Effects of metoprolol and propranolol on furosemide-stimulated renin release in healthy subjects

Summary The effects of single doses of the beta₁-receptor antagonist metoprolol (40 mg orally), propranolol (40 mg orally) and placebo were compared on furosemide-stimulated plasma renin activity (PRA) in seven healthy subjects. In the placebo studies, PRA increased by 0.59±0.18 ng×ml^–1×h^–1 60 minutes after intravenous administration of 30–60 mg furosemide. After propranolol and metoprolol, the corresponding increases in PRA were significantly less pronounced amounting to 0.16±0.06 and 0.24±0.08 ng×ml^–1×h^–1, respectively. The resting heart rate was reduced to the same extent after the two beta-blockers, which means that the two drugs had been given in equipotent beta₁-receptor blocking doses. It is suggested that the release of renin from the kidney may partly be mediated via an adrenergic beta₁-receptor.Metoprolol (piNN)=H 93/26=CGP 2175     

Pharmacokinetics of oral salbutamol controlled-release in Asian patients with asthma

Summary Using a double blind, double dummy crossover design, single dose and steady state pharmacokinetics of oral controlled release (SCR) salbutamol 4 mg and 8 mg tablets b. d. has been studied in 8 Asian patients.Plasma salbutamol was measured over 12 h. In 8 patients the single dose mean C_max was 4.2 ng·ml^–1 and 7.7 ng·ml^–1 after 4 and 8 mg, respectively. In 5 patients the steady state mean C_max, C_min and t_max were 8.1 ng·ml^–1 and 4.7 ng·ml^–1 and 6 h for the 4 mg tablets and 14.1 ng·ml^–1 and 7.1 ng·ml^–1 and 4 h for the 8 mg tablets.It is concluded that both doses of SCR show features of controlled release and that they produced a relatively constant plasma level of salbutamol in Asian patients.     

The effect of exercise on atropine pharmacokinetics

Summary Seven healthy males (19–32 y) underwent each of four separate conditions in a repeated measures design. Five of these subjects underwent an additional trial. In four of five trials subjects received 2.0 mg atropine sulfate intramuscularly in the anterolateral portion of the left thigh: at rest (T1); following completion of a single exercise (Ex) bout (T2), (Each bout consisted of 25 min of stationary cycling at 40% VO₂ max with 5 min of seated rest), prior to three Ex bouts (T3) and following one and prior to three Ex bouts (T5). Trial 4 (T4) was the same as T3 with the substitution of a saline placebo. Serum samples were collected over a 12 h period and atropine concentration was determined by RIA. Ex trials were compared to T1.Ex prior to atropine (T2) significantly decreased the mean volume of distribution (V_z, 278 vs 2321). Ex in T3 significantly decreased the serum half life (t_1/2, 4.2 vs 3.5 h), V_z (278 vs 1981), and clearance (CL, 763 vs 638 ml·min^–1) and significantly increased the peak concentration (Cp, 6.7 vs 12.3 ng·ml^–1) and area under the curve (AUC, 44.1 vs 53.1 ng·ml^–1). In T5, Ex significantly decreased the t_1/2 (3.4 h), V_z (182 l) and CL (575 ml·min^–1) and significantly increased the absorption rate constant (ka, 0.482 vs 1.1 min^–1), elimination rate constant (ke, 0.0012 vs 0.0015 min^–1), C_p (14 ng·ml^–1) and AUC (53.3 ng·h·ml^–1).These results demonstrate that moderate Ex either prior to and/or immediately following drug administration has the capacity to significantly modify atropine pharmacokinetics.Portions of this work were presented at the annual meeting of The American Society for Pharmacology and Experimental Therapeutics, Montreal, Canada, October 1988The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the opinions of the Department of the Army or the Department of Defense.     

