Renal and hormonal effects and tolerance of an ANP analogue in healthy man

Summary The effect of an analogue of atrial natriuretic peptide (P-ANP) on glomerular filtration rate (GFR), renal plasma flow (RPF), urinary flow rate, urinary sodium excretion, tubular function estimated by the lithium clearance technique, and plasma levels of sodium and water homeostatic hormones, has been studied in 40 healthy males. Placebo or P-ANP 0.3, 1.5, or 3.0 g·kg^–1 bwt were given as an intravenous bolus injection to different groups.P-ANP did not cause any immediate change in GFR or RPF, but significant dose-dependent increases in filtration fraction, urinary flow rate and urinary excretion rate of sodium were detected during the first 30 min after administration. Proximal absolute and fractional tubular reabsorption and distal absolute tubular reabsorption of sodium did not change after injection of P-ANP, while the distal fractional reabsorption of sodium was reduced in a dose dependent manner during the first 30 min.Plasma angiotensin II and aldosterone were significantly increased 30 and 150 min after dosage, whereas plasma atrial natriuretic peptide, plasma arginine vasopressin, and urinary excretion of prostaglandin E₂ were unchanged. Cyclic guanosine monophosphate both in plasma and urine were increased in a dose-dependent manner.P-ANP cause a significant reduction in diastolic blood pressure and an increase in pulse rate. Two subjects had vasovagal syncope 30–60 min after injection of P-ANP.It is concluded that P-ANP has natriuretic, diuretic and hypotensive properties in healthy man.     

RENAL HANDLING OF ENDOGENOUS LITHIUM IN EXPERIMENTAL DIABETES MELLITUS IN THE RAT

1. The usefulness of determining the renal handling of endogenous lithium as a marker of proximal tubular sodium reabsorption was assessed in streptozotocin induced diabetes mellitus in the Sprague-Dawley rat. 2. The clearance and fractional excretion of lithium were determined before and following the development of diabetes mellitus, and compared with measurements of proximal tubular reabsorption made directly using micropuncture techniques. Endogenous lithium was measured in order to avoid the toxic tubular effects of exogenously administered lithium salts. 3. Although a trend existed for a reduction in the fractional excretion of lithium in diabetic animals (1.8 +/- 0.3 vs 2.4 +/- 0.5%; P greater than 0.20), this did not reach statistical significance and did not accurately reflect the change in directly measured tubular Na reabsorption. 4. The decrease in proximal tubular Na reabsorption demonstrated in diabetic animals treated with phlorizin was not significantly reflected in the fractional lithium excretion, although again a corresponding trend was evident (1.9 +/- 0.8 vs 0.6 +/- 0.2%; P greater than 0.10. 5. In summary, the significant alterations in tubular Na handling in diabetes mellitus, previously demonstrated directly using micropuncture techniques, are not reflected in the renal handling of endogenous lithium. This indirect method is inadequate to assess proximal tubular Na transport in experimental diabetes mellitus.     

Influence of captopril on renal hemodynamics and segmental tubular reabsorption of sodium in humans

Acute angiotensin-converting enzyme inhibitors (ACEIs) have been found to induce natriuresis in humans as well as in experimental animals. However, the tubular sites involved have not been precisely evaluated in humans. Using both free-water and lithium clearance, the latter as a marker of proximal tubular reabsorption, we measured segmental tubular movement of sodium before and after acute captopril administration in eight healthy normotensive volunteers on normal sodium diet. Captopril decreased slightly but significantly glomerular filtration rate (GFR), filtration fraction, and mean arterial pressure (MAP), whereas renal plasma flow (RPF) was unchanged. Captopril acutely increased excretion rate and fractional excretion of sodium. When assessed by lithium clearance, both absolute and fractional proximal reabsorption of sodium and fractional distal reabsorption of sodium were found to be decreased by captopril. When assessed by free-water clearance, both fractional proximal and distal reabsorption of sodium were found to be decreased by captopril but only the decrease in fractional proximal reabsorption was significant. These results indicate that captopril-induced natriuretic effect is due to decreased sodium reabsorption in both proximal and distal sites of the nephron. Shifts in segmental tubular sodium reabsorption obtained from either free-water or lithium clearance are directionally similar but quantitatively different. Results obtained from lithium clearance indicate that the rate of fluid delivery to the diluting segment is at least twice as great as that estimated from free-water calculations. Lithium clearance techniques therefore appear to be more sensitive in detecting subtle changes in segmental tubular reabsorption.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of nicardipine on renal hemodynamics and segmental tubular reabsorption of sodium in humans

