats/min for 10 days). In healthy dogs, 5 to 150 ng/kg/min iloprost increased renal plasma flow without affecting glomerular filtration rate and decreased urine flow without affecting natriuresis. PGE2 at the same dosages increased renal plasma flow and urinary sodium excretion without changing the glomerular filtration rate or amount of diuresis. In dogs with low cardiac output and lower basal renal plasma flow, iloprost did not change renal plasma flow, but decreased glomerular filtration rate and filtration fraction. In these animals, PGE2 insignificantly increased renal plasma flow, but significantly augmented urine flow and sodium excretion. We therefore conclude that in an experimental low cardiac output state, PGI2 may cause a deterioration of renal function. In contrast, PGE2 induces natriuresis and diuresis despite an attenuated increase in renal plasma flow. Thus, PGE2 promises to exert a more favorable profile of renal effects in heart failure therapy.     

Modulation of the natriuretic response to atrial natriuretic peptide by alterations in peritubular Starling forces in the rat

The mechanisms underlying the natriuretic response to infusions of atrial natriuretic peptide (ANP) remain incompletely defined. By acting as renal vasodilators, atrial peptides may serve to alter peritubular capillary physical forces and favor a decrease in tubule solute reabsorption. Therefore, we studied the effects of known modifiers of intrarenal Starling forces on the natriuresis induced by infusion of intravenous hANP [4-28] (0.5 microgram/kg/min) in anesthetized, euvolemic Munich-Wistar rats. In the first series of studies, infusion of ANP resulted in a significant natriuresis, diuresis, and increase in inulin clearance and in a slight fall in systemic arterial pressure, as compared to vehicle infusion. Subsequent elevation of renal perfusion pressure by superimposition of angiotensin II infusion (0.1-0.2 microgram/kg/min i.v.) on continued ANP infusion resulted in marked further enhancement of natriuresis, independent of changes in glomerular filtration rate (GFR). In the second set of experiments, in which oncotic pressure in the postglomerular capillaries was elevated by hyperoncotic exchange transfusion, administration of ANP did not result in natriuresis, even though GFR increased by the same magnitude as that seen in isooncotic animals given ANP. These observations are consistent with the view that peritubular capillary hydraulic and oncotic pressures modulate the natriuretic and diuretic effects of ANP.     

Candesartan cilexetil and renal hemodynamics in hypertensive patients

This randomized, double-blind, placebo-controlled crossover study evaluated the effects of the angiotensin II type 1 (AT1)-receptor blocker candesartan cilexetil on renal blood perfusion and glomerular filtration in patients with primary hypertension with diastolic blood pressure of 100 to 114 mm Hg. After a 4-week placebo run-in period, patients were randomized to receive either 16 mg candesartan cilexetil or placebo once daily for 6 weeks, after which they were switched to the alternative treatment. At the end of each period, 24 h after the last dose, renal assessments were made and the plasma renin activity, plasma concentrations of angiotensin II, aldosterone, and catecholamines were measured. Compared with placebo, candesartan cilexetil significantly reduced mean arterial pressure, by 8 mm Hg (95% confidence interval [CI], 3;12). Renal vascular resistance was significantly reduced by 0.03 mm Hg/mL min(-1) (95% CI, 0.01; 0.06). There was a small nonsignificant increase in renal plasma flow. The filtration fraction fell slightly from 0.24 to 0.22 (95% CI, -0.00, 0.04). As expected, angiotensin II concentrations and plasma renin activity were increased and the aldosterone concentrations were reduced. Catecholamine concentrations were unaffected. In conclusion, 6 weeks' treatment with 16 mg candesartan cilexetil once daily induced a reduction of renal vascular resistance and a trend toward increased renal plasma flow despite a reduction in mean arterial pressure. Because the glomerular filtration rate was maintained the filtration fraction was reduced, indicating a decreased glomerular capillary pressure.     

Glucose-induced changes in renal haemodynamics in proteinuric Type 1 (insulin-dependent) diabetic patients: inhibition by acetylsalicilic acid infusion

