Preliminary Flow Modeling by Hybrid Automata Alternating Continuous Reaction and Discrete Transit for Pharmacokinetics.

In traditional pharmacokinetic models, blood flow or liquid transit is often expressed as first-order kinetics. When the flow expression by first-order kinetics is used for dynamic simulation, the flow velocity illogically depends on the step size of a solver of ordinary differential equations. In this study, we propose flow modeling using hybrid automata that combine ordinary differential equations and recursive equations, and we have preliminarily applied the constructed models to several examples. The blood concentration-time profiles of p-aminohippurate and propranolol after intravenous administration were successfully reproduced by simple hybrid automata. The simulation results of one-dimensional tube flow have demonstrated that the fluid velocity in the hybrid automata was independent of the step size of the ordinary differential equation solver. A body fluid model coordinated various flows in a human body with scheduled daily activities and could be used as a drug container to describe formulation-dependent disposition of 5-aminosalicylic acid and enterohepatic circulation of a virtual drug. These findings suggested that flow modeling using hybrid automata could avoid the logical inconsistency in the traditional pharmacokinetic modeling and that the hybrid automata have high versatility and a wide range of applicability to pharmacokinetic analysis. Because our method can define various intervals for multiple recursive equations, the resolution of a specific part of a model can be adjusted relatively freely while the whole body is being roughly modeled, which would be beneficial to refine a coarse model into a fine model in future. SIGNIFICANCE STATEMENT: There is a logical inconsistency in flow expression by first-order kinetics in ordinary differential equations used in traditional pharmacokinetic modeling. It is difficult to model a whole human body using flow models in partial differential equations because of the excessive calculation costs. Our simulations on tube flow and body fluids have demonstrated that the flow modeling using hybrid automata could avoid the problems. The preliminary applications of hybrid automata to several examples highlighted its high versatility in pharmacokinetic analysis.

Effects of the nitric oxide synthase inhibitor ronopterin (VAS203) on renal function in healthy volunteers.

AIMS: Reduced nitric oxide (NO) availability may adversely affect renal perfusion and glomerular filtration. The aim of the present study was to characterize in detail the pharmacological effects of VAS203, an inhibitor of NO synthase, on renal haemodynamics in humans. METHODS: This double-blind, randomized, placebo-controlled, cross-over phase-I-study comprised 18 healthy men. Renal haemodynamics were assessed with constant-infusion input-clearance technique with p-aminohippurate and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR), respectively. After baseline measurement, a constant infusion of the tetrahydrobiopterin analogue ronopterin (VAS203, total 10 mg/kg body weight) or placebo was administered at random order for 6 hours additionally. After a wash-out phase of 28 days, the second course was applied. In parallel, markers of early kidney injury and renal function were assessed repeatedly up to 48 hours after starting VAS203/placebo-infusion. RESULTS: VAS203-infusion resulted in a significant decrease of RPF (P < .0001) and GFR (P < .001) compared to placebo, but magnitude was within the physiological range. RPF and GFR recovered partly 2 hours after end of VAS203-infusion and was normal at beginning of the second infusion period. Compared to placebo, preglomerular resistance (P < .0001), and to lesser extent postglomerular resistance (P < .0001) increased, resulting in a decrease of intraglomerular pressure (P < .01). No treatment related effect on markers of early kidney injury, and on renal function (P for all >.20) have been observed. CONCLUSIONS: Our phase-I-study in healthy humans indicates that VAS203 (10 mg/kg body weight) reduces renal perfusion and glomerular function within the physiological range mainly due to vasoconstriction at the preglomerular site.

U-shaped relationship between serum uric acid levels and intrarenal hemodynamic parameters in healthy subjects.