Pharmacokinetics and pharmacodynamics of thiazinamium in asthmatic patients

Summary The pharmacokinetics and pharmacodynamics of thiazinamium (Multergan) were studied after intravenous and intramuscular administration to 7 males with chronic reversible airways obstruction.Disposition after i.v. administration was described by a clearance of 0.54 l·min^–1, central compartment volume of 14.8 l, distribution rate constant 0.092 min^–1, and an elimination rate constant of 0.0044 min^–1. The corresponding estimates after i.m. administration were 0.324 l·min^–1, 34.1 l, 0.035 min^–1, and 0.0018 min^–1. The bronchodilator response (expressed as % predicted FEV1) after i.v. administration was characterized by maximum increase in FEV1 of 33.9%, with an EC₅₀ of 12.8 ng·ml^–1 and an equilibration half-time of 11 min. Corresponding parameter estimates after i.m. administration were 32.2%, 18.8 ng·ml^–1, and 9 min.Anticholinergic activity, measured by the change in heart rate after i.v. administration, showed maximum increase of 76 beats·min^–1, with an EC₅₀ of 176 ng·ml^–1 and an equilibration half-time of 1.3 min. After i.m. administration the corresponding values were 120 beats·min^–1, 250 ng·ml^–1, and 3 min.The optimal plasma concentration of thiazinamium was about 100 ng·ml^–1, which should give a near maximal bronchodilator response (over 80% of predicted normal) and a heart rate of about 100 beats·min^–1.     

A double-blind placebo controlled dose response study of noberastine on histamine induced weal and flare

Summary The antihistaminic effects of 7 days treatment with each of three doses of noberastine (10, 20 and 30 mg) were compared to placebo in 12 healthy male volunteers. The antihistaminic activity was assessed from the inhibition of weal and flare formation after intradermal histamine injections. For both weal and flare there was a highly significant effect of treatment with each of the three doses of noberastine, compared to placebo. The 30 mg daily dose produced the maximum inhibition of weal and flare. The daily mean values for the assessment of sedation by visual analogue scales at 09.00 h, 15.00 h and 21.00 h showed no significant treatment, or order, effect for any of the three doses of noberastine compared to placebo. The mean steady-state plasma concentrations of noberastine were significantly higher with increasing daily doses of noberastine (trough concentrations: 1.0, 1.6 and 2.2 ng·ml^–1; peak concentrations: 3.5, 13.4 and 20.9 ng·ml^–1 for 10, 20 and 30 mg daily dose, respectively). The percentage weal inhibition correlated (r=0.77) with steady-state noberastine plasma trough levels. The percentage flare inhibition showed a weaker correlation (r=0.35) with steady-state noberastine plasma trough levels.     

Removal of famotidine by haemodialysis in elderly anuric patients

Summary The effect of haemodialysis on the pharmacokinetics of oral famotidine has been studied in five elderly anuric patients. Famotidine 20 mg was administered in a cross-over design to patients on and not on haemodialysis.The elimination rate constant of haemodialysis (k) was 4.6-fold larger than the systemic elimination rate constant (k_e). Although the mean maximum serum concentration of famotidine during haemodialysis (141.5 ng·ml^–1) was not significantly lower than that without haemodialysis (195.6 ng·ml^–1), the AUC up to 5 h during haemodialysis was significantly decreased to 58.1% of the value without it.The data suggest that famotidine is dialysable by haemodialysis.     

Interaction of talinolol and sulfasalazine in the human gastrointestinal tract

Summary The absorption of talinolol (TA) 50 mg was investigated without and together with the co-administration of sulfasalazine (SASP) 4 g in 11 healthy young volunteers, in order to clarify gastrointestinal transit of TA.Without SASP, the t_max of TA was 2.8 h, C_max was 112 ng·ml^–1 and the half life was 12 h; the AUC_o-t was 958 ng·ml^–1·h.In the case of concomitant administration of SASP, TA was found only in serum from 3 individuals, with a C_max of 23 ng·ml^–1 and a mean AUC_o-t of 84 ng·ml^–1·h. TA was not detectable in 5 subjects and it was at the limit of detection (2 ng·ml^–1) in 3 subjects. Pharmacokinetic analysis was not possible in any of those individuals.The reason for the interaction appears to be the adsorption of TA by SASP. An interval of 2–3 h should elapse between giving SASP and other drugs.     

The pharmacokinetics and pharmacodynamics of sublingual and oral alprazolam in the post-prandial state

Summary We gave 12 healthy male volunteers 1 mg of alprazolam or placebo on three occasions after a standard breakfast in a double-blind, randomized, single-dose, three-way crossover study.The three trials were: (a) oral alprazolam and sublingual placebo; (b) oral placebo and sublingual alprazolam; (c) placebo by both routes.Plasma alprazolam concentrations during 24 h after each dose were measured by electron-capture gas-liquid chromatography.Peak plasma concentrations were reached later after sublingual than oral dosage (2.8 vs 1.8 h, P<0.01). Other kinetic variables were not significantly different: peak plasma concentration, 11.3 vs 12.0 ng·ml^–1; elimination half-life, 12.5 vs 11.7 h; and total area under the plasma concentration versus time curve, 197 vs 186 h·ng·ml^–1.Pharmacodynamic measures showed that sublingual and oral alprazolam both produced sedation, fatigue, impaired digit symbol substitution, slowing of reaction time, and impairment of the acquisition and recall of information. These changes were initially observed at 0.5 h after dosage and lasted up to 8 h.In general the two routes were significantly different from placebo but not from each other.     