Calcium antagonists induced natriuresis in humans as well as in experimental animals. However, the tubular sites involved have not been precisely evaluated in humans. Using both free-water and lithium clearance, the latter as a marker of absolute sodium distal delivery, we measured segmental tubular movement of sodium before and after acute intravenous (i.v.) nicardipine administration 2.5 mg as a single dose in eight healthy normotensive volunteers on normal sodium diet. Nicardipine decreased slightly but significantly the mean arterial pressure (MAP) (from 98.9 +/- 8.8 to 91.8 +/- 9.2 mm Hg; p less than 0.01) and the renal vascular resistance (from 6,142 +/- 1,082 to 5,578 +/- 893 dynes.s/cm5 . 1.73 m2; p less than 0.05), whereas the glomerular filtration rate (GFR), the renal plasma flow (RPF), and the filtration fraction (FF) were unchanged. Nicardipine acutely increased the absolute and the fractional excretion of sodium (from 282 +/- 60 to 427 +/- 152 mumol/min.1.73 m2; p less than 0.01 and from 0.015 +/- 0.004 to 0.023 +/- 0.013; p less than 0.01, respectively). When assessed by either lithium clearance or free-water clearance, both proximal and distal fractional reabsorption of sodium were decreased by nicardipine. These results indicate that the nicardipine-induced natriuretic effect is due to decreased sodium reabsorption in both proximal and distal sites of the nephron. Shifts in segmental tubular sodium reabsorption obtained from either free-water or lithium clearance were directionally similar but quantitatively different.     

Effect of pinacidil on renal haemodynamics,tubular function and plasma levels of angiotensin II,aldosterone and atrial natriuretic peptide in healthy man

Summary The effects of pinacidil on renal haemodynamics, tubular function evaluated by the lithium clearance technique and the plasma levels of angiotensin II (Ang II), aldosterone (Aldo) and atrial natriuretic peptide (ANP) have been evaluated in 12 healthy volunteers given pinacidil 0.1 mg/kg IV in comparison with a placebo given to 13 different healthy volunteers.Pinacidil induced significant reductions in glomerular filtration rate (–5%), renal plasma flow (–12%), urine output (–35%), urinary sodium excretion (–20%), and the fractional excretion of sodium (–17%) and potassium (–29%). Lithium clearance and proximal and distal absolute and fractional reabsorption of sodium were not significantly changed. Ang II and Aldo were significantly increased (80% and 115%, respectively) and ANP was unchanged. The mean arterial blood pressure was not significantly changed by pinacidil, but the heart rate was increased (22%).It is concluded that bolus IV injection of pinacidil in healthy subjects reduced renal blood flow, urine volume and the urinary excretion of sodium and potassium, whereas segmental tubular function was unchanged. The increase in heart rate and activation of the renin-agiotensin-aldosterone system are most likely to be secondary to stimulation of the sympathetic nervous system caused by the vasodilator effect of pinacidil.     

Effect Of Age On Renal Functional And Orthostatic Vascular Response In Healthy Men

