Effects of the highly selective kappa opioid, U-50, 488, on renal function in the anesthetized dog

Intravenous administration of U-50,488 (a chemically novel and highly selective kappa agonist) resulted in dose-dependent increases in urine formation in anesthetized dogs. The increase in urine formation was not accompanied by an increase in sodium or potassium excretion; thus, U-50,488 behaved like a water diuretic. In addition, a dose-dependent fall in blood pressure was noted after U-50,488 administration. Despite the effect on blood pressure, no changes in renal plasma flow (p-aminohippurate clearance) or glomerular filtration rate (inulin clearance) were detected at any dose tested. Apparently, the diuresis was primarily due to tubular effects and not to changes in renal hemodynamics. Intravenous infusion of antidiuretic hormone (2 pmol/min/kg) abolished completely the diuretic response to U-50,488 (5 mg/kg). This implied that the diuresis was mediated by an effect of the drug on antidiuretic hormone.     

Renal tubular effects of chronic phosphate depletion.

The effects of chronic phosphate depletion on renal tubular function were evaluated by micropuncture and free water clearance studies in the dog. Proximal tubular punctures demonstrated that chronic hypophosphatemia led to a reduction in ratio of tubular fluid to plasma inulin in late superficial tubular from 1.59+/-0.08 in control animals to 1.29+/-0.06 in phosphate-depleted dogs, with proportional inhibition of calcium and sodium reabsorption. The chronic decrease in proximal tubular fluid reabsorption was confirmed by the analysis of sustained water diuresis in conscious, phosphate-depleted dogs, before and after repletion of body PO4 stores, and in control animals. Urine flow rate/100 ml glomerular filtration rate (V/GFR) was significantly higher in PO4 DEPLETION THAN CONTROL (15.8+/-1.1 VS. 10.7+/-0.82). In addition, acetazolamide infusion did not increase V/GFR in phosphate-depleted dogs (15.8+/-1.1 vs. 17.16+/-0.9), supporting the conclusion that inhibition of proximal tubular fluid reabsorption was responsible for the elevated urine flow rate. PO4 repletion over 5 days reduced V/GFR to 9.2+/-0.7 despite no change in urine osmolality and no change in GFR, further suggesting a specific reversible alteration in proximal tubular reabsorption in phosphate depletion. Although hypercalciuria was a constant finding in phosphate depletion (fractional excretion of calcium of 2.04+/-0.4% vs. 0.47+/-0.13% in controls), the enhanced distal delivery of calcium was not a crucial factor; acute phosphate infusion reduced urinary calcium excretion to control values without affecting the reduced proximal tubular reabsorption in either intact or thyroparathyroidectomized phosphate-depleted dogs the change in distal nephron calcium reabsorption was independent of parathyroid hormone (PTH) levels since infusion of PTH failed to alter urinary calcium excretion. We conclude that chronic phosphate depletion leads to a reversible, sustained inhibition in proximal tubular reabsorptive fuction as well as a specific decrease in distal nephron calcium reabsorption. This latter reabsorptive defect is sensitive to phosplate infusion but not corrected by PTH.     

Lithium clearance and renal tubular sodium handling during acute and long-term nifedipine treatment in essential hypertension

1. In two separate studies the lithium clearance method was used to evaluate the influence of acute and long-term nifedipine treatment on renal tubular sodium reabsorption. 2. In the acute study, after a 4 week placebo period two doses of 20 mg of nifedipine decreased supine blood pressure from 155/101 (20.6/13.5) +/- 11/4 (1.5/0.5) to 139/88 (18.5/11.7) +/- 16/9 (2.1/1.2) mmHg (kPa) (means +/- SD; P less than 0.01). Lithium clearance, glomerular filtration rate and sodium clearance did not change. Therefore the calculated values of absolute proximal and absolute distal sodium reabsorption rates were also unchanged, as were potassium clearance, urine flow and body weight. 3. In the long-term study, lithium clearance, glomerular filtration rate, sodium clearance, potassium clearance, urine flow and body fluid volumes were measured after a 4 weeks placebo period and after 6 and 12 weeks of nifedipine treatment. As compared with placebo, mean supine blood pressure decreased significantly. The glomerular filtration rate did not change but lithium clearance fell by 30%. Consequently, the absolute and the fractional proximal sodium reabsorption increased significantly. The fractional distal sodium reabsorption did not change. Sodium clearance, fractional sodium excretion, potassium clearance, plasma volume and extracellular fluid volume were also unchanged. 4. In conclusion, we found no changes of renal tubular sodium reabsorption during acute nifedipine treatment, whereas long-term nifedipine treatment caused a redistribution of tubular sodium reabsorption without a change in overall sodium excretion or body fluid compartments.     

