ACUTE EFFECT OF PHYSIOLOGICAL CONCENTRATIONS OF VASOPRESSIN ON RAT RENAL FUNCTION

1. The antidiuretic, pressor and electrolyte transport effects of arginine vasopressin (AVP) were simultaneously evaluated in the anaesthetized water diuretic rat. Increasing concentrations of AVP (7.5, 75 and 750 ng/kg bolus and per h), were used to produce plasma levels which approximate the physiological range (4.8 ± 2.4, 35.7 ± 12.5, 85.2 ± 16.1 pg/mL respectively). 2. Administration of a minimally effective antidiuretic dose (7.5 ng) increased mean urine osmolality (from 101 ± 7 to 312 ± 89 mosmol/kg) without altering mean arterial pressure (MAP), renal plasma flow (RPF) or glomerular filtration rate (GFR). A maximal antidiuretic dose of AVP (75 ng) increased mean urine osmolality to 2002 ± 109 mosmol/kg and was associated with significant mean increases in MAP (9 mmHg), RPF and GFR (25%) by 30–60 min. A further ten-fold increase in AVP (750 ng) produced a greater increase in MAP (116 ± 6 to 134 ± 7 mmHg; P < 0.01) as well as increasing RPF and GFR by 35.5 and 38.9% respectively. 3. Increasing concentrations of AVP also progressively increased the fractional excretion of sodium, potassium and phosphate. However, fractional calcium and magnesium excretion was significantly decreased with maximal and supramaximal concentrations. 4. These studies support evidence that AVP is a pressor hormone in physiological concentrations in baroreceptor intact animals. Its role in renal electrolyte transport is unclear. Measured increases in RPF and GFR with the maximal and supramaximal AVP concentrations appear to be correlated with the increase in MAP.     

EFFECT OF ARGININE VASOPRESSIN AND PARATHYROID HORMONE-RELATED PROTEIN ON RENAL FUNCTION IN THE OVINE FOETUS

1. The effects of intravenous infusions of arginine vasopressin (AVP), parathyroid hormone-related protein (PTHrP) and AVP + PTHrP on renal function in intact ovine foetuses at 100–125 days of gestation were examined. 2. A low dose of AVP (5.5 ± 0.9 pmol/h) increased plasma AVP concentrations from 0.6 pmol/L to 2.1 ± 0.4 pmol/L (mean ± s.e.m; n= 8). This dose caused a significant reduction in free water clearance (C_H2O; P<0.001), without any significant change in fetal arterial blood pressure, glomerular filtration rate (GFR), or the urinary excretion rates of sodium, calcium or 3', 5'-cyclic adenosine monophosphate (CAMP). 3. Infusions of PTHrP (1 nmol/h), with or without 1 nmol bolus dose, significantly increased (P<0.05) urine osmolality (Uosm), but did not synergize with AVP in reducing C_H2O. 4. It is concluded that AVP and PTHrP do not act synergistically on the kidney of the intact ovine foetus.     