1. Few studies have been reported concerning the effect of ageing on renal functional and vascular responses to various stresses during ordinary life. In the present study, we examined the effect of age on changes in renal sodium handling and renal vascular resistance (RVR) in response to standing from a supine position in subjects with normal renal function. 2. We selected 43 healthy males in the second through to the seventh decade of life and gave them a constant dietary sodium intake before the study period. Renal function was estimated by standard clearance methods with the subject in a state of euvolaemia. 3. The mean daily urinary excretion of sodium was 236 ± 22 mEq. Standing from a supine position was associated with significant decreases (P < 0.0001) in creatinine clearance (from 125 ± 18 to 117 ± 19 mL/min per 1.73 m ² ), sodium excretion (from 178 ± 29 to 97 ± 23 μ Eq/min) and fractional excretion of sodium (from 1.02 ± 0.19 to 0.60 ± 0.13%). A significant increase (P < 0.0001) in the RVR index (from 0.11 ± 0.03 to 0.14 ± 0.04 units) was noted. Univariate analysis indicated that while the change in RVR associated with standing was significantly diminished (P < 0.05) in older subjects, orthostatic changes in other parameters associated with standing were minimally influenced by age. 4. In conclusion, although the renal vascular response is impaired in advanced age, the renal functional response to orthostasis is otherwise maintained in healthy elderly subjects under conditions of normal sodium intake and clinical euvolaemia.     

PATHWAYS LINKING RENAL EXCRETION AND ARTERIAL PRESSURE WITH VASCULAR STRUCTURE AND FUNCTION

1. A brief review is presented which summarizes the role of the kidney in the long-term regulation of arterial pressure and the mechanism whereby changes in body fluid volume can influence the function and structure of the systemic vasculature. 2. Studies indicate that the kidney detects changes of arterial pressure via changes of medullary blood flow which in the volume expanded state is poorly autoregulated. Elevations of renal arterial pressure raise vasa recta capillary pressure and renal interstitial fluid pressure, which in turn reduces tubular reabsorption of sodium and water. 3. The sensitivity of the pressure-diuresis relationship is controlled by renal sympathetic nerve activity and a variety of hormone and autocrine systems. 4. Evidence is also reviewed which shows that small changes of blood volume (5%) resulting from reduced renal excretion can acutely and chronically result in 25% increases of total peripheral resistance and arterial pressure. 5. Short-term increases of vascular resistance are predicted by regional autoregulatory responses while long-term elevations of vascular resistance appear to result from the structural changes of large vessel hypertrophy and microvascular rarefaction within skeletal muscle.     

Effects of ozolinone,a diuretic active metabolite of etozoline,on renal function

Summary The renal action of 3-methyl-4-oxo-5-piperidino-thiazolidine-2-ylidine (ozolinone), a metabolite of the diuretic etozoline (Elkapin), was studied in anaesthetized dogs after i.v. injection and compared with the renal effects of furosemide. The diuretic action of ozolinone was rapid in onset and of short duration. Thesmallest effective i.v. dose was 1 mg\kg^–1. Maximal diuretic capacity was reached at 50 mg\kg^–1 i.v. Fractional tubular sodium reabsorption was depressed to 67% at maximal effective doses.Ozolinone had similar renal actions to those of furosemide. Like furosemide, ozolinone increased renal blood flow, slightly decreased glomerular filtration rate, depressed tubular chloride reabsorption more than sodium reabsorption, increased potassium excretion, lowered the pH of urine, decreased urinary osmolarity towards isotonicity and depressed tubular PAH secretion. As regards the effective doses and the maximal changes of tubular sodium excretion, ozolinone was somewhat less potent than furosemide.     

Effect of moxonidine on urinary electrolyte excretion and renal haemodynamics in man