Hyperuricemia has been reported to affect renal hemodynamics. In a recent study, both low and high levels of serum uric acid (SUA) were found to be associated with loss of kidney function. The goal of this study was to evaluate the relationship between SUA levels and intrarenal hemodynamic parameters in healthy subjects, using plasma clearance of para-aminohippurate (CPAH) and inulin (Cin). Renal and glomerular hemodynamics were evaluated by simultaneous measurements of CPAH and Cin in 48 healthy subjects (54.6 ± 13.4 yr). Intrarenal hemodynamic parameters, including efferent and afferent (Ra) arteriolar resistance, were calculated using Gómez's formulas. Relationships of SUA levels with these intrarenal hemodynamic parameters were examined. In quadratic regression analysis, SUA levels had a significant inverse U-shaped relationship with Cin (P < 0.0001, R2 = 0.350) and CPAH (P = 0.0093, R2 = 0.188) and a U-shaped relationship with Ra (P = 0.0011, R2 = 0.262). In multiple regression analysis with normal (3.5-6.0 mg/dl) and mildly low or high (<3.5 or >6.0 mg/dl) SUA levels entered as dummy variables of zero and one, respectively, mildly low or high SUA levels were significantly and independently associated with Ra (ß = 0.230, P = 0.0403) after adjustment for several factors (R2 = 0.597, P < 0.0001). Both mild hyperuricemia and mild hypouricemia are significantly associated with increased Ra, although weakly. The increase in Ra in subjects with mild hyperuricemia or hypouricemia may be related to renal hemodynamic abnormalities, possibly leading to a decline in renal function.

Impact of the induced organic anion transporter 1 (Oat1) renal expression by furosemide on the pharmacokinetics of organic anions.

AIM: Furosemide is a loop diuretic. Different authors demonstrated that continuous administration of furosemide modulates the expression of organic anion transporters. This study was undertaken to simultaneously evaluate the effects of furosemide pretreatment on organic anion transporter 1 (Oat1) and multidrug resistance protein 2 (Mrp2) renal expressions, on p-aminohippurate (PAH) pharmacokinetics and on renal and urinary PAH levels in rats. METHODS: Male Wistar rats were treated with furosemide (6 mg/100 g body weight per day, subcutaneously, 4 days) (treated group) or saline (control group). On the fifth day, PAH was administered as a bolus infusion in the femoral vein, and plasma samples were obtained from femoral artery at different time points. PAH levels in renal tissue and urine were also assessed. Renal Oat1 and Mrp2 expressions were evaluated by western blotting. RESULTS: Furosemide pretreatment increased both the expression of Oat1 and Mrp2. PAH plasma concentrations decreased following a biexponential function. The furosemide-treated group showed higher PAH plasma levels, a lower systemic clearance and elimination rate constant from the peripheral compartment, indicating that PAH renal elimination was decreased. PAH levels in renal tissue were significantly elevated and in urine appeared to be significantly lower as compared with control animals. CONCLUSIONS: Furosemide pretreatment caused a significant decrease of PAH renal elimination, despite Oat1 and Mrp2 augmented renal expression. The goal of the present study is the addition of important information in the wide gap of knowledge that exists about drug-drug interactions. Because of furosemide worldwide use, the data obtained are interesting and useful in terms of translation to clinical practice.

Plasma 25-hydroxyvitamin D and regulation of the renin-angiotensin system in humans.

Vitamin D regulates the renin-angiotensin system (RAS) in experimental animals, but corresponding human data are limited. We examined the relation between plasma 25-hydroxyvitamin D and elements of the RAS in 184 normotensive individuals in high sodium balance; these included circulating levels of plasma renin activity and angiotensin II (Ang II) and the renal plasma flow response to infused Ang II, which is an indirect measure of the intrinsic RAS activity in the kidney. Compared with individuals with sufficient 25-hydroxyvitamin D levels (> or = 30.0 ng/mL), those with insufficiency (15.0 to 29.9 ng/mL) and deficiency (<15.0 ng/mL) had higher circulating Ang II levels (P for trend=0.03). Moreover, those with vitamin D deficiency had significantly blunted renal plasma flow responses to infused Ang II (mean decrease of 115 mL/min per 1.73 m(2) in renal plasma flow versus 145 mL/min per 1.73 m(2) among those with sufficient vitamin D levels; P for trend=0.009). Although plasma renin activity was higher among individuals with insufficient levels of vitamin D, the result was not statistically significant. These data suggest that low plasma 25-hydroxyvitamin D levels may result in upregulation of the RAS in otherwise healthy humans.