EVIDENCE OF AN ADENOSINE-DEPENDENT MECHANISM IN THE HYPOTENSIVE EFFECT OF l-ARGININE IN MAN

1. The hypothesis that endogenous adenosine could play a role in the haemodynamic response to l-arginine is investigated. 2. The study has been divided into two parts. The first part was a single blind, randomized, placebo-controlled study in which L-arginine i.v. infusion (0.07 mmol/kg per min) in five healthy volunteers caused a significant fall in systolic (-14.2%, from 129.0 ± 8.2 to 110.6 ± 8.5 mmHg; F= 62.89, P<0.0l), diastolic (-16%, from 80.0 ± 7.9 to 67.2 ± 7.0 mmHg; F= 18.97, P < 0.0l) and mean (-15.5%, from 96.4 ± 6.7 to 81.4 ± 6.5 mmHg; F= 28.78, P< 0.01) arterial blood pressure, with a concomitant increase of plasma adenosine concentration (from 244.0 ± 32.2 to 637.0 ± 43.4 nmol/L; F= 79.3 P<10.01). Maximal effects were obtained at the end of L-arginine infusion: haemodynamic parameters returned to basal values in about 30 min while adenosine concentrations normalized in about 15 min. Saline infusion had no effect on these parameters. 3. In the second study the effect of L-arginine i.v. infusion on arterial blood pressure, lower limb blood flow and plasma adenosine, before and after theophylline treatment (1000 mg/day for 3 days, p.o.) was examined. In 10 healthy volunteers the i.v. infusion of l-arginine (0.07 mmol/kg per min) was followed by the same haemodynamic changes as reported above and by a Significant increase in lower limb blood flow (+ 36.7%, from 2.18 ± 0.40 to 2.98 ± 0.71mL/min/lOOmL;t = 4.61, P< 0.01). Pretreatment with theophylline, an adenosine-receptor antagonist, did not affect basal values of arterial pressure, lower limb blood flow and adenosine concentration. The pretreatment with theophylline reduced maximal decrease in systolic pressure (- 8.2 vs -15%), in mean pressure (- 9.9 vs -13.7%) and maximal increase in lower limb blood flow (+19 vs + 37%) caused by i.v. infusion of l-arginine (0.07 mmol/kg per rnin). Such a treatment allowed a progressive restoration of basal blood pressure values and of blood flow, during the second half of l-arginine infusion. This observation was confirmed by the analysis of the area under the curves (AUC). A significant difference in AUC values before and after treatment was obtained for systolic pressure (t = 8.25, P< O.Ol), mean pressure (t= 6.67, P<0.0l) and blood flow (t= 2.31, P<0.05). 4. Theophylline study suggested that the endogenous adenosine increase is sufficient to participate at least in part in the haemodynamic changes caused by l-arginine and that it is involved in a secondary response to l-arginine.     

Renal electrolyte and fluid handling in the rat following chloroquine and/or ethanol administration

We postulated that chloroquine and/or ethanol affect plasma arginine vasopressin (AVP) concentrations to alter renal function. Therefore, we studied the effects of chloroquine and/or ethanol on plasma AVP concentrations and fluid, urinary Na(+) and K(+) outputs in separate groups of anaesthetized Sprague-Dawley (SD) rats challenged with a continuous jugular infusion of 0.077 M NaCl at 150 microl.min(-1). After a 3-h equilibration period, vehicle, chloroquine (0.06 microg. min(-1)), ethanol (2.4 or 24 microg.min(-1)) or both chloroquine and ethanol were added to the infusate after 1 h (control) for 1 h 20 min (treatment). The animals were switched back to the infusate alone for the final 1 h 40 min recovery periods. Urine flow Na(+) and K(+) excretion rates were determined at 20-min intervals over the subsequent 4-h postequilibration period. Blood was collected from separate groups of animals at the end of treatment period or equivalent time for control animals for measurement of plasma aldosterone and AVP concentrations by radioimmunoassay. Simultaneous chloroquine and ethanol infusion significantly (p < 0.01) increased plasma chloroquine concentrations in an ethanol dose-dependent manner by comparison with animals administered chloroquine alone. Chloroquine infusion alone (0.06 microg.min(-1)) and/or ethanol (2.4 or 24 microg.min(-1)) elevated plasma AVP concentrations from 9.73 +/- 1.64 fmol.l(-1) in control rats to 15.65 +/- 2.49 fmol.l(-1), 17. 39 +/- 4.21 fmol.l(-1), and 33.87 +/- 6.18 fmol.l(-1), respectively. Separate administration of chloroquine or ethanol at low dose rates increased urinary Na(+) excretion rates. We conclude that the impairment of renal electrolyte handling associated with chloroquine administration may be exacerbated by ethanol.     

ACUTE LITHIUM ADMINISTRATION IMPAIRS THE ACTION OF PARATHYROID HORMONE ON RAT RENAL CALCIUM,MAGNESIUM AND PHOSPHATE TRANSPORT*