Moxonidine and related compounds have been recently introduced into antihypertensive therapy. It is thought that these drugs exert their blood pressure lowering effect through interaction with nonadrenergic receptors in the central nervous system, i.e. imidazoline receptors, although the contribution of specific interaction with ₂-receptors is still under debate. Imidazoline receptors have recently been documented in the renal proximal tubule. In experimental studies, interaction of imidazolines with these receptors decreased the activity of the Na⁺/H⁺ antiporter and induced natriuresis. To quantitate the effect of the imidazoline receptor agonist moxonidine on renal sodium handling and renal haemodynamics in man, we examined ten healthy normotensive males (aged 25 ± 4 years) in a double blind placebo-controlled study using a crossover design. Subjects were studied on a standardized salt intake (50 mmol per day). On the 7th and 10th study day they were randomly allocated to receive either i.v. placebo or i.v. 0.2 mg moxonidine. Urinary electrolyte excretion, lithium clearance (as an index of proximal tubular sodium handling), glomerular filtration rate (GFR), effective renal plasma flow (ERPF), renal vascular resistance (RVR), mean arterial blood pressure (MAP), plasma renin activity (PRA) and plasma noradrenaline (NA) levels were assessed. Injection of moxonidine did not increase fractional sodium excretion or lithium clearance. Specifically, antinatriuresis was not observed after injection of moxonidine despite a significant decrease in MAP from 91 to 85 mmHg and a significant increase in PRA. MAP and PRA did not change with administration of placebo. Injection of moxonidine did not affect GFR and RVR; ERPF decreased slightly but not significantly. Acute administration of 0.2 mg i.v. moxonidine decreased blood pressure in healthy volunteers on standardized salt intake, but did not affect natriuresis, proximal tubular sodium reabsorption or glomerular filtration rate. The absence of an antinatriuretic response despite a decrease in blood pressure suggests a direct facilitation of natriuresis by moxonidine.     

Diuretic and natriuretic effects of nifedipine in healthy persons.

1. We have studied the diuretic and natriuretic effects and the tubular site of action of nifedipine using free water clearance (CH2O) and lithium clearance. 2. We have compared the effects of nifedipine (10 mg p.o.) with those of placebo and of frusemide (40 mg p.o.) in seven healthy volunteers during maximal water diuresis. 3. Compared with placebo, nifedipine caused a significant rise in urinary flow rate and CH2O, paralleled by significant increases in fractional excretion of sodium and lithium. The rise in sodium excretion was not accompanied by an increase in potassium excretion. 4. Frusemide caused increases in sodium and lithium excretion, comparable with the effects seen after nifedipine. CH2O did not change however. 5. Our study demonstrates that nifedipine has a clear diuretic and natriuretic effect in healthy volunteers, which is predominantly established by interference with proximal tubular sodium reabsorption. Lithium clearance did not allow us to differentiate between nifedipine and frusemide effects, thus questioning the reliability of lithium as a marker of proximal tubular sodium reabsorption.     

Nonlinear disposition of lithium in rats and saturation of its tubular reabsorption by the sodium‐phosphate cotransporter as a cause

We previously reported the contribution of sodium‐phosphate cotransporter to the tubular reabsorption of lithium in rats. In the present study, the dose dependency of the renal handling of lithium was examined in rats. When lithium chloride at 1.25 mg/kg, 2.5 mg/kg and 25 mg/kg was intravenously injected as a bolus, the areas under the plasma concentration‐time curve of lithium until 60 minutes were calculated to be 6.23 mEq·min/l, 8.77 mEq·min/l and 64.6 mEq·min/l, respectively. The renal clearance of lithium and its fractional excretion increased with increments in the dose administered. The renal clearance of lithium strongly correlated with the urinary excretion rate of phosphate in the 1.25 mg/kg group (r = 0.840) and 2.5 mg/kg group (r = 0.773), whereas this correlation was weak in the 25 mg/kg group (r = 0.306). The infusion of foscarnet, a typical inhibitor of sodium‐phosphate cotransporter, decreased the fractional reabsorption of lithium in rats administered lithium chloride at 2.5 mg/kg, but did not affect it in rats administered 25 mg/kg. These results demonstrate the nonlinearity of the renal excretion of lithium in rats, with the saturation of lithium reabsorption by the sodium‐phosphate cotransporter potentially being involved.     

Effects of rilmenidine on stress-induced peak blood pressure and renal function.