Growth hormone-releasing activity of hexarelin in humans

Hexarelin is a new hexapeptide (His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH₂) that stimulates the release of growth hormone both in vitro and in vivo. In this double-blind, placebo-controlled, rising-dose study we evaluated the growth hormone releasing activity of hexarelin in healthy human subjects. Twelve adult male volunteers received single intravenous boluses of 0.5, 1 and 2 ·g·kg^–1 hexarelin as well as placebo. For safety, drug doses were given in a rising-dose fashion with placebo randomly inserted into the sequence. Plasma growth hormone concentrations increased dose-dependently after the injection of the peptide, peaking at about 30 min and then decreasing to baseline values within 240 min with a half-life of about 55 min. The mean peak plasma growth hormone concentrations (C_max) were 3.9, 26.9, 52.3, 55.0 ng·ml^–1 after 0, 0.5, 1 and 2 g·kg^–1, respectively. The corresponding areas under the curve of growth hormone plasma levels from drug injection to 180 min (AUC_0–180) were 0.135, 1.412, 2.918 and 3.695 g·min·ml^–1. The theoretical maximum response (E_max) and the dose that produces half of the maximum response (ED₅₀) were estimated using logistic regression. The calculated ED₅₀ values were 0.50 and 0.64 g·kg^–1 for C_max and AUC_0–180, respectively. The corresponding E_maxs were 55.1 ng·ml^–1 and 3936 ng·min·ml^–1, thus indicating that the effect after the 2 g·kg^–1 dose is very close to the maximal response. Plasma glucose, luteinising hormone, follicle-stimulating hormone, thyroid-stimulating hormone and insulin-like growth factor I were unaffected by hexarelin administration, while the peptide caused a slight increase in prolactin, cortisol and adrenocorticotropic hormone levels. Hexarelin was well tolerated in all subjects. The results of this study indicate that intravenous administration of hexarelin in man produces a substantial and dose-dependent increase of growth hormone plasma concentrations.     

Total and free steady-state plasma levels and pharmacokinetics of nifedipine in patients with terminal renal failure

Summary The total and free steady-state plasma levels of nifedipine in patients with renal failure have been compared with those in subjects with normal renal function. Studies were done after administration of nifedipine 10 mg t.d.s. p.o. for 5 days, after i.v. infusion of 4·4 mg, and after a single 10 mg oral dose.The systemic clearance of nifedipine after a single i.v.-dose was higher in subjects with renal insufficiency (854 ml/min) than in those with normal renal function (468 ml/min). After the single oral dose the AUC (6100 ng·min·ml^–1) and maximum plasma concentration (75.0 ng·ml^–1) were lower than in subjects with normal renal function (19300 ng·ml^–1; 122 ng·ml^–1). The plasma protein binding of nifedipine averaged 95.5% in normal subjects and 94.8% in patients with renal failure.Although free and total steady-state plasma levels of nifedipine tended to be somewhat lower than normal in renal failure, the changes in pharmacokinetics and decreased protein binding of nifedipine did not result in a significantly different steady-state plasma level of the drug. The blood pressure response to a given plasma nifedipine level appeared to be enhanced in renal failure.     

The tolerability,pharmacokinetics and lack of effect on plasma cholesterol of 447C88, an AcylCoA:Cholesterol Acyl Transferase (ACAT) inhibitor with low bioavailability,in healthy volunteers