Summary The effect of hyperglycaemia on renal function in diabetic nephropathy remains poorly understood. We investigated the renal haemodynamic response to an acute plasma glucose rise from sustained euglycaemia to sustained hyperglycaemia in eight persistently proteinuric Type 1 (insulin-dependent) diabetic patients. Studies were performed in a double-blind cross-over manner after i.v. injection of 450 mg lysine acetylsalicilate (equivalent to 250 mg acetylsalicilic acid) or equal volume of 0.9% NaCl (isotonic saline). In the isotonic saline experiments hyperglycaemia produced a significant rise, by approximately 35%, in glomerular filtration rate in all patients from 41.5±5.2 to 55±6 ml·min^–1·1.73 m^–2 (p<0.005) and an increase in sodium paraminohippurate clearance from 178±22.7 to 220±20.0 ml·min^–1·1.73 m^–2 (p<0.05). These changes took place within the first 30 min of glucose infusion and were maintained for a 90 min hyperglycaemic period. Filtration fraction did not change significantly. Infusion of lysine acetylsalicilate lowered baseline glomerular filtration rate (isotonic saline vs lysine acetylsalicilate 41.5±5.2 vs 30.0±5.7 ml·min^–1·1.73 m^–2; p<0.05) and significantly blunted the rise in glomerular filtration rate during hyperglycaemia (glomerular filtration rate increment: saline vs lysine acetylsalicilate: 13.6±2.8 vs 5.3±1.8 ml·min^–1 ·1.73 m^–2; p<0.005). The effects on renal plasma flow were similarly blunted. In five additional patients, time- and volume-controlled isotonic saline experiments during sustained euglycaemia showed no significant changes in glomerular filtration rate and sodium paraminohippurate clearance. In Type 1 diabetic patients with advanced renal failure, acute hyperglycaemia induces a significant elevation in glomerular filtration rate and renal plasma flow which is likely to be mediated by renal prostaglandin production.     

Effect of enalapril in subjects with hypertension associated with moderate to severe renal dysfunction

The purpose of this study was to define the effect of the angiotensin-converting enzyme inhibitor, enalapril maleate, on blood pressure, renal function, protein excretion, and potassium homeostasis in patients with hypertension associated with moderate to severe renal dysfunction. Nine patients, having an initial inulin clearance between 9 and 48 mL/min/1.73 m2, were treated with enalapril monotherapy (n = 6) or enalapril/furosemide (n = 3) combination therapy. Systolic and diastolic blood pressures were well controlled. Supine plasma renin activity was stimulated; the supine plasma aldosterone level was suppressed, with a resultant increase in the serum potassium level. Clinical hyperkalemia was not observed. Glomerular filtration rate, assessed by inulin and creatinine clearances, was not significantly changed. Effective renal plasma flow, assessed by paraaminohippurate clearance was significantly increased, with a resultant decrease in filtration fraction. Importantly, urinary protein excretion was markedly reduced. These results suggest that enalapril therapy produces efferent arteriolar dilitation with preservation of the glomerular filtration rate. Enalapril therapy may also blunt the effects of angiotensin II on transglomerular passage of protein, as demonstrated by reduced proteinuria. These findings suggest that interruption of the renin-angiotensin system in patients with preexisting renal disease may have renal protective effects.     

Effects of Tolvaptan on Systemic and Renal Hemodynamic Function in Dogs with Congestive Heart Failure

Purpose

We investigated the effects of tolvaptan, a vasopressin V₂-receptor antagonist, on diuretic response and systemic and renal hemodynamic characteristics in conscious dogs with congestive heart failure (CHF). We also compared these effects with those of furosemide, a loop diuretic.

Methods

CHF was induced by rapid right-ventricular pacing at 260 beats/min for at least 3 weeks, and maintained with a pacing rate of 220–240 beats/min. CHF dogs were orally given tolvaptan (10 mg/kg), furosemide (10 mg/kg) and vehicle in random order during the stable CHF state. Urine excretion, systemic and renal hemodynamic parameters, and plasma hormone levels were measured over 6-hour periods after drug administration.

Results

Tolvaptan induced aquaresis with an increase in free water clearance, resulting in a significant increase in serum sodium concentrations and a decrease in cumulative water balance. Tolvaptan also decreased pulmonary capillary wedge pressure without affecting systemic vascular resistance, glomerular filtration rate or renal blood flow. Tolvaptan tended to increase plasma arginine vasopressin concentrations but did not affect plasma renin activity. In contrast, furosemide induced clear saluresis with increased electrolyte excretion, resulting in decreased pulmonary capillary wedge pressure. However, furosemide also decreased serum potassium concentration and increased plasma arginine vasopressin concentrations and plasma renin activity.

Conclusion

Tolvaptan elicited a potent aquaretic response and reduced the cardiac preload without unfavorable effects on systemic or renal hemodynamics, the renin–angiotensin–aldosterone system, or the sympathetic nervous system in CHF dogs. Thus, tolvaptan may offer a novel approach to remove excess water congestion from patients with CHF.