Hepatic metabolism of 2-hydroxy-4-methylthiobutyrate in growing lambs.

This study was undertaken to determine how, and where, 2-hydroxy-4-methylthiobutyrate (HMTBA) can augment Met metabolism in lambs. Four lambs (initial body weight of 50 kg, SE = 2, and 6 mo of age) prepared with catheters in the mesenteric, portal, hepatic, and jugular veins plus the aorta, were fed at 1.5x maintenance on a grass hay, barley, fish meal, molasses/pre-mix (5:3:1:1, as fed) diet, supplied as hourly meals. Lambs were infused for 10 h with [methyl-2H3]Met (0.11 mmol/h) in a jugular vein and p-aminohippurate into the mesenteric vein. From 1 h onwards, successive 3-h infusions of saline (control), 0.55 mg/min (3.67 micromol/min), and 4.44 mg/min (29.6 micromol/min) of HMTBA were also infused into the mesenteric vein. Plasma, sampled continuously, was collected every 20 min during the last 60 min of each infusion. All infused HMTBA was recovered at the portal vein with 25% extracted subsequently by the liver. Portal appearance of total Cys and Met was unaltered by HMTBA infusion, but net splanchnic appearance of Cys increased (0.04, 0.08, 0.23 mmol/h, SEM = 0.05), whereas Met decreased (0.14, -0.01, -0.21 mmol/h, SED = 0.05). Despite this, arterial Met increased (27.0, 30.7, 51.5 microM, SEM = 2.1) as did Met irreversible loss rate (27.6, 28.7, 40.1 micromol/h, SEM = 0.51), equivalent to 40% of the HMTBA reentering the plasma after conversion to Met. These data indicate that, in ruminants, HMTBA is probably converted to Met within peripheral tissues; that is, where the metabolic need for Met exists.

A new HPLC method to determine glomerular filtration rate and effective renal plasma flow in conscious dogs by single intravenous administration of iohexol and p-aminohippuric acid.

A high-performance liquid chromatography method to determine iohexol (IOX) and p-aminohippuric acid (PAH) in the plasma of dogs is evaluated according to recovery, reproducibility, and linearity utilizing a gradient pump. The mobile phase consists of 50mM sodium dihydrogen phosphate with 0.5mM tetrabutylammonium chloride, the pH is adjusted to 4.1, methanol is added to the final ratio of 90:10 (v/v), the flow rate is set at 1 mL/min, and separation is achieved with an ODS2 Luna column. The UV detector is set at 254 nm. IOX and PAH are used for evaluation of the effective renal plasma flow (ERPF) and glomerular filtration rate (GFR). The present method tested in three dogs demonstrates the accuracy in the evaluation of ERPF and GFR. Because of its precision and simplicity and low cost, it can be considered a good tool for ERPF and GFR in small animal practice.

Hypertension after neonatal uninephrectomy in rats precedes glomerular damage.