1. Chronic lithium (Li⁺) treatment commonly produces a state of hyperparathyroidism in humans and rat although the mechanism is unknown. 2. The present study evaluated the acute effect of Li⁺ on renal electrolyte transport, particularly Ca²⁺ and Mg²⁺ in thyroparathyroidectomized (TPTX) and intact rats. 3. The acute administration of Li⁺ significantly increased water, sodium, potassium and phosphate excretion in both TPTX and intact animals; however, Ca²⁺ and Mg²⁺ excretion was only increased in the intact group. Fractional excretion (FE) of Ca²⁺ and Mg²⁺ increased from 2.2±0.2 to 3.5±0.3% and 12±2 to 18±2%, respectively (P<0.01). 4. In further experiments in TPTX rats, Li⁺ administration inhibited the usual reduction in urine Ca²⁺ and Mg²⁺ excretion following parathyroid hormone (PTH) administration and inhibited the phosphaturia. However, supramaximal concentrations of PTH overcame this inhibitory effect. For example, an FE_Ca of 3.8±0.2% was reduced to 1.4±0.2% and 1.7±0.2% with maximal and supramaximal PTH concentrations, respectively, while in the presence of Li⁺ an FE_ca of 4.0±0.2 was decreased to 2.8±0.2 and then 1.9±0.3% with the same PTH concentrations. 5. The inhibitory effect of Li⁺ was reduced with a lower plasma Li⁺ concentration (0.7±0.2 vs 1.6–1.8 mmol/L). The FE_Mg results were comparable. 6. These results demonstrate that Li⁺ directly inhibits PTH-mediated renal reabsorption of Ca²⁺ and Mg²⁺ and also blunts PTH-mediated phosphaturia. Therefore, the hyperparathyroidism in humans following Li⁺ treatment may be a consequence of reduced renal Ca²⁺ reabsorption.     

THE EFFECT OF ADRENALECTOMY ON WATER PERMEABILITY IN RAT PAPILLARY COLLECTING DUCT

1. Chronic adrenal insufficiency impairs maximal urine concentration, probably in part due to reduced medullary tonicity but also possibly by inhibition of distal nephron water transport. This latter defect has been demonstrated in rabbit but not in rat. 2. Since the time between adrenalectomy and experiment was different in rabbit and rat studies, diffusional water permeability was evaluated in the papillary collecting duct in the absence and presence of submaximal (20 μU/mL) and supramaximal (200 μU/mL) arginine vasopressin (AVP) in adrenalectomized rats at 7, 14 and 21 days. 3. Experimentation 7 days after adrenalectomy failed to demonstrate significantly altered basal or AVP-induced water permeability which increased by 23 and 78% with submaximal and supramaximal concentrations, respectively. Submaximal AVP concentrations also induced a comparable change in water permeability in adrenalectomized rats at 14 days; however, 21 days after adrenalectomy, diffusional water permeability was not increased by 20 μU/mL AVP (3.31 ±.22 to 3.31 ±.24 μm/s). Nevertheless, the effect of a supramaximal AVP concentration (200 μU/mL) was not altered by adrenalectomy (4.54 ±.39 to 8.08 ±.96; P<0.01). Incubation of collecting ducts in aldosterone for 2 h did not reverse the inhibitory effect of chronic adrenalectomy on AVP-stimulated water transport. 4. These studies suggest that mineralocorticoid withdrawal does impair the hydro-osmotic action of AVP in the rat papillary collecting duct but that this effect takes between 14 and 21 days to occur.     

乙醇对豚鼠心室肌细胞钙钠离子通道电流的影响

目的：观察乙醇对豚鼠心室肌细胞L-型钙离子通道电流（IGLL）和电压依赖性钠离子通道电流（INa）的影响，并探讨两者在乙醇致心肌损伤中的意义。方法：采用蛋白酶消化的成年豚鼠单个心室肌细胞及膜片钳全细胞技术，记录不同浓度乙醇对ICal.和INa的作用。结果：（1）乙醇抑制ICaL峰值，24mmol/L和240mmol/L乙醇抑制率差异有统计学意义（P〈0．05）。（2）24、80、240mmol／L乙醇使ICaL的电流-电压（I-V）曲线上移，在各测试电压下，电流均减小，但不影响曲线形状，用乙醇后最大激活电压仍在0mV左右。（3）24mmol／L乙醇基本不影响I、峰值，80、240mm01]L乙醇抑制I。峰值，与24mmol／L乙醇的抑制率差异有统计学意义（P〈0．05）。（4）24mmol／L乙醇对INa的I-V曲线无明显影响。80、240mmol／L乙醇使INa的I-V曲线上移，在各测试电压下，电流均减小，曲线形状无明显改变，用药后最大激活电压仍在-30mV左右。结论：致毒浓度（24mmol／L）的乙醇对ICal.具有明显抑制作用，可导致心肌产生负性肌力作用，动作电位时程缩短，诱发心律失常。但致毒浓度（24mmol／L）的乙醇不影响INa，而致死浓度（80mmol／L）对INa有明显抑制作用。     

Synergistic action of pyrazole on ethanol incoordination: differential metabolic and central nervous system effects