Renal sodium retention in cirrhosis: relation to aldosterone and nephron site.

1. In a group of patients with cirrhosis who showed a wide range of values for the rate of renal sodium excretion, the latter was found to be inversely related to both the plasma concentration and rate of renal excretion of aldosterone. However, for a given sodium excretion the values for aldosterone were significantly lower in the patients than for a group of healthy control subjects. These findings suggest either an increased renal tubular sensitivity to aldosterone or the participation of other factors in the pathogenesis of the sodium retention. 2. Based on measurements of the rate of urine flow and the clearances of free water and inulin during a maximal water diuresis, the fractional reabsorption of sodium by the 'proximal', 'diluting segment' and 'distal' segments of the nephron was estimated. For patients retaining sodium the enhanced reabsorption occurred at both proximal and distal sites, the latter being quantitatively more important. There was no significantly enhanced sodium reabsorption in the diluting segment.     

Increased Clearance of Antipyrine and d-Propranolol after Phenobarbital Treatment in the Monkey: RELATIVE CONTRIBUTIONS OF ENZYME INDUCTION AND INCREASED HEPATIC BLOOD FLOW

The effects of phenobarbital treatment for 12 days on the regional distribution of blood flow and on the disposition of two model drugs, antipyrine and d-propranolol, have been determined in six unanesthetized rhesus monkeys. Phenobarbital significantly increased total hepatic blood flow from 179+/-15 to 239+/-27 ml/min. Liver weight was increased to a similar degree (34%) in phenobarbital-treated animals as compared to control monkeys. The clearance of both antipyrine and d-propranolol was increased and the half-life decreased significantly by phenobarbital. Analysis of the data by a perfusion-limited pharmacokinetic model showed that the changes in antipyrine clearance were due almost entirely to enzyme induction. On the other hand, with d-propranolol, the increase in liver blood flow contributed as much to the enhanced clearance as did the stimulation of drug metabolism. The mechanism by which phenobarbital produces the frequently observed increase in drug clearance, therefore, depends upon the initial clearance value of the drug. For low clearance drugs like antipyrine, clearance changes occur largely as a result of enzyme induction. With higher clearance drugs, the effects of increased hepatic blood flow become progressively more important the greater the initial clearance value.     

Effects of Felodipine on the dog kidney: a lithium clearance study.

This study was performed in order to investigate the possible influence of sympathetic nerve activity on the effects of the dihydropyridine calcium antagonist felodipine on absolute and fractional reabsorption rates of sodium and water in proximal and distal tubular segments in the dog kidney. Clearance of 51Cr-EDTA was used as a measure of glomerular filtration rate (GFR). GFR, urinary excretion rates of sodium and water, and lithium clearance (C-Li) were used for assessing the absolute and fractional tubular reabsorption rates. Felodipine infusion into the right renal artery increased renal vascular conductance (renal blood flow divided by renal arteriovenous pressure gradient) significantly (by 9%) while GFR remained unchanged. Calculated absolute proximal reabsorption rates remained unchanged while distal sodium reabsorption rate increased significantly from 2.1 +/- 0.3 to 2.7 +/- 0.4 mmol min-1. Sodium clearance (C-Na) increased from 0.22 +/- 0.08 to 0.40 +/- 0.07 ml min-1. The alpha-adrenergic blockade with phentolamine did not affect renal haemodynamic or excretory variables, nor did it influence the haemodynamic response to felodipine. After alpha-adrenergic blockade felodipine caused an increase in C-Na from 0.28 +/- 0.06 ml min-1 to 0.63 +/- 0.04 ml min-1, which was significantly greater than that measured after felodipine alone. The distal load (C-Li) was not significantly different from that obtained after felodipine alone, but distal sodium reabsorption rate increased less significantly after alpha-adrenergic blockade. The results suggest that felodipine, by its effect on tubular flow and/or composition, activates local alpha-adrenergic reflex mechanism(s), which stimulates distal sodium reabsorption, thereby attenuating the natriuretic effect.     