447C88 (N-Heptyl-N-(2,4 difluoro-4-6-(2(-4-(2,2 dimethylpropyl)phenyl)ethyl)phenyl)urea) is an inhibitor of human microsomal AcylCoA:Cholesterol acyltransferase (ACAT) with an IC₅₀ of 10.2 ng·ml^–1 (23 nM). It is poorly absorbed but 5 mg·kg^–1·day^–1 completely abolishes the rise in plasma cholesterol in cholesterol-fed rats.In this study, twelve healthy, male volunteers received single, oral doses of 25, 50, 100, 200, 400 and 800 mg of 447C88 (n+8) or placebo (n+4) with food in a double-blind study with at least a week between occasions. The 400 mg dose was repeated after an overnight fast. Subsequently, fourteen different volunteers received a single 200 mg dose of 447C88 (n+8) or placebo (n+6) with food and, a week later, the same dose twice daily for 10 days; all doses were given with food.All doses were well tolerated with no significant changes in vital signs, full blood counts or plasma biochemical profiles. Plasma concentrations of 447C88 were unquantifiable after the fasting dose and low after all other doses. Mean C_max and AUC were 1.8 ng·ml^–1 and 9.0 ng·ml^–1·h after 200 mg rising to 5.4 ng·ml^–1 and 23.8 ng·ml^–1·h respectively after 800 mg; t_1/2 was 1.3 to 5.2 h. After 10 days dosing, plasma 447C88 concentrations were higher in the evening than the morning probably due to administration of the evening dose with more food. There were no significant changes in plasma triglcerides or total, LDL- or HDL-cholesterol after dosing with 447C88.     

A lack of pharmacokinetic interaction between ranitidine and piroxicam

Summary The effects of piroxicam (40 mg) on the pharmacokinetics of ranitidine (150 mg) and of ranitidine (150 mg bid) on the pharmacokinetics of piroxicam (20 mg) were assessed in two 2-way crossover studies in two groups of 18 healthy male subjects.In the first study there were no statistically significant differences between the pharmacokinetic variables for ranitidine in the presence or absence of piroxicam. The mean maximum plasma concentration (C_max) was 467 ng·ml^–1 for ranitidine alone and 466 ng·ml^–1 in the presence of piroxicam; mean area under the plasma concentration vs time curve (AUC) was 2460 h·ng ml^–1 and 2551 h·ng ml^–1 respectively; and the mean terminal half-life (t 1/2) was 3.6 h and 3.8 h respectively.In the second study there were no statistically significant differences between the pharmacokinetic variables for piroxicam in the presence or absence of ranitidine. The mean C_max was 2.1 ·ml^–1 in the presence of placebo and 2.0 g·ml^–1 in the presence of ranitidine respectively; mean AUC was 133 h·g ml^–1 and 137 h·g ml^–1 respectively, and the mean t 1/2 was 53.6 h and 54.5 h respectively.     

The pharmacokinetics of amiloride-hydrochlorothiazide combination in the young and elderly

Summary The pharmacokinetics of amiloride and hydrochlorothiazide were studied in 12 healthy young volunteers following a single dose of a fixed combination of amiloride and hydrochlorothiazide and in 11 elderly hypertensive patients at steady-state. Following modelling of the single dose data, simulated steady-state plasma concentrations for the 2 drugs were generated to examine the effect of age and/or hypertension on pharmacokinetics.The apparent systemic plasma clearance for both amiloride and hydrochlorothiazide was significantly reduced in the elderly when compared to the young (from 753 to 325 ml·min^–1, amiloride; and from 418 to 157 ml·min^–1, hydrochlorothiazide). The plasma concentrations at steady state for both drugs were greatly increased in the elderly patients (Amiloride: from 7 to 25 ng·ml^–1, C_ss,max; from 2 to 8 ng·ml^–1, C_ss,min; and from 4 to 14 ng·ml^–1, C_av; Hydrochlorothiazide: from 184 to 651 ng·ml^–1, C_ss,max; from 31 to 121 ng·ml^–1, C_ss,min; and from 89 to 273 ng·ml^–1, C_av).The decreased clearance of the diuretics in the elderly was believed due to deterioration of renal function, and there was a significant correlation between the plasma clearance of hydrochlorothiazide and creatinine clearance in both age groups (r=0.62, young;r=0.72, elderly).As a result of the pharmacokinetic findings caution may be indicated in the clinical dosage of the diuretics particularly when in fixed dose combination.     

The effect of atrial natriuretic peptide on plasma renin activity,plasma aldosterone,and urinary dopamine in man

Summary The acute natriuretic effect of human atrial natriuretic peptide (ANP) has been well described in man. We have now studied possible hormonal mediators of this effect.We studied six healthy volunteers on two occasions when they received either an infusion of ANP of 1.5 pmol·kg^–1·min^–1 for 30 min followed by 15 pmol·kg^–1·min^–1 for a further 30 min, or matching vehicle infusions in a randomized single-blind fashion.On the placebo day, plasma renin activity (PRA) rose from 1.26±0.08 to 1.57±0.14 ng A1·ml^–1·h^–1, while on the ANP study day PRA fell from 1.45±0.15 to 1.28±0.05 ng A1·ml^–1·h^–1 (p<0.01). No significant changes were found in plasma aldosterone concentrations or in urinary dopamine excretion.These results provide evidence that ANP suppresses renin release in man.     