The influence of pyrazole on ethanol-induced incoordination was measured by a modified tilting-plane technique. Pyrazole (1–77 mmol/kg; 120 mg/kg) and/or ethanol (32.6 mmol/kg; 1.5 g/kg) was given intraperitoneally to rats. Impairment of coordination was related to blood ethanol concentrations. The mean maximal impairment was significant in all conditions. For ethanol alone the maximal impairment was 8.7%, for pyrazole alone 4.8% and for ethanol + pyrazole 16.5 %. Ethanol alone induced a total impairment, assessed planimetrically, of 530 units. Pyrazole alone induced an impairment gradually increasing with time (totally 1070 units). When pyrazole was combined with ethanol, the rate of ethanol elimination was reduced by 81%, and the time it remained in the blood was prolonged from 196 ± 11 to 850 ± 16 min. The rate of disappearance was reduced from 8.05 to 1.57 μg/ml per min. The total impairment increased to 5600 units, indicating a synergistic interaction between ethanol and pyrazole, which is contrary to the normalizing effects of pyrazole on ethanol-induced metabolic changes. A “post-drug” impairment was observed one week after pyrazole, while no such effects were found after repeated administration of saline or ethanol alone in control animals. Thus, pyrazole showed acute and long-term toxic eifects.     

EFFECTS OF PROLONGED (48 H) INFUSION OF CORTISOL ON BLOOD PRESSURE, RENAL FUNCTION AND FETAL FLUIDS IN THE IMMATURE OVINE FOETUS

1. This study describes the effects of prolonged (48 h) infusion of cortisol into ovine foetuses (100–110 days of gestation: term is 150 days) at a time when endogenous plasma cortisol concentrations are <5 nmol/L. 2. In four chronically cannulated foetuses (107 ± 0.9 day) the infusion of saline (0.9% NaCl; w: v 0.19 mL/h, 48 h) had no effect on blood pressure, renal function, or composition of amniotic and allantoic fluids. 3. In six foetuses (107 ± 1 day) the infusion of cortisol (250 μg/h) increased plasma cortisol concentrations from 4.1 ± 0.7 to 118 ± 9 nmol/L (P < 0.001), increased mean arterial pressure from 34 ± 1 to 40 ± 1 mmHg (P < 0.001), increased glomerular filtration rate (P<0.05), urine flow rate, and free water clearance (P<0.01). 4. There was a significant increase in excretion rates of potassium and creatinine as a result of cortisol infusion, but no natriuresis, indicating some functional maturation of the fetal kidney. 5. Cortisol infusion had no effect on the volumes of amniotic and allantoic fluids; allantoic fluid composition was unchanged; significant decreases occurred in amniotic fluid osmolality, sodium and chloride concentrations, and in lung liquid osmolality, potassium, creatinine, magnesium, glucose and fructose concentrations. 6. Thus prolonged exposure of the immature ovine foetus to elevated cortisol concentrations produced significant alterations in the water and electrolyte balance of the foetus.     

MECHANISMS UNDERLYING THE DECREASE IN CIRCULATING ANGIOTENSIN II CONCENTRATION AFTER SODIUM LOADING

1. Acute sodium loading causes a rapid decrease in the circulating concentration of angiotensin II (AngII), which is apparent from 5 min after sodium administration. This could result from an increase in AngII catabolism and/or a decrease in AngII synthesis/secretion. However, the major determinant of AngII synthesis is thought to be a change in plasma renin activity, which occurs over a longer time frame (15 min). 2. To investigate the mechanisms underlying the rapid decrease in plasma AngII engendered by sodium administration, we performed metabolic clearance studies in male New Zealand white rabbits before and after a hypertonic sodium load of 1.5 mmol/kg as 0.513 mol/L saline i.v. bolus. 3. The metabolic clearance rate of AngII increased significantly from 42.2 ± 9.0 mL/min per kg before sodium to 110.8±33.7 mL/min per kg after sodium administration (P<0.05). The calculated or theoretical secretion rate decreased from 1470.7±404.2 to 573.5 ± 139.5 fmol/min per kg (P<0.025) in response to sodium. 4. We conclude that an increase in AngII metabolism and a decrease in synthesis/secretion contribute to the reduction in circulating AngII, which occurs in the first 60–90 min after sodium loading.     