The effect of the plasma bicarbonate level on proximal tubule sodium reabsorption in NH4Cl-loaded dogs.

In an attempt to examine the effects of mild and severe chronic metabolic acidosis on proximal tubule sodium reabsorption, 6 dogs were given 10 mEq. per kilogram per day and 5 dogs were given 20mEq. per kilogram per day of ammonium chloride for 3 days and compared to 12 normal dogs during a steady-state water diuresis and following the administration of ethacrynic acid (EA) intravenously (2 mg. per kilogram) utilizing standard clearance methodology, In the severely acidotic group (pH decrease is greater tthan 0.2) plasma pH was 7.08 +/- 0.06 and plasma bicarbonate was 6.3 +/- 1.0 Eq. per liter compared to a pH of 7.33 +/-0.02 and bicarbonate of 13.4 +/- 0.7 in mild acidosis (pH decrease is less than 0.2). During a steady-state water diuresis urine flow was 14.2 +/- 0.9 in severely acidotic compared to 10.5 +/-0.7 ml. per minute per 100 ml. glomerular filtration rate (GFR) in normal dogs (p is less than 0.01). Following EA sodium clearance increased 38.4 +/- 3.5 in severely acidotic dogs and 27.6 +/- 2.0 ml. per minute per 100 ml. GFR in normal dogs (p is less than 0.02). In mild acidosis, steady-state fractional urine flow and the increase in fractional sodium clearance following EA were not significantly different than normal dogs. We conclude that chronic metabolic acidosis leads to an increase in distal solute load and enhanced natriuretic effect of EA secondary to a decrease in proximal tubule sodium reabsorption which may be dependent upon the degree of reduction in the plasma bicarbonate level.     

Antinatriuretic effect of acute morphine administration in conscious rats

The renal response to the acute administration of morphine was examined in conscious, chronically catheterized, nonhydrated rats. After control clearance periods, morphine sulfate was injected i.v. at 4 mg/kg followed by an infusion of 2 mg/kg X hr. Morphine caused an increase in urine flow which was variable in magnitude and duration. The initial diuresis was not maintained despite continued morphine administration and replacement of lost fluid. Compared to vehicle treatment morphine also induced marked sodium and chloride retention which was sustained throughout the 2-hr infusion period. There were no changes in blood pressure or heart during the clearance periods, although an initial transient hypotension and bradycardia were observed with morphine injection. There were no changes in glomerular filtration rate which could account for the antinatriuresis. Naloxone pretreatment blocked all of the observed renal responses. The results indicate that morphine exerts its effects on electrolyte excretion by enhancing renal tubular sodium or chloride reabsorption rather than changes in systemic hemodynamics or glomerular filtration rate. In a separate series of experiments, urine osmolality, osmolar clearance and free water clearance were estimated. All rats receiving morphine transiently excreted a hypotonic urine (minimum 183 +/- 23 mOsmol/kg of H2O) with a reduction in osmolar clearance and a sharp increase in free water clearance. These findings are consistent with a temporary inhibition of vasopressin release by morphine.     