The present study was designed to determine whether adult hypertension caused by a reduced number of nephrons from birth is due to preceding glomerular damage. Newborn male Sprague-Dawley rat pups were uninephrectomized during the first 24 hours after birth (UNX rats). At 20 weeks of age, chronically instrumented UNX animals were hypertensive on a normal-sodium (0.20%) diet compared with sham-operated controls (142+/-2 versus 124+/-2 mm Hg in controls). Body weights and the total kidney-to-body weight ratio were not significantly different in adult UNX animals compared with controls. Glomerular filtration rate (GFR) was reduced by 49% in UNX rats (1.85+/-0.24 versus 3.65+/-0.22 mL/min). Urine protein excretions were higher in UNX rats (20+/-2 versus 7+/-1 mg/d in controls). On a high-sodium (3.15%) diet, arterial pressure increased more in UNX than in controls (28+/-9 versus 3+/-1 mm Hg). In contrast, in animals studied at 8 weeks of age, GFR was only reduced by 26% in UNX animals (2.02+/-0.06 versus 2.73+/-0.07 mL/min). Their hypertension (125+/-2 versus 117+/-2 mm Hg) was also salt sensitive (increase on high-sodium diet of 35+/-11 versus 8+/-2 mm Hg in controls) but was not associated with proteinuria or histological signs of glomerular disease. Number of glomeruli per kidney in UNX animals was not different from controls, but individual glomerular volume increased by 41%. Thus, surgical removal of 50% of the nephrons, when done during development, causes reduced renal function and salt-sensitive hypertension in adulthood. Hypertension is present earlier in life than signs of glomerular disease, which suggests that hypertension is a major contributor to rather than primarily resulting from onset of renal disease.

External pudic venous reflux into the mammary vein in lactating dairy cows.

A representative blood sample from the mammary vein depends on the functional integrity of the valves in the external pudic vein (EPV). To determine if the EPV valves maintain blood flow into the inguinal direction during the second and subsequent lactations, we used eight lactating cows catheterized in the EPV, the lateral branch of the cranial mammary vein (MV), and the external pudic artery (EPA). The averaged daily milk yields were 25.0 +/- 1.8 kg in cows in second lactation and 31.5 +/- 2.9 kg in older cows. The relative time taken by a pulse dose of p-amino hippuric acid (PAH) injected into the EPV, to reach the EPA and the MV, was measured in a first trial. In a second trial, we assessed the extent of alteration of the mammary PAH blood concentration with blood originating from other tissues using a continuous infusion of PAH into the EPA simultaneously with blocking or not any EPV backflux. From the first experiment, the PAH injected into the EPV appeared first in the EPA and then in the MV in cows in second lactation, suggesting that blood flow was towards the inguinal region. But in a third-lactation cow, the order of appearance was reversed. In parallel, the occlusion trial demonstrated that the concentration of PAH in the MV was diluted by 14 to 39% with blood draining nonmammary tissues only in cows in third or fourth lactation. This resulting reversed flow from the EPV towards the MV would have a detrimental impact on conclusions of mammary gland metabolism studies conducted with cows in their third lactation or higher.

Specific determination of PAH and its N-acetyl metabolite by HPLC increases the accuracy and precision of PAH clearance measurements.

PAH (N-(4-aminobenzoyl)-glycin) clearance measurements have been used for 50 years in clinical research for the determination of renal plasma flow. The quantitation of PAH in plasma or urine is generally performed by colorimetric method after diazotation reaction. Although straightforward, the measurements must be corrected for the nonspecific residual response observed in blank plasma. We have therefore developed an HPLC method for the specific determination of PAH and its metabolite NAc-PAH using a gradient elution ion-pair reverse-phase chromatography with UV detection. The Nacetyltransferase (NAT-1 or NAT-2 dependent) activity does not seem clinically relevant nor does it affect notably PAH clearances, although NAc-PAH represents 10.2 +/- 2.7% of the PAH excreted unchanged in 12 healthy subjects. The performance of the HPLC technique has been compared with the colorimetric method using urine and plasma samples collected from 12 healthy volunteers following a priming dose of PAH followed by a constant rate infusion. Good correlations (r = 0.94 and 0.97, for plasma and urine respectively) are found between the results obtained with both techniques. However, the colorimetric method gives higher concentrations of PAH in urine while the concentrations in plasma are lower than those determined by HPLC. Hence, both renal (CLR = U x V/P) and systemic (CLS = Rinf/Css) clearances are systematically higher (35.1%, resp. 17.8%) with the colorimetric method. The fraction of PAH excreted by the kidney CLR/CLS calculated from HPLC data (n = 143) is, as expected, always < 1 (mean = 0.73 +/- 0.11), whereas the colorimetric method gives a mean extraction ratio of 0.87 +/- 0.13 implying unphysio-logical values (> 1) in some cases. In conclusion HPLC not only enables the simultaneous quantitation of PAH and NAc-PAH, but may also provide more accurate and precise PAH clearance measurements.