DETERMINANTS OF THE KINETICS OF VERY LOW-DENSITY LIPOPROTEIN APOLIPOPROTEIN B-100 IN NON-OBESE MEN

1. Apolipoprotein B-100 (ApoB) is the principal structural and functional protein of the pro-atherogenic lipoproteins. Elevated plasma apoB is an independent risk factor for coronary artery disease. In the present study we aimed to assess the factors that determine the kinetics of apoB in the very low-density lipoprotein (VLDL) in healthy men. 2. We studied 17 non-obese men who were consuming an ad libitum diet and had the following characteristics: mean (± SD) age 45.5 ± 9.7 years, body mass index (BMI) 25.1 ± 1.4 kg/m², waist: hip ratio 0.91 ± 0.04, serum cholesterol 5.2 ± 0.6 mmol/L, triglycerides 1.08 ± 0.53 mmol/L and high-density lipoprotein-cholesterol 1.24 ± 0.31 mmol/L. Daily dietary intake was as follows: total fat 76 ± 26 g, carbohydrate 238 ± 67 g, protein 103 ± 33 g and alcohol 20 ± 16 g. 3. The kinetics of VLDL ApoB were studied using a primed, constant infusion (1 mg/kg per h) of l-[¹³C]-leucine over 8 h with measurement of isotopic enrichment of ApoB using gas chroma-tography/mass spectrometry. The fractional turnover rate of VLDL ApoB was estimated using a monoexponential function. The mean (± SD) absolute hepatic secretion rate (ASR) of ApoB was 8.5 ± 4.6 mg/kg per day and the fractional catabolic rate (FCR) was 7.9 ± 5.6 pools/day. The ASR was significantly correlated with the waist: hip ratio (r= 0.60; P= 0.04), but not with age, BMI, weight or nutrient intake. The FCR was significantly and inversely correlated with plasma triglycerides (r =—0.53; P= 0.03) and alcohol intake (r = -0.48; P= 0.05). 4. In conclusion, the hepatic secretion of VLDL ApoB in non-obese, healthy men is primarily determined by the waist: hip ratio, a measure of visceral fat. This is consistent with the hypothesis that the rate of lipid substrate supply to the liver regulates the output of ApoB. The fractional catabolism of VLDL ApoB may, however, be inversely related to alcohol intake and appears to determine the plasma concentration of triglycerides.     

EFFECT OF CROSS-FOSTERING ON NEONATAL SODIUM BALANCE AND ADULT BLOOD PRESSURE IN THE SPONTANEOUSLY HYPERTENSIVE RAT

1. The aim of the present study was to compare electrolyte handling in naturally reared neonatal spontaneously hypertensive rats (SHR) with those reared by a Wistar-Kyoto (WKY) rat foster mother (denoted SHRX), as cross-fostering SHR pups to a WKY rat dam lowers adult blood pressure in the SHR. 2. The electrolyte content of WKY rat and SHR dams’ milk was determined and electrolyte intake and urinary excretion rates were calculated in both naturally reared and cross-fostered WKY rat and SHR pups. 3. The milk sodium concentration fell in both strains (WKY rat: 31.8 ± 2.0 to 15.2 ± 1.2 mmol/L; SHR 31.9 ± 2.5 to 18.2 ± 1.6 mmol/L; P < 0.001), as did potassium (P < 0.001), over lactation, but there were no differences between strains. Calcium and magnesium concentrations increased (P< 0.001), although SHR dam's milk contained less calcium (P < 0.001) than that of WKY rat dams during the third week of lactation. 4. Spontaneously hypertensive rat pups ingested less milk (P<0.05) than WKY rat pups; therefore, their cumulative sodium intake over postnatal days 4–15 was significantly lower than that of WKY rat pups (WKY rat vs SHR: 84.4 ± 3.6 vs 59.7 ± 2.6 μmol/g bodyweight, respectively; P < 0.05) and fostered SHRX pups (77.7 ± 7.0 μmol/g bodyweight; P < 0.05). Potassium and magnesium intakes were comparable between SHR, WKY rat and SHRX pups, but SHR pups ingested significantly less calcium than either WKY rat pups (136.1 ± 6.4 vs 200.1 ± 9.5p, mol/g bodyweight, respectively; P<0.05) or SHRX pups (200.0 ± 18.0 μmol/g bodyweight; P<0.05). 5. These data show that the neonatal SHR experiences a period of sodium deficiency during the developmental stage when cross-fostering is effective in lowering blood pressure. This is consistent with the reported up-regulation of the renin-angiotensin system observed in SHR at this time and may have a long-term influence on blood pressure.     