     

Impaired renal water excretion in early hepatic cirrhosis. Lack of relationship between renal water excretion and plasma levels of arginine vasopressin, angiotensin II, and aldosterone after water loading

An oral water load of 20 ml per kg body weight was given to 9 patients with hepatic cirrhosis and 11 healthy controls. Urinary output, free water clearance, and plasma concentrations of arginine vasopressin, angiotensin II and aldosterone were determined before and three times during the first 4 h after loading. In the cirrhotic patients urinary output was significantly lower after loading than in the control subjects, mainly because of a lower free water clearance, and, in contrast to the healthy controls, the cirrhotic patients did not have natriuresis after water loading. No differences were found between patients and controls in arginine vasopressin, angiotensin II, aldosterone, or creatinine clearance. It is concluded that patients with well-compensated cirrhosis of the liver have an impaired ability to excrete sodium and water. This phenomenon does not seem to be due to increased arginine vasopressin secretion, activation of the renin-angiotensin-aldosterone system, or a decreased glomerular filtration rate.     

Glomerular and tubular antinatriuretic actions of low-dose angiotensin II infusion in man.

OBJECTIVE: The aim was to study the physiological effects of angiotensin II upon the glomerular and tubular handling of sodium. DESIGN: Healthy volunteers were examined before and during infusion with either low-dose angiotensin II (n = 11) or placebo (n = 13). METHODS: Lithium clearance was used to estimate the segmental tubular reabsorption of sodium. RESULTS: During infusion with angiotensin II a sustained and marked fall in renal plasma flow was observed. The glomerular filtration rate (GFR) decreased to a minor extent so that the filtration fraction increased during angiotensin II infusion. Angiotensin II caused an extensive and instantaneous fall in both urinary flow and urinary sodium excretion. Proximal absolute reabsorption of sodium was unchanged despite the fall in GFR, showing that proximal fractional reabsorption was enhanced by angiotensin II. Distal absolute reabsorption was decreased during the entire period of angiotensin II infusion. However, when the distal reabsorption was related to the delivery of sodium from the proximal tubules, distal fractional reabsorption in fact increased after 30 min angiotensin II infusion. None of the measured parameters changed during infusion with placebo. A significant increase in plasma aldosterone was observed 30 min after the start of the angiotensin II infusion. Plasma atrial natriuretic peptide did not change during infusion with either angiotensin II or placebo. CONCLUSIONS: We conclude that physiological increments in angiotensin II affect glomerular haemodynamics and cause a marked antinatriuresis in man. The antinatriuretic effect of angiotensin II is caused initially by a combination of a decrease in the GFR and an increase in proximal fractional sodium reabsorption, and later by the enhanced distal fractional reabsorption of sodium.     

Hyper-responsiveness to angiotensin II is related to cardiac structural adaptation in hypertensive subjects.

BACKGROUND: Angiotensin II has been found to be a growth stimulating factor for myocardial cells. In humans, angiotensin II infusion causes vasoconstriction in systemic and renal vasculature and leads to aldosterone secretion. Our hypothesis was that hyper-responsiveness to angiotensin II is related to left ventricular mass in human essential hypertension. METHODS AND RESULTS: In 30 normotensive individuals and 30 subjects with mild essential hypertension (white men, mean age 26+/-3 years), the responsiveness to angiotensin II was assessed by measuring changes in mean arterial pressure, renal blood flow, glomerular filtration rate and aldosterone secretion in response to i.v. angiotensin II infusion (0.5 and 3.0 ng/kg per min). The provoked changes to angiotensin II infusion were similar in the normotensive and hypertensive group with the exception of an exaggerated increase in mean arterial pressure in hypertensives (14+/-5 versus 10+/-5 mm Hg, P<0.001 at 3.0 ng/kg per min angiotensin II). The increase in mean arterial pressure was correlated with left ventricular mass in hypertensive subjects (angiotensin II 0.5 ng/kg per min: r = 0.49, P<0.005; angiotensin II 3.0 ng/kg per min: r = 0.35, P<0.05); no such correlation was found in the normotensive group. After taking into account baseline mean arterial pressure and body mass index, the increase in mean arterial pressure to angiotensin II 0.5 ng/kg per min was still correlated with left ventricular mass (partial r = 0.50, P<0.01). Similarly, the change of glomerular filtration rate but not of renal blood flow in response to angiotensin II 0.5 ng/kg per min was correlated with left ventricular mass, (r = 0.42, P<0.02) in the hypertensive group but not in the normotensive one. This relationship remained significant even after taking baseline glomerular filtration rate, mean arterial pressure and body mass index into account (partial r = 0.43, P<0.05). CONCLUSION: Hyper-responsiveness to angiotensin II is related to an increased left ventricular mass in hypertensive subjects independent of blood pressure.