In vitro protein binding of propafenone in normal and uraemic human sera

Summary The protein binding of propafenone, a Class I antiarrhythmic agent, was studied in vitro using a selective and sensitive electron-capture detection gas-liquid capillary chromatographic assay method developed in our laboratory.The concentration-dependency of the serum protein binding of propafenone was confirmed in vitro by equilibrium dialysis, using serum obtained from healthy human subjects and patients with chronic renal failure.In normal serum the unbound fraction of propafenone was 0.027 at a propafenone concentration of 0.25 µg · ml^–1, 0.041 within the therapeutic concentration range (0.5–2 µg · ml^–1), 0.138 at a propafenone concentration of 25 µg · ml^–1, and 0.187 when the propafenone concentration was increased to 100 µg · ml^–1.There was no evidence of significant concentration-dependent changes in unbound fraction within the propafenone concentration range of 0.5–1.5 µg · ml^–1. However, concentration-dependent binding was demonstrated at concentrations greater than 1.5 µg · ml^–1.A high-affinity, low-capacity binding site (K₁=6.53×10⁵ l · mol^–1; n₁P₁=1.73×10^–4 mol · l^–1) and a low-affinity, high-capacity binding site (K₂=8.77×10³ l · mol^–1; n₂P₂=8.57×10^–3 mol · ×l^–1) were identified.In pooled uraemic serum the unbound fraction of propafenone was approximately 50% of that of normal serum throughout the concentration range studied (1–5 µg · ml^–1). In sera from patients with chronic renal failure the increase in propafenone binding ratio or the decrease in unbound fraction was associated with the increase in alpha₁-acid glycoprotein concentrations, and there was a correlation (r=0.8302) between alpha₁-acid glycoprotein concentration and the propafenone binding ratio.     

Pharmacokinetic interaction between cyclosporin and diltiazem

Summary Previous reports have indicated that administration of the calcium antagonist diltiazem results in major changes in the pharmacokinetics of cyclosporin A (CyA). A new clinical trial was undertaken in 22 renal transplant patients receiving a constant dose of cyclosporin to further explore this interaction. Coadministration of diltiazem for one week produced an increase in the blood concentration of CyA and its metabolites 17 and 18 in almost all patients, but no increase in CyA metabolites 1 and 21. The mean whole blood CyA trough level determined by HPLC rose from 117 ng·ml^–1 to 170 ng·ml^–1 after one week on diltiazem, and the mean trough level of metabolite 17 rose similarly from 184 ng·ml^–1 before to 336 ng·ml^–1.Based on experiments with microsomes from human liver the effect of diltiazem was due to noncompetitve inhibition of CyA-metabolism by diltiazem, and the increased concentration of metabolite 17 might have been due to stronger inhibition of its secondary metabolism steps.     

Studies on hydralazine

Summary After oral administration of a single 50 mg dose of hydralazine (Apresoline^®), the serum half-life (T1/2) and bioavailability (AUC_0–) were assessed in 16 healthy volunteers. The half-life was 2.57±0.14 h (S.E.) in 10 slow acetylators of sulphadimidine, and 2.18±0.15 h in 6 fast acetylators (difference not statistically significant). AUC_0– was significantly higher in slow acetylators, at 1.04±0.10 µg·hour·ml^–1, compared to 0.66±0.12 µg·hour·ml^–1 in the fast acetylators (p<0.025). Treatment with Apresoline^® 25 mg tid produced minimum serum concentrations at steady-state of 57.3±7.3 ng·ml^–1 and 33.4±4.2 ng·ml^–1 in 8 slow and 5 fast acetylators, respectively (p<0.05). The corresponding maximum concentrations were 228.8±20.3 ng·ml^–1 and 147.6±15.0 ng·ml^–1 in slow and fast acetylators, respectively (p<0.025). First-pass metabolism of hydralazine could explain the difference in bioavailability of the drug between fast and slow acetylators, without any corresponding difference in the elimination rate of the drug in the post-distributive phase.     