Dysfunction of the endothelium and constriction of the isolated rat's middle cerebral artery in low sodium environment in the presence of vasopressin

Hyponatraemia, a water–electrolyte disorder diagnosed in patients with subarachnoid haemorrhage (SAH), increases a risk of persistent vasospasm. In majority of cases, hyponatraemia results from inappropriate secretion of vasopressin (AVP). The effect of AVP-associated hyponatraemia on cerebral vasculature is unknown. The present study aimed to elucidate the role of AVP in the response of the middle cerebral artery (MCA) of the rat to hyponatraemia. Isolated, cannulated, and pressurized rat MCAs were perfused/superfused with physiological (Na⁺ = 144 mmol/L) buffer or low-sodium (Na⁺ = 121 mmol/L) buffer containing either AVP or angiotensin II (ANG II). ANG II was used to check if the effect of low plasma sodium concentration combined with AVP on the MCA tone is unique to vasopressin. At physiological Na⁺ concentration, vasopressin (1.4 × 10⁻¹¹ mol/L) or angiotensin II (10⁻⁹ mol/L) resulted in relaxation of the MCA. Substitution of low-sodium for the normal sodium buffer with the same concentration of AVP, resulted in the constriction of the MCA. This effect was absent after removal of the endothelium, administration of vasopressin V₁ receptor antagonist or concomitant inhibition of endothelin-1 receptors and synthesis of thromboxane A_2. In contrast, no constriction of the MCA in low-sodium buffer was observed when AVP was replaced with ANG II. Our data suggest that presence of vasopressin and low sodium ion concentration results in the change of endothelium phenotype from pro-vasodilatory to pro-vasoconstrictory. This phenomenon may be an overlooked factor contributing to vasospasm in SAH patients with hyponatraemia caused by inappropriate antidiuretic hormone secretion (SIADH).     

Blood disposition and urinary excretion kinetics of methazolamide following oral administration to human subjects

The pharmacokinetic disposition of methazolamide (MTZ) was studied in five healthy volunteers following administration of a single oral dose. Drug concentrations in blood, plasma, and urine were measured by HPLC. Over the range of plasma concentrations observed in vivo, MTZ free fraction (measured by ultrafiltration) was 0.28. Being a carbonic anhydrase inhibitor, MTZ would be expected to distribute into, and be sequestered by, red blood cells. For this reason, MTZ disposition was characterized utilizing blood concentrations as the reference. Using a two-compartment model, a series of differential equations were simultaneously fitted to blood concentrations and urinary excretion data generating estimates for k₁₀ (0.035±0.019 h⁻¹), k₁₂ (0.200±0.036 h⁻¹), k₂₁ (0.077±0.046 h⁻¹), k_a (0.304±0.064 h⁻¹), V_c (1.1±0.18 L) and f_r (fraction excreted renally, 0.61±0.14). Total blood clearance was 0.037±0.020 L h⁻¹. The model estimate of elimination half-life (126±61 h) was consistent with drug binding to a high affinity carbonic anhydrase isozyme in the erythocyte. Estimates of MTZ renal clearance and renal excretion ratio were 0.021±0.010 L h⁻¹ and 0.16±0.06, respectively. Overall, the prolonged elimination of MTZ from the blood is the result of extensive erythrocyte distribution and tubular reabsorption by the kidney. © 1998 John Wiley & Sons, Ltd.     

Prednisolone metasulphobenzoate foam retention enemas suppress the hypothalamo-pituitary-adrenal axis

Background: Corticosteroid enemas represent effective treatment for ulcerative proctitis, but absorption into the systemic circulation may have undesirable metabolic consequences. Prednisolone metasulphobenzoate, a lipophobic corticosteroid derivative, is designed to be absorbed poorly through the recto-sigmoid mucosa, but the effects of foam enema preparations upon the hypothalamo-pituitary-adrenal axis have not been examined. Methods: Nine patients suffering from active ulcerative proctitis underwent four weeks of therapy with prednisolone metasulphobenzoate foam enemas. The hypothalamo-pituitary-adrenal axis, denned using the modified single-dose metyrapone test, glucose homeostasis and lipid profiles were studied before and after treatment. Results: The hypothalamo-pituitary-adrenal axis was significantly depressed after the treatment period; mean stimulated plasma Cortisol concentration fell from 384 ± 244 (s.d.) to 288±252 nmol/L, P < 0.02; stimulated mean plasma 11-deoxyCortisol concentration fell from 677 ± 333 to 407 ± 326 nmol/L, P < 0.01. Mean fasting plasma glucose, insulin, C-peptide, fructosamine and triglyceride concentration were unchanged, whilst the mean serum cholesterol concentrations rose from 5.6 ± 1.1 to 6.0± 1.2 mmol/L (not significant). Conclusion: Prednisolone metasulphobenzoate foam enemas have significant systemic and endocrine metabolic effects, which could assume importance with long-term therapy.     