Plasma clearance in the rat of a furan dicarboxylic acid which accumulates in uremia.

The furan dicarboxylic acid 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (5-propyl FPA) accumulates in the plasma of patients with chronic renal failure and has been implicated in several aspects of the uremic syndrome: the defective binding of organic acids in uremic plasma, inhibition of active tubular secretion, anemia and the severity of neurological symptoms. Evidence from experiments with rat kidney slices suggests that 5-propyl FPA undergoes active tubular secretion, and so its clearance after an intravenous bolus dose (5 mg/kg; 21 mumol/kg) was investigated in anaesthetized female Wistar albino rats in vivo. The effects of intravenous bolus doses of p-aminohippuric acid (PAH) and probenecid on the clearance of this dose of 5-propyl FPA were also studied. The mean values (N = 16) for plasma half-life, plasma clearance and apparent volume of distribution of 5-propyl FPA were 3.6 hours, 2.4 ml . min(-1) . kg(-1) and 0.69 liter . kg(-1), respectively. An equimolar dose of PAH did not affect the clearance of 5-propyl FPA, but a tenfold higher molar dose of PAH (40.4 mg/kg) increased the area under the plasma-concentration time curve of 5-propyl FPA, and there was a trend towards a decrease in the clearance and a prolongation of the half-life. Probenecid at a fivefold higher dose than 5-propyl FPA had a similar effect to PAH and increased the AUC of 5-propyl FPA. PAH and probenecid decreased the plasma clearance of 5-propyl FPA, which is evidence that this uremic metabolite undergoes active tubular secretion. It follows that 5-propyl FPA could therefore inhibit the secretion of other organic acids.

Pretreatment with p-aminohippurate inhibits the renal uptake and accumulation of injected inorganic mercury in the rat.

The effects of intravenous pretreatment with the organic anion p-aminohippurate (PAH) on the disposition of intravenously administered inorganic mercury in the kidneys, liver and blood were evaluated in rats. In dose-response experiments, the renal uptake (and/or accumulation) of mercury, 1 h after the injection of a nontoxic 0.5 mumol/kg dose of mercuric chloride (HgCl2), was significantly reduced in rats when a 1.0, 3.3 or 10 mmol/kg dose of PAH was administered 5 min prior to the injection of HgCl2. This reduction was due to reduced uptake of mercury in both the renal cortex and outer stripe of the outer medulla. Near maximal inhibition appeared to be achieved with the 10 mmol/kg dose of PAH. Inhibition of the uptake (an/or accumulation) of mercury in the renal cortex and outer stripe of the outer medulla, 1 h after the injection of the nontoxic dose of HgCl2, was also detected in experiments where HgCl2 was injected 5, 30, 60 or 180 min after pretreatment with a 10 mmol/kg dose of PAH. The renal uptake of mercury was inhibited significantly when the nontoxic dose of inorganic mercury was administered 5, 30, or 60, but not 180 min after pretreatment with the 10 mmol/kg dose of PAH. In another experiment, the renal burden of mercury was significantly reduced for 24 h when pretreatment with a 10 mmol/kg dose of PAH was administered 5 min prior to the injection of HgCl2. Pretreatment with PAH did not have an effect on the hepatic disposition of mercury, but it did cause a significant increase in the fraction of mercury present in the plasma of blood. In summary, the findings in the present study indicate that pretreatment with PAH inhibits the renal uptake of injected inorganic mercury in a dose-dependent and time-dependent manner. In addition, the findings tend to indicate that some fraction of the mercury that enters into renal tubular epithelial cells is by a mechanism involving the organic anion transport system.