Norepinephrine and vital organ blood flow

OBJECTIVE: To test whether norepinephrine (NE) infusion at 0.4 microg kg(-1) min(-1) adversely affects regional blood flow in the normal mammalian circulation. DESIGN AND SETTING: Randomized cross-over experimental animal study in a university-affiliated physiology institute. SUBJECTS: Six merino ewes. INTERVENTIONS: Staged insertion of transit-time flow probes around the ascending aorta and circumflex coronary, superior mesenteric and left renal arteries. In conscious animals with chronically embedded flow probes randomization to either 6 h of placebo (saline) or drug (NE at 0.4 microg kg(-1) min(-1)). MEASUREMENTS AND RESULTS: Compared to placebo, NE significantly increased mean arterial pressure (84.4 vs. 103.8 mmHg), heart rate (61.0 vs. 74.6 bpm) and cardiac output (3.76 vs. 4.78 l/min). These changes were associated with an increase in coronary blood flow (24.2 vs. 37.4 ml/min) and renal blood flow (215.2 vs. 282.0 ml/min) but no change in mesenteric blood flow. The increase in renal and coronary blood flow was associated with an increase in regional conductance (regional vasodilatation), while mesenteric conductance fell (mesenteric vasoconstriction). Urine output (91+/-17 vs. 491+/-360 ml/h) and creatinine clearance (61+/-18 vs. 89+/-12 ml/min) increased during NE infusion. CONCLUSIONS: NE infusion does not induce vital organ ischaemia in the normal mammalian circulation. Furthermore, it results in a significant increase in coronary and renal blood flow with a concomitant improvement in urine output and creatinine clearance.     

Renal hemodynamic and tubular transport effects of nitrendipine

Nitrendipine, a 1,4-dihydropyridine derivative, is a new calcium entry blocker with marked antihypertensive effects. Because relatively few data are available regarding its renal effects, we studied the drug's action on renal hemodynamics and electrolyte excretion in normal male volunteers. During sustained water diuresis, 5 to 10 mg nitrendipine given orally caused an increase in urine flow rate and a modest but consistent increase in sodium excretion (from 1.0% to 2.2% of filtered load, P less than 0.01). Furthermore, both solute-free water clearance and percentage of free water excreted rose (from 10.1 +/- 0.6 ml/min to 12.0 +/- 0.8 ml/min and from 8.7% +/- 0.5% to 10.5% +/- 1.1%, respectively, P less than 0.05 in each case). In addition, during the peak effect of the drug on sodium and free water excretion, there was no consistent change in either glomerular filtration rate or effective renal plasma flow. Nitrendipine was also phosphaturic and calciuric but did not alter acid excretion. When administered to subjects with hydropenia receiving hypertonic saline infusion, the drug had no effect on solute-free water reabsorption. We interpret these results to indicate that nitrendipine has direct tubular effects on renal electrolyte transport and that the locus of these effects is probably the proximal tubule. Thus, nitrendipine appears to differ from other calcium channel blockers in that it does not reduce glomerular filtration rate and is mildly natriuretic, rather than sodium retentive.     

Cardiovascular and renal responses to acute cold exposure in water-loaded man.

Changes in oxygen uptake, cardiac output, heart rate, stroke volume, central blood volume, arteriovenous oxygen difference, aortic, pulmonary arterial, and right atrial blood pressure, systemic vascular resistance, hematocrit, circulating plasma volume, urine flow, fractional sodium excretion, and free water clearance were studied in eight healthy volunteers in stable water diuresis, exposed to cold by means of air at +15 degrees C and at a speed of 0.5 m/sec. A decrease in circulating plasma volume and systemic vascular resistance was found during cold stress. Mean aortic blood pressure, sodium excretion, cardiac output, oxygen uptake, arteriovenous oxygen difference, and hematocrit increased. No changes in urine flow or in clearance of free water could be demonstrated. Heart rate, stroke volume, and central blood volume showed significant increases in cold. The results are interpreted to suggest that exposure to cold raises the arterial blood pressure by an increase in cardiac output, thereby increasing capillary hydrostatic pressure in certain vascular areas, including the renal vascular bed. This negatively affects capillary reabsorption processes in the kidney, causing a reduction in tubular sodium reabsorption, thus giving rise to a natriuresis. In other areas it seems to cause a shift of fluid towards the intersitial space.     