Rilmenidine is an imidazoline I1-receptor agonist that centrally acts by reducing the sympathetic tone. There is strong experimental evidence that natriuresis could be evoked by proximal tubular I1-receptors that have also been isolated in human kidneys. However, in humans, the natriuretic effects of proximal tubular I1-receptors have never been demonstrated. Because stress tests elicited a sympathetically mediated increase in blood pressure and in sodium reabsorption, this study examined whether a short-term infusion of rilmenidine (1 mg) may interfere with stress-induced cardiovascular response and renal sodium handling in normotensive men, in a double-blind, crossover, placebo-controlled study. The stress test used is an efficient and reproducible computerized version of the Stroop's stress test. During the experimental sessions, both basal and stress renal functional parameters were determined: glomerular filtration rate, renal plasma flow, filtration fraction, sodium excretion, and segmental sodium tubular reabsorption (lithium clearance). During the placebo phase, stress induced a significant increase in systolic blood pressure (SBP; 22.2+/-10.1 mm Hg) and diastolic blood pressure (DBP; 11.0+/-5.0 mm Hg). During stress, glomerular filtration rate and renal plasma flow tended to decrease, resulting in a nonsignificant increase in filtration fraction. Despite the increase in BP, stress induced a significant decrease in sodium excretion that was due mainly to a nonsignificant increase in sodium reabsorption in the proximal parts of the tubules. Rilmenidine significantly reduced rest and stress BP, but the cardiovascular reactivity to stress was not altered. The treatment slightly decreased basal glomerular filtration rate and increased renal plasma flow, so that the filtration fraction significantly decreased. The treatment-related decrease in BP was associated with a significant increase in basal sodium reabsorption. Stress-induced modifications in renal function and sodium handling were not altered by the treatment. In conclusion, rilmenidine reduced rest BP and preserved stress-induced reactivity in BP and heart rate. Renal effects of rilmenidine are characterized by a decrease in glomerular filtration rate and in filtration fraction and an increase in sodium reabsorption. The study failed to demonstrate any effect of rilmenidine on stress-induced increase in sodium reabsorption.     

Renal digoxin clearance: Dependence on plasma digoxin and diuresis

Summary The renal handling of digoxin in animals involves glomerular filtration, tubular secretion and tubular reabsorption, while only glomerular filtration and tubular secretion have been described in humans. The influence of plasma digoxin and urine flow on the renal handling of digoxin was investigated in 6 healthy volunteers. Non-glomerular renal excretion of digoxin (tubular secretion minus tubular reabsorption) was inversely correlated with plasma digoxin concentration and directly with urine flow. Hence, the present study demonstrated the occurrence of tubular reabsorption in addition to glomerular filtration and tubular secretion of digoxin. The results suggest that renal clearance of digoxin should be increased by increased urine flow, which might be of importance during digoxin toxicity.     

RENAL DENERVATION POTENTIATES THE NATRIURETIC AND DIURETIC EFFECTS OF ATRIAL NATRIURETIC PEPTIDE IN ANAESTHETIZED RABBITS

1. The role of the renal nerves in modulating the action of atrial natriuretic peptide (ANP) in the kidney was studied by comparing the responses to ANP in innervated and surgically denervated kidneys in anaesthetized rabbits. 2. A low dose of ANP (0.05 μg/kg per min, i.v.) was used to minimize the confounding effects of systemic hypotension. 3. The natriuretic and diuretic responses to ANP were significantly greater in denervated kidneys than in kidneys with intact innervation. Sodium excretion from denervated kidneys rose by 7.49 ± 3.11 μmol/min in response to ANP (-55%, P<0.05) compared to 0.84 ± 0.59 μmol/min (-28%, NS) in innervated kidneys. Urine flow increased markedly in denervated kidneys by 73.2 ± 29.9 μmol/min (-60%, P<0.05) but not in innervated kidneys. 4. Fractional sodium excretion increased significantly in denervated kidneys in response to ANP (median 2.3% to median 3.0%, P<0.05). 5. Renal blood flow, glomerular filtration rate (GFR) and glomerular capillary pressure were unchanged in response to ANP in either denervated or innervated kidneys. Pre-glomerular vascular resistance fell in denervated kidneys during ANP infusion. 6. The natriuresis and diuresis observed in the denervated kidneys, due to an increased fractional excretion of sodium without increases in GFR or glomerular capillary pressure, is consistent with effects of ANP on tubular reabsorption of sodium. 7. Thus, ANP produced a natriuresis and diuresis at a low dose in denervated but not in innervated kidneys. This indicates that reflex activation of renal nerves may antagonize the renal effects of ANP.     