METABOLISM OF URIDINE IN EXPANDED EXTRACELLULAR VOLUME STATES

1. Uridine and uridine monophosphate (UMP) are natriuretic and a vasopressor in intact rats. In deoxycorticosterone acetate (DOCA)-salt hypertensive rats metabolic clearance rate (MCR) of uridine is raised and basal plasma uridine diminished, suggesting that metabolism of uridine is linked to changes in extracellular space. 2. Plasma uridine concentration was raised in 38 patients with chronic renal failure compared with age- and sex-matched healthy controls (8.49 μmol/L, 4.37–13.74 μmol/L median, interquartile range, and 2.64 μmol/L 2.51–2.74 μmol/L, respectively, P < 0.001). Plasma uridine was significantly diminished after isotonic fluid removal by ultrafiltration (UF) from 7.25 μmol/L (3.7–11.08) to 5.07 μmol/L (3.3–8.3), P < 0.001, whereas concentration of marker solutes urea and creatinine remained unchanged. During haemodialysis (HD), plasma uridine fell significantly from its pre-HD level. 3. In an animal model of expanded extracellular space the one-kidney, one-clip rat, plasma uridine was significantly higher (20.56±1.19 μmol/L, P < 0.01) and MCR diminished (34.93 ± 3.44 mL/kg per min, P < 0.01) compared with sham-operated animals (plasma uridine 12.14 ± 1.07 and MCR 53.59 ± 4.11 mL/ kg per min). Uridine or UMP did not inhibit Na⁺, K⁺-ATPase in either of the two assay systems. 4. It was concluded that catabolism of uridine is reduced by extracellular expansion and probably increased by volume reduction by UF. Such a function may be due to the presence of a hypertensive natriuretic factor postulated by Dahl and de Wardener (1980), but would not be consistent with the ouabain-like factor postulated by other workers in this situation because it has no inhibitory effect on Na⁺, K⁺-ATPase.     

ABNORMALITY OF THE GLOMERULAR ANGIOTENSIN II RECEPTOR IN EXPERIMENTAL DIABETIC NEPHROPATHY

1. The combined effect of diabetes and hypertension on the plasma angiotensin II (AII)/glomerular AII receptor (AII-R) relationship in streptozotocin-induced diabetes was investigated as well as the effect of glycaemic control on this relationship. 2. Diabetes was induced in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats with streptozotocin 60 mg/kg and blood sugars maintained between 18–21 mmol/L (uncontrolled diabetes) and 4–8 mmol/L (controlled diabetes). Rats were killed on days 1 and 7. Angiotensin II receptor was estimated by saturation analysis and plasma AII by radio-immunoassay. 3. Angiotensin II receptors were significantly higher in non-diabetic SHR than WKY rats (708 ± 62 and 388 ± 36 fmol/mg protein, respectively, P = 0.0008). Plasma AII were comparable in both groups (47 ± 2.7, 38 ± 3.5 pg/mL, respectively) and a significant inverse relationship between AII/AII-R was observed (WKY P = 0.02 and SHR P = 0.004). 4. On day 7, plasma AII and AII-R levels in diabetic groups were comparable with those of their non-diabetic controls. Diabetic WKY rats maintained an inverse correlation between AII and AII-R (controlled P= 0.04 and uncontrolled P= 0.015), but this did not occur in the SHR. 5. Absence of receptor response to varying ligand concentrations in the diabetic SHR may contribute to the development of nephropathy. Glycaemic control does not appear to reverse this abnormality in the SHR, so that co-existent hypertension may have a more direct influence on renal function.     