Effects of increased sodium delivery on distal tubular sodium reabsorption with and without volume expansion in man

The separate effects of volume expansion and of increased delivery of sodium on sodium reabsorption in the diluting segment of the distal nephron were studied in man. In six normal subjects during a sustained water diuresis, sodium delivery to the distal nephron was increased without volume expansion by the administration of acetazolamide. In these subjects, free water clearance rose linearly as a function of urine flow. In five patients with complete, central diabetes insipidus, distal sodium delivery was increased by the infusion of hypertonic saline during a sustained water diuresis. In four of these five patients, changes in free water clearance were also observed during hypertonic saline diuresis in the presence of distal blockade of sodium reabsorption with chlorothiazide. At high rates of distal delivery the following observations were made: (a) free water clearance was lower and fractional sodium excretion higher during saline diuresis compared to acetazolamide diuresis; (b) although free water clearance was moderately reduced by chlorothiazide at low rates of urine flow, there was no difference in free water clearance between saline loading alone and saline plus chlorothiazide at high rates of urine flow; and (c) during saline loading free water clearance rose without evidence of a limit when increased distal delivery was accompanied by spontaneous increases in glomerular filtration rate, but tended toward a limit when glomerular filtration rate remained constant.The data indicate that during acute volume expansion with saline, there is a decrease in the fraction of delivered sodium reabsorbed in the distal nephron when compared to the response of the distal nephron to comparable increases in distal sodium delivery in the absence of volume expansion.     

Possible tubular site of action in anesthetized dogs of a synthetic alpha-human atrial natriuretic polypeptide

Intrarenal arterial infusion of a synthetic alpha-human atrial natriuretic polypeptide (alpha-hANP) in a dose of 5.0 micrograms/min to anesthetized dogs led to a significant increase in urine flow and urinary excretion of electrolytes. Tubular sites of action of alpha-hANP were determined by using free water clearance techniques and in stop-flow experiments. During water diuresis, free water clearance did not increase in proportion to the increase in urine flow rate. Intrarenal administration of the peptide to dehydrated animals resulted in no change in solute-free water reabsorption, notwithstanding a significant increase in osmolar clearance. These data suggest that the peptide acts on the diluting segment of the ascending limb of Henle and also at the distal nephrons, findings which support data obtained in stop-flow experiments. Infusion of the peptide lowered inulin concentration and elevated sodium concentration in the stop-flow urine from the distal tubules and collecting duct. It is tentatively concluded that alpha-hANP produces potent diuretic and natriuretic responses by suppressing water and sodium transport in the distal portion of the nephron.     

Possible mechanisms of polyuria in progressive chronic renal failure

AIM: Elucidation of the role of saluresis and osmotic diuresis in renal function of patients with chronic renal failure. MATERIAL AND METHODS: The trial included 68 subjects, among them 25 patients with chronic renal failure (CRF) of the third and fourth degree aged 16 to 72 years. Enzyme immunoassay was used to measure osmolality, sodium, potassium, magnesium, calcium and creatinine concentrations in the serum and urine as well as urine prostaglandin E2. RESULTS: Renal function was studied in CRF patients with a 75-90% fall of glomerular filtration rate. Creatinine clearance was 19.9 +/- 0.96, it varied in different patients from 10.6 to 29.7 ml/min. It is shown that diuresis does not correlate with the total ion excretion (Na+ plus K+)(r = 0.946, p < 0.0001). A correlation was found between excretion of these ions and Mg2+ ions this indicating location of reabsorption reduction in the thick ascending limb of Henle loop. In CRF patients (Na+ plus K+) excretion correlated with PGE2 excretion (r = 0.65, p < 0.0001). CONCLUSION: It is suggested that at this stage of chronic renal failure the mechanism of a diuresis increase is not due to osmotic diuresis but rather to secretion of prostaglandin E2 which inhibits cation reabsorption and stimulates diuresis. Differences are considered between osmotic diuresis and different types of saluresis; their possible mechanisms are discussed.     