System identification of the low-dose kinetics of p-aminohippuric acid.

The renal clearance of p-aminohippuric acid, due to tubular secretion in addition to glomerular filtration, can only be determined by kinetic experiments. Maximal information can be gained from observed temporal marker concentration profiles by fitting dynamic mathematical models of the processes involved, such as absorption, distribution, and elimination, to the kinetic data. Thereby the values of the system constants, such as fractional elimination or fractional distribution rates, and their accuracy measures are determined by methods which are based firstly on measured time-dependent data elicited in an individual test object by perturbing inputs and secondly, on mathematical formulations of prior knowledge of the underlying physiological system. Such methods of model adaptation are called system identification. In this context a computer-based method of system identification and error estimation for the system constants of two-compartment models matched a dynamic concentration profiles of p-aminohippuric acid is presented. The method is used of single-injection experiments to demonstrate that such a technique is able to correctly estimate the clearance of p-aminohippuric acid if sufficiently long experimental protocols are chosen, and to ascertain the sufficient length of a protocol for an individual subject. The renal clearance of p-aminohippuric acid is known to exhibit concentration-dependence generally, but to achieve its maximal value when low doses are applied. The present study deals with the low-dose kinetics of p-aminohippuric acid.

Furosemide dynamics in conscious rabbits: modulation by arginine vasopressin.

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 (UPgE2V; p < 0.01). The increase in UPgE2V 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 mumol/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.

Evaluation of two intravenous single-bolus methods for measuring effective renal plasma flow.

This open-label, three-way crossover study examined the feasibility of measuring effective renal plasma flow (ERPF) using a single intravenous (IV) bolus method. Eight healthy young adults (four women aged 28 +/- 5 years [mean +/- SD] and four men aged 30 +/- 7 years) received on separate days an IV bolus of p-aminohippurate (PAH) 10 mg/kg, an IV bolus of phenolsulfonphthalein (PSP) 1 mg/kg, and the standard constant-rate IV infusion of PAH. The renal clearance (CLR) and plasma clearance (CLP) of PAH after constant infusion were 623.7 +/- 62.9 and 869.0 +/- 58.8 mL/min/1.73 m2, respectively. After PAH bolus injection, CLR and CLP were 538.9 +/- 110.8 and 677.6 +/- 122.4 mL/min/1.73 m2, respectively. After PSP bolus injection, CLR and CLP were 252.8 +/- 57.9 and 350.0 +/- 41.3 mL/min/1.73 m2, respectively. The ERPF measured by PSP bolus injection was significantly lower (P < 0.05) than by PAH infusion. The CLP of PAH after IV bolus injection was significantly lower than after IV infusion when men and women were analyzed together (P < 0.05). However, there appeared to be a greater magnitude of difference between the CLR after IV bolus and infusion of PAH for women than for men. In summary, PSP administered as an IV bolus injection does not appear to be a reliable marker of ERPF. The difference in ERPF determined by the PAH infusion and bolus methods may require further evaluation.

The concentration-dependent disposition of intravenous p-aminohippurate in subjects with normal and impaired renal function.