EFFECTS OF RENAL DENERVATION AND ATRIAL NATRIURETIC FACTOR ON TUBULAR REABSORPTION IN ANAESTHETIZED RATS

1. The effects of acute unilateral renal denervation were examined in 17 anaesthetized rats. Renal haemodynamic changes were monitored using standard clearance techniques. Lithium clearance was used to assess fractional proximal sodium and water reabsorption. 2. Denervation resulted in ipsilateral renal vasodilatation with marked natriuresis and diuresis, a small increase (15%, P less than 0.05) in glomerular filtration rate (GFR) and a consequent reduction in filtration fraction. Fractional lithium reabsorption decreased (67.3 +/- 2.9% to 54.5 +/- 4.0%, P less than 0.01) and absolute proximal reabsorption did not change, indicating impairment of proximal glomerulotubular balance (GTB). No similar changes in haemodynamic or transport parameters were observed in the contralateral, innervated kidney, although vascular resistance increased. 3. In 9 experiments following denervation of the left kidney, systemic low dose infusion (10 ng/min) of atrial natriuretic factor (ANF) resulted in a fall in mean arterial blood pressure from 116 +/- 3 mmHg to 107 +/- 3 mmHg (P less than 0.05). In the denervated kidney ANF increased urine flow rate and sodium excretion to rates above those established following denervation alone. However, in the right kidney, despite the increased filtered load (35%, P less than 0.01), the natriuretic and diuretic responses to ANF were abolished. 4. In the denervated kidney, ANF further reduced the fractional reabsorption of lithium from 53.6 +/- 2.3% to 45.6 +/- 3.8% (P less than 0.05). GFR increased by 32% (a total of 49% higher than during pretreatment) but absolute proximal reabsorption (APR) did not change. However, in the right, innervated kidney ANF infusion produced a 35% increase in GFR accompanied by a 53% rise in APR. 5. It is concluded that the natriuresis induced by unilateral denervation is due predominantly to impaired proximal GTB. The natriuretic action of ANF was associated with further impairment of proximal GTB, not dependent upon decreasing activity of renal sympathetic nerves, but was abolished when filtration fraction and renal sympathetic tone were elevated.     

The diuretic action of 8-cyclopentyl-1,3-dipropylxanthine, a selective A1 adenosine receptor antagonist.

1. The diuretic effect of the selective A1 adenosine receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPX), was investigated in anaesthetized rats. 2. CPX (0.1 mg kg-1, i.v.) produced significant increases in urine flow, and the excretion rate and fractional excretion of both sodium and chloride. By contrast, CPX administration did not result in any significant change in the excretion of potassium. 3. The diuretic effect of CPX was accompanied by a transient increase in inulin clearance although p-amino-hippurate clearance was unaffected, indicating the CPX induced a temporary elevation of glomerular filtration rate but no change in renal blood flow. 4. The fractional excretion of lithium (a marker of delivery of fluid out of the proximal tubule) was also significantly increased by CPX. However, other measures of tubular function derived from lithium clearance indicated that there were no changes in the handling of sodium or water in the distal regions of the nephron. 5. CPX did not significantly alter the relationship between either free water reabsorption or free water clearance and the distal delivery of sodium, which suggests that CPX does not affect the renal concentration/dilution mechanism. 6. The results of this study show that the diuresis and increased excretion of sodium and chloride induced by CPX (0.1 mg kg-1) in the rat, occurs with only transient elevation in glomerular filtration rate and no change in renal blood flow. The primary reason for the diuresis appears to be inhibition of sodium reabsorption in the proximal tubule.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal hemodynamic and excretory effects of n-0861, a non-xanthine adenosine A1-receptor antagonist