Furosemide pharmacodynamics: effect of respiratory and acid-base disturbances

The aims of this study were to investigate the effect of changes in arterial blood gases and pH on furosemide pharmacodynamics and kinetics. Five groups of conscious rabbits were used: a control group breathing air with normoxia and normocarbia; a second group with hypercapnia and respiratory acidosis; a third with hypoxemia; a fourth with hypercapnia and respiratory acidosis combined with hypoxemia (HCHO); and the fifth group with metabolic acidosis. All experimental conditions, except hypoxemia, increased sodium tubular reabsorption and therefore, decreased urinary excretion of sodium. Renal blood flow was decreased by HCHO and metabolic acidosis. In response to 5 mg/kv i.v. of furosemide, natriuresis and diuresis were decreased by an average of 44% in animals with HCHO (P less than .05). The kinetics of furosemide were not affected by any of the experimental conditions except HCHO, in which the renal clearance of furosemide was reduced from 7.5 +/- 1.4 ml/min/kg (controls) to 2.7 +/- 0.7 ml/min/kg (P less than .05). The reduction in renal clearance of furosemide was associated with a decrease in urinary excretion of sodium (P less than .05). The reduction in renal clearance of furosemide was probably secondary to the decrease in renal blood flow and an increase in furosemide tubular reabsorption. Finally, HCHO did not decrease plasma volume, suggesting that the reduction in renal blood flow was secondary to blood flow distribution. In conclusion, only hypercapnia and respiratory acidosis combined with hypoxemia decreases the natriuretic and diuretic effect of furosemide.     

Vancomycin pharmacokinetics, renal handling, and nonrenal clearances in normal human subjects

The renal handling of vancomycin is unknown. Previously reported studies have not achieved steady-state conditions with constant vancomycin concentrations. We measured systemic vancomycin clearance simultaneously with the renal clearances of vancomycin, creatinine, inulin, and para-aminohippurate in nine healthy subjects at steady-state serum vancomycin concentrations of 7 and 14 mg/L. For all steady-state observations the renal clearance of vancomycin was 89 +/- 11 ml/min (mean +/- SE), the clearance of inulin 105 +/- 9 ml/min, the clearance of creatinine 117 +/- 9 ml/min, and the clearance of para-aminohippuric acid 496 +/- 41 ml/min. The systemic clearance of vancomycin was 131 +/- 7 ml/min. The clearances of creatinine, inulin, and para-aminohippuric acid and the renal clearance of vancomycin were not statistically different at both steady-state vancomycin concentrations. The ratio of the renal clearance of vancomycin to the clearance of inulin was 0.89 +/- 0.06 and to creatinine clearance 0.79 +/- 0.05. Both ratios were independent of vancomycin concentration, urine flow rate, and filtration fraction. The systemic clearance of vancomycin was 10% greater at serum vancomycin concentrations of 14 mg/L than at 7 mg/L (p less than 0.05) because of an increase in the nonrenal clearance. Therefore in healthy subjects, 30% of the systemic vancomycin clearance is by nonrenal mechanisms and this nonrenal clearance is concentration dependent. Assuming protein binding to be between 10% and 20%, renal vancomycin excretion is predominantly by glomerular filtration. Small amounts of tubular vancomycin transport cannot be excluded by these techniques.     

Renal actions of theophylline and atrial natriuretic peptide in humans: a comparison by means of clearance studies

The hypothesis that the methylxanthine theophylline and atrial natriuretic peptide (ANP) have similar actions in the kidney was tested. Doses of equal natriuretic potency were administered to seven healthy men during maximal water diuresis. Theophylline (1.2 mg/kg/min) increased sodium excretion to 3-fold, increased glomerular filtration rate and filtration fraction and had no effect on estimated renal plasma flow. Increments were also found in maximal urine flow, distal delivery index and fractional lithium clearance. Diluting segment reabsorption index decreased, and minimal urine osmolality increased. ANP, of which the dose was low (0.01 micrograms/kg/min), had similar effects on sodium excretion, glomerular filtration rate, filtration fraction, minimal urine osmolality and diluting segment reabsorption index, but it decreased estimated renal plasma flow and had no effect on distal delivery and fractional lithium clearance. In a third clearance study ANP was infused after 3 days of treatment with theophylline. The only difference observed was that theophylline prevented the ANP-induced fall in estimated renal plasma flow. Theophylline did not enhance the natriuretic effect of ANP nor its effect to stimulate urinary cyclic guanosine monophosphate. Pretreatment with theophylline had raised plasma renin activity, but the effect of ANP to lower plasma renin activity was not diminished. Our observations agree with the idea that theophylline and ANP act via common mechanisms in the kidney. However, ANP effects are independent of theophylline's action.     