Effect of Erythromycin on Ethanol's Pharmacokinetics and Perception of Intoxication

Study Objective . To determine the effect of erythromycin on ethanol's pharmacokinetics and perception of intoxication. Design . Double-blind, randomized, placebo-controlled, crossover study. Setting . A clinical research center. Participants . Ten healthy volunteers. Interventions . Erythromycin base 500 mg or identical placebo was administered 3 times/day for 7 days. On day 8, ethanol 0.8 g/kg was administered by mouth concurrently with erythromycin or placebo. A 2-week washout period was allowed between each treatment arm. Measurements and Main Results . Twelve blood samples were obtained over a 12-hour period to determine ethanol concentrations. Perception of intoxication was determined at each time point using a 10-cm visual analog scale. Ethanol concentrations were determined using a gas chromatographic method. Mean ± SD ethanol pharmacokinetics for erythromycin versus placebo were time to peak ethanol plasma concentrations 1.1 ± 0.4 hours versus 1.3 ± 0.3 hours, peak ethanol concentrations 118 ± 18 mg/dl versus 114 ± 27 mg/dl, ethanol oral clearance (CL/F) 2.9 ± 0.8 ml/min/kg versus 3.4 ± 2.2 ml/min/kg, and area under the curve 481 ± 104 mg·hour/dl versus 465 ± 132 mg·hour/dl (p>0.05). The blood ethanol concentrations and perception of intoxication scores on a visual analog scale were well correlated (r²=0.78, p<0.01). Mean ± SD areas under the effect versus time curve were 35.1 ± 20.7 cm/hour and 31.5 ± 18.2 cm/hour for erythromycin and placebo, respectively (p>0.05). Conclusion . Oral erythromycin base 1500 mg/day compared with placebo does not alter ethanol's pharmacokinetics or perception of intoxication in healthy volunteers.     

Urinary clearance of 11-nor-9-carboxy-Δ9-tetrahydrocannabinol: A detailed pharmacokinetic analysis

Urine is a common matrix for screening for cannabis use. Urine assays typically measure total 11-nor-9-carboxy-Δ⁹-tetrahydrocannabinol (THCCOOH) concentrations after hydrolysis cleaves the glucuronide. Urine THCCOOH concentration is adjusted by urine creatinine concentration or specific gravity, to account for variable hydration states. Therefore, we performed a population pharmacokinetic analysis of the urinary THCCOOH excretion, urinary flow rate, and creatinine excretion rate data. Urine was obtained over 168 h from six subjects who smoked low- (15.8 mg) and high-dose (33.8 mg) Δ⁹-tetrahydrocannabinol (THC) cigarettes on two occasions. Samples were analyzed for THCCOOH concentration by gas chromatography–mass spectrometry (GC-MS) and volume, time, and creatinine concentration measured. A population pharmacokinetic model of the urinary clearance of THCCOOH was created from these data, and potential covariates of urine creatinine concentration and urine creatinine excretion rate were assessed. Elimination clearance of THCCOOH was estimated as 0.104 ± 0.088 L/min, and its urinary clearance was 0.0022 ± 0.0015 L/min. Total urine excretion of THCCOOH was estimated at 2.3%. Urine flow rate and urine creatinine concentrations were significantly correlated, r² = 0.35. Creatinine excretion rate was 129.6 ± 71.0 ml/min, and the intrasubject variability was 31%–52% (SD%) during the week. Urinary creatinine excretion rate was a significant covariate for the urinary clearance of THCCOOH. Creatinine clearance is a significant covariate for urinary THCCOOH clearance. Only 2%–3% of bioavailable THC is excreted as THCCOOH and THCCOO-glucuronide via the urine. Correction of urine drug and/or metabolite concentration with urine creatinine concentration or specific gravity may be more problematic than previously appreciated.     

RENAL AUTOTRANSPLANTS IN SHEEP: INVESTIGATION OF RENAL FUNCTION AND RENOVASCULAR HYPERTENSION

1. A novel surgical preparation of sheep with a cervical renal autotransplant has been developed. 2. Glomerular filtration rate and effective renal plasma flow were 25.1 ± 1.0 ml/min and 208 ± 10 ml/min respectively (n= 26). 3. The responses to water load and deprivation, to AVP injection, to Na depletion and intravenous hypertonic saline load show the kidneys responded in an appropriate physiological manner. 4. Constriction of the carotid-renal artery to reduce mean renal arterial pressure to 23 ± 4 mmHg (n= 4) resulted in an increase in systemic mean arterial pressure from 70 ± 4 mmHg to 75 ± 4 mmHg within 5 min. Systemic blood pressure further increased to 110 ± 7 mmHg with 2 h of constriction, when renal arterial pressure had increased to 45 ± 2 mmHg.