Pharmacokinetics of cyclosporine in hyperlipidaemic long-term survivors of heart transplantation

Summary Cyclosporine (Cy) binds to lipoproteins in plasma. In order to test if its pharmacokinetics would be modified when efficient lipid-lowering treatment is introduced, a study has been done of Cy pharmacokinetics and any interaction with the lipid-lowering agent fenofibrate in hyperlipidaemic long-term, survivors of heart transplantation. Fenofibrate 200 mg once daily significantly reduced blood lipids (cholesterol 6.5 vs 7.7 mmol/l; apoprotein B 1.2 vs 1.6 g/l) but did not modify mean whole blood Cy trough levels (113 before fenofibrate vs 103 ng·ml^–1), C_max (812 ng·ml^–1 by RIA and 757 ng·ml^–1 by HPLC before fenofibrate versus 865 and 741 respectively, during fenofibrate); t_max (1.6 and 1.7 h before fenofibrate versus 1.4 and 1.4 h respectively), and t_1/2 (13.9 and 11.1 h versus 9.5 and 10.7 h).The only adverse effect was an increase in creatinine (157 vs 145 mmol/l). Further studies are needed to investigate the mechanism of Cy-fenofibrate nephrotoxicity and to evaluate the long-term efficiency and safety of fenofibrate after heart transplantation.Michel de Lorgeril is a fellow from la Fondation pour la Recherche Médicale     

Sublingual captopril — a pharmacokinetic and pharmacodynamic evaluation

Summary In this study we compared the pharmacokinetics and pharmacodynamics of captopril after sublingual and peroral administration. Single 25 mg doses of captopril were administered sublingually and perorally on two different occasions in a randomised cross-over fashion to eight healthy volunteers aged 22–35 years. The kinetics of unchanged captopril, plasma renin activity (PRA), BP and heart rate were studied over three hours after both peroral and sublingual administration of captopril.Mean pharmacokinetic parameters for unchanged captopril after sublingual administration were: C_max, 234 ng·ml^–1; t_max, 45 min; AUC (0–3 h), 15.1 g·ml^–1. min. Mean pharmacokinetic parameters for unchanged captopril after peroral administration were: C_max, 228 ng·ml^–1; t_max, 75 min; AUC (0–3 h), 17.0 g·ml^–1. min. t_max was significantly shorter when captopril was administered sublingually; all other pharmacokinetic parameters were equivalent.The plasma captopril concentrations achieved post drug administration led to increases in PRA and reductions in BP. t_max for PRA was 86 min for sublingual captopril and 113 min for perorally administered drug. Peak PRA values were, however, not significantly different. BP, as expected, was not reduced dramatically in these healthy volunteer subjects, however, in systolic BP vs time profiles, BP was significantly lower after volunteers received sublingual captopril. Heart rate increased slightly after captopril administration; there were no differences between the two routes of administration. Administration of captopril sublingually, therefore led to a more rapid attainment of plasma captopril concentrations and had a more rapid onset of pharmacological effect when compared with peroral administration.     

Plasma insulin during physiological and pathophysiological changes in atrial natriuretic factor

Summary Changes in plasma insulin in response to a physiological or pathophysiological elevation in circulating atrial natriuretic factor (ANF) have been investigated.Plasma insulin, glucose, immunoreactive (ir) ANF, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), absolute and fractional excretion of sodium (FENa), have been measured in 14 volunteers before and during infusion of low doses of ANF or vehicle (V). Each subject received single-blind in a randomized sequence at 2 week-intervals: V alone, or ANF 4, 8 and 16 ng·kg^–1·min^–1, indused over 90 min.Plasma irANF was increased 2.5- to 11-fold during the ANF infusion as compared to the test with the vehicle. Plasma insulin did not change during V administration (baseline vs V: 22 vs 21 U·ml^–1) and was unchanged during ANF at 4, 8 and 16 ng·kg^–1·min^–1 (19, 19, 21 U·ml^–1, respectively). Blood pressure, ERPF and GFR were not affected, and diuresis, FENa and urinary Na excretion were increased significantly and dose-dependently during ANF, but not V infusion. Compared to baseline, ANF 4, 8 and 16 ng·kg^–1·min^–1 increased urinary Na excretion by 147, 241 and 446 mol·min^–1, respectively.The findings indicate that, in normal humans, an acute increase in irANF within or slightly above the physiological range, which modified natriuresis and diuresis, did not alter circulating plasma insulin.The work was supported in part by the Swiss National Science Foundation