The acute effect of acetazolamide on glomerular filtration rate and proximal tubular reabsorption of sodium and water in normal man

The acute effects on kidney function of acetazolamide (250 mg) given intravenously were evaluated in seven healthy subjects. Glomerular filtration rate was measured as the renal clearance of 51Cr-EDTA, and fluid flow rate out of the proximal tubules was assessed by measurement of the renal lithium clearance. An 18% decline in glomerular filtration rate (ml/min) was observed after acetazolamide administration (109 +/- 16 vs 89 +/- 14, p less than 0.02), while lithium clearance (ml/min) increased by 35% (30 +/- 5 vs 38 +/- 8, p less than 0.02). Absolute proximal tubular reabsorption of water (ml/min) was reduced by about one third (79 +/- 12 vs 51 +/- 9, p less than 0.02), and fractional proximal reabsorption of water and sodium (%) declined (73 +/- 2 vs 58 +/- 6, p less than 0.02). Renal sodium clearance and absolute distal reabsorption of sodium increased, while fractional distal reabsorption of sodium declined. Acetazolamide reduces absolute and fractional proximal tubular reabsorption of sodium and water, and glomerular filtration rate. Primarily, this induces an increase in the output of fluid from the proximal tubules accounting for the diuretic effect of the drug. The acute fall in glomerular filtration rate is probably mediated by a temporary increase in proximal intratubular pressure and activation of the tubuloglomerular feedback mechanism.     

Effects of quinidine on the renal tubular and biliary transport of digoxin: in vivo and in vitro studies in the dog

Quinidine is known to inhibit the renal clearance of digoxin without affecting glomerular filtration rate. The renal interaction between these drugs was investigated by a combination of in vivo and in vitro methods. The uptake of digoxin by brush border membrane vesicles was not affected by quinidine. Similarly, digoxin did not inhibit the uptake of the cation N-methylnicotinamide by these vesicles and did not alter the binding kinetics of digoxin to the Na+, K+-adenosine triphosphatase by the antiluminal membrane vesicles. By using the in vivo multiple indicator dilution technique transtubular transport of digoxin was documented; renal-artery infusion of quinidine did not affect the recovery of digoxin in the renal vein or urine. Clearance studies documented that the decrease in the renal clearance of digoxin is paralleled by a significant fall in renal blood flow evidenced by a decrease in p-aminohippuric acid clearance. It is concluded that quinidine inhibits the renal excretion of digoxin not by competition at the tubular cell membrane level, but rather by decreasing renal blood flow. A parallel decrease in biliary clearance of digoxin is documented and may suggest a similar mechanism.     

A new oral renal vasodilator, fenoldopam

Fenoldopam, a dopamine agonist, was evaluated in renal clearance studies during water diuresis after oral doses of 25, 50, and 100 mg. After the 100-mg dose there was an increase in urine flow rate, paraaminohippurate clearance, free water clearance, and an increase in the fractional excretion of sodium, calcium, and uric acid. These effects were evident within the first hour, peaked during the second hour, and lasted about 3 hr. Doses of 50 and 25 mg induced smaller increases. There was no significant change in inulin clearance at any dose. To elucidate the mechanism of action, the studies were repeated after treatment with a dopamine-receptor antagonist (metoclopramide). Metoclopramide greatly diminished the renal effects of fenoldopam. These findings indicate that fenoldopam is an active renal vasodilator in man and increases urine volume, free water clearance, and fractional excretion of sodium by stimulation of renal dopamine receptors.