1. The disposition and kinetics of p-aminohippuric acid (PAH) were studied in 27 healthy male volunteers, 10 healthy female volunteers and 10 patients with chronic renal impairment following rapid intravenous injection of 10 mg kg-1. In addition, the renal clearances of PAH and its metabolite N-acetyl-PAH were measured in 10 of the healthy male volunteers following conventional administration of PAH by loading dose and constant infusion, and in another eight during sequential 'step-up' and 'step-down' infusions intended to maintain low, medium and high plasma concentrations below the threshold for onset of saturation of tubular transport. 2. PAH was eliminated rapidly with a mean half-life of less than 30 min in the healthy volunteers and 72 min in the renal patients. The corresponding estimates for acetyl-PAH were 49 and 153 min. In both groups the rate of disappearance of PAH slowed progressively over the period of observation and there was no true log-linear terminal elimination phase. 3. In the healthy volunteers about 50% of the dose was excreted in the urine in 30 min with quantitative recovery in 3 h. In 8 h, 17% of the dose was recovered as acetyl-PAH. In the patients with renal impairment the 8 h recovery was only 83.6% of the dose with 26.9% of the total appearing as acetyl-PAH. 4. The volume of distribution (Vss) of PAH was 16-18 l in the healthy subjects and renal patients. Acetyl-PAH appeared to have a much larger distribution volume (mean 65.5 l in the healthy volunteers). 5. In the healthy volunteers the renal clearance of PAH fell dramatically from 599 +/- 115 ml min-1 1.73m-2 during the first hour after administration to 300 +/- 208 ml min-1 1.73 m-2 during the second hour (P < 0.001). The corresponding renal clearances of acetyl-PAH were 775 +/- 196 and 916 +/- 212 ml min-1 1.73 m-2. In the patients with renal impairment the renal clearance of PAH fell from 194 +/- 83 ml min-1 1.73 m-2 in the first hour to only 61 +/- 19 ml min-1 1.73 m-2 from 4 to 6 h. Over the same period there was no significant fall in the clearances of acetyl-PAH or total PAH (acetyl-PAH + PAH).(ABSTRACT TRUNCATED AT 400 WORDS)

Normotensive normoxic men undergoing water diuresis fail to respond to stimulation of their peripheral arterial chemoreceptors by almitrine with an increase in plasma concentrations of atrial natriuretic factor.

The purpose of this study was to investigate the possible participation of atrial natriuretic factor (ANF) in the natriuretic and diuretic response occurring after stimulation of the peripheral arterial chemoreceptors by almitrine bismesylate in normoxic humans. The experiments were performed in 14 healthy male volunteers undergoing water diuresis. Each subject participated in two experiments. In one of them they ingested 100-mg almitrine at 12 p.m. The other study served as a control. Surprisingly, our subjects responded to almitrine with an elevation of urine flow only, whereas sodium excretion remained almost unchanged over the whole period of the experiments. As regards ANF plasma concentrations, no statistically significant differences between the control and the almitrine group could be observed. Moreover, no direct connection between ANF plasma concentrations and renal volume excretion was detectable. We conclude that a specific stimulation of peripheral arterial chemoreceptors by almitrine in humans undergoing water diuresis did not seem to raise ANF plasma concentrations as is the case at high altitude. Therefore we would suggest that there exists no specific reflex influence of these receptors on ANF release.

[The stimulation of organic acid secretion in the kidneys of the frog Rana temporaria with the repeated administration of para-aminohippurate and triiodothyronine]. / Stimuliatsiia sekretsii organicheskikh kislot v pochkakh liagushki Rana temporaria pri neodnokratnom vvedenii paraaminogippurata i triiodtironina.

Investigating possible ways of the increase in the rate of organic acid transport in the kidney of frogs, it has been demonstrated that animals which passed hypobiosis exhibit the increase in maximum capacity of the kidney to secretion of paraaminohippurate during substrate stimulation evoked by the injection of this salt twice a day within three days, as well as by the injection of triiodthyronine once a day within three days. The effect produced is similar to kidney reaction in adult mammals.

Influence of probenecid on P-amino hippurate kinetics.

The influence of probenecid on p-amino hippurate (PAH) kinetics was investigated in rat. Probenecid was administered i.p. (25, 50, 100, 150 and 200 mg/kg) two hours before PAH administration (25 mg/kg i.v.). The distribution and the rate of elimination of PAH was influenced by probenecid co-administration: the distribution decreased after probenecid doses higher than 150 mg/kg and the rate of elimination decreased after doses higher than 50 mg/kg.