The renal hemodynamic and excretory effects of intravenous N-0861, a non-xanthine adenosine A₁-receptor antagonist, were evaluated in conscious and anesthetized male Sprague-Dawely rats. In conscious rats, N-0861 (10, 30 μmol/kg, iv) significantly increased the excretion of urine, Na⁺, and K⁺; U_ClV was increased only in the rats treated with 10 μmol/kg, N-0861. The relative excretion of K⁺ was similar to that of Na⁺. Lower doses of N-0861 (1, 3 μmol/kg, iv) had no effect. During clearance studies in anesthetized rats, N-0861 (3, 10, 30 μmol/kg, iv) had little effect on systemic or renal hemodynamics, but provoked significant saluresis that was poorly related to dose, and that was characterized by a somewhat greater excretion of Na⁺ and Cl^?? relative to K⁺. These results indicate that the selective adenosine A₁ receptor antagonist N-0861 has little influence on resting renal hemodynamics and suggest that the natriuretic responses are due to inhibition of tubular Na⁺ reabsorption.     

EFFECTS OF TORASEMIDE ON RENAL HAEMODYNAMICS AND FUNCTION IN ANAESTHETIZED DOGS

1. We examined the effects of torasemide (0.3 and 1 mg/kg i.v.) on renal haemodynamics and function employing renal clearance and stop-flow techniques in anaesthetized dogs and compared these with furosemide (1 and 3 mg/kg i.v.). 2. Torasemide and furosemide did not influence renal haemodynamics, in the renal clearance study, but caused a dose-related and significant increase in urine flow and urinary excretion of sodium and potassium. Torasemide and furosemide increased fractional excretion of sodium in the distal tubules with a relatively small increase in the fractional excretion of lithium (index of sodium excretion at the proximal tubules, FELi). The diuretic profile of torasemide was of long duration, compared with that of furosemide. 3. Torasemide and furosemide inhibited sodium reabsorption at the distal portion of the tubules in the stop-flow study. 4. It is suggested from these results, that the main diuretic site of action of torasemide is the ascending limb of the loop of Henlé.     

DIURETIC EFFECT INDUCED BY INTRARENAL INFUSION OF NISOLDIPINE IN ANAESTHETIZED DOGS

1. Renal effects of nisoldipine, a potent calcium channel blocker, were examined in anaesthetized dogs. 2. Intrarenal arterial infusion of nisoldipine (10, 50 ng/kg per min) did not influence mean systemic blood pressure and renal haemodynamics, but did cause dose-related increases in urine flow and urinary excretion of electrolytes. During nisoldipine infusion at the higher dose, the levels of fractional excretion of sodium, potassium and chloride were significantly elevated. 3. In the lithium clearance study, fractional lithium excretion, an index of fractional sodium excretion in the proximal tubules, was unchanged even with the higher dose of nisoldipine, whereas fractional sodium excretion in the distal tubules markedly increased. 4. Nisoldipine elicited a significant increment in osmolar clearance without altering the reabsorption of free water. 5. Thus, intrarenal administration of nisoldipine at a non-hypotensive dose to anaesthetized dogs produced a significant diuretic effect without alteration in renal haemodynamics. Results in lithium clearance and free water clearance studies suggest that nisoldipine exerts a diuretic action by inhibiting sodium transport at the distal nephron segments beyond the proximal tubules.     

Acute effects of lead on renal electrolyte excretion and plasma renin activity

Since lead accumulates in the kidney and interferes with the renal transport of amino acids and glucose, we tested the hypothesis that acute doses of lead also reduce tubular electrolyte reabsorption and alter the secretion of renin. In sodium pentobarbital-anesthetized dogs, acute iv lead increased the excretion of sodium, potassium, calcium, and water, despite a constant glomerular filtration rate; therefore lead reduced the tubular reabsorption of these substances. Lead also caused an increase in plasma renin activity. The threshold dose of acutely administered lead necessary to elicit these responses was determined in dose-response experiments on unanesthetized rats; a dose of 0.1 mg of lead/kg was sufficient to cause significant increases in plasma renin and the renal excretion of sodium. Lead concentrations in the tissues of the rats were measured in samples taken immediately at the conclusion of the study; the threshold dose of lead was associated with very low blood lead (< 5 μg/100 ml) and kidney lead (1.2 μg/g wet wt). These effects of lead are discussed with regard to their possible clinical significance.