BLOOD VOLUME MEASUREMENTS IN THE NEONATAL LAMB: VALIDATION OF A METHOD USING [51Cr]-LABELLED RED CELLS

1. The reproducibility of blood volume measurements, using [⁵¹Cr]-labelled red blood cells (RBC) was tested in three lambs, 79–89 days of age, and the accuracy was tested in eight lambs, 83± 0.4 days of age, in which blood volume was measured simultaneously by [⁵¹Cr]-RBC and [¹²⁵I]-gamma globulin plus haematocrit (hct). 2. The blood volumes (mean ± s.e.) of the three lambs, on four occasions, were 64.5± 2.5, 68.8 ± 2.9 and 63.9 ± 3.7 mL/kg, respectively, and the coefficients of variation were 7.8, 8.6 and 11.6%, respectively. 3. The mean blood volume of eight lambs was 60.9 ± 3.3 mL/kg by [⁵¹Cr]-RBC, and 60.8 ± 2.4 mL/ kg from plasma volume and hct. These were not statistically different. 4. Arterial hct was 31.2 ± 0.5%, which was not statistically different from the whole body hct of 31.2 ±2.6%. 5. It is concluded that [⁵¹Cr]-RBC can be used to measure accurate and reproducible blood volumes in lambs.     

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.     

HYPOTENSIVE EFFECT OF CHRONICALLY INFUSED ADRENOMEDULLIN IN CONSCIOUS WISTAR-KYOTO AND SPONTANEOUSLY HYPERTENSIVE RATS

1. The hypotensive effect of chronically infused human adrenomedullin (hAM), a potent vasodilator peptide that has been reported to have a natriuretic action, was examined in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). 2. Conscious WKY rats and SHR were infused with 200 ng/h synthetic hAM for 14 days by means of osmotic minipumps. Control groups were infused at the same schedule with 0.9% saline. Systolic blood pressure (SBP) and daily urinary excretion of Na⁺ and K⁺ were measured before and during the infusion period. In addition, plasma renin activity (PRA), aldosterone and hAM concentrations were measured on day 14 of infusion. 3. A significant reduction in SBP was observed in hAM-treated SHR at day 2 and SBP remained significantly lower throughout the experiment compared with control SHR. Similarly, SBP in the hAM-treated WKY rats was found to be significantly lower than in control WKY rats during infusion. However, the hypotensive effect was not accompanied by any significant increase in urinary volume or Na⁺ excretion in hAM-treated rats of either strain. Chronic infusion with hAM significantly suppressed PRA and lowered the concentration of plasma aldosterone in WKY rats but not in SHR. The plasma hAM levels in treated WKY rats and SHR were 0.0 ± 9.4 and 0.6 ± 0.2 fmol/mL, respectively. 4. These findings demonstrate that chronically infused hAM has a hypotensive effect in both WKY rats and SHR without an increase in urinary volume or Na⁺ excretion at a plasma AM concentration within the physiological limit.     

URAEMIA IS NECESSARY FOR ERYTHROPOIETIN-INDUCED HYPERTENSION IN RATS

1. There is no experimental proof that renal insufficiency is a necessary condition for hypertension during erythropoietin treatment. 2. The present study compares the effect of 3 weeks treatment with r-hu EPO (50i.u./kg) on systolic blood pressure (SBP), haematocrit and plasma cGMP in an animal model of chronic renal failure (remnant kidney model excision) and sham-operated rats. 3. Sub-total nephrectomy induced a significant fall in haematocrit and a significant increase in plasma creatinine levels. Treatment with r-hu EPO resulted in a significant haematocrit increase in uraemic as well as in non-uraemic rats. Despite this effect, r-hu EPO treatment had no effect on SBP in sham-operated rats. On the contrary, this treatment caused significant SBP elevation in uraemic ratq in these rats, SBP increase did not correlate with haematocrit increase. 4. Plasma cGMP concentrations were significantly higher in uraemic compared to sham-operated rats and were not modified by r-hu EPO treatment. 5. This study provides evidence that renal insufficiency in rats is a prerequisite for the development of hypertension during erythropoietin treatment.     

Pharmacokinetics and Antidiuretic Effect of High‐Dose Desmopressin in Patients with Chronic Renal Failure

Abstract: High‐dose desmopressin shortens the bleeding time in uraemia. The aim of this study was to investigate the pharmacokinetics and the antidiuretic effect of desmopressin when given in a dose normally used for haemostasis to patients with reduced renal function. Ten patients with chronic renal failure of varying aetiology were enrolled in the study. The age was 58 (20–76) years (median and range), serum creatinine 447 (309–691) μmol/l and plasma clearance of iohexol 16 (8–19) ml/min./1.73 m² body surface. After baseline measurements, desmopressin was infused at a dose of 0.3 μg/kg. The plasma concentration of desmopressin was followed for 26 hr during and after the infusion and the pharmacokinetic parameters were estimated by compartmental analysis. Urine volume and osmolality, as well as body weight, blood pressure, heart rate, haematocrit, serum osmolality, electrolytes and creatinine, were measured repeatedly during the day before and for two days after the infusion. The total clearance of desmopressin was 0.35 (0.21–0.47) ml/min./kg, the volume of distribution at steady state was 0.30 (0.17–0.38) l/kg and the terminal half‐life 9.7 (8.4–16) hr. After administration of desmopressin, urine osmolality increased significantly, by approximately 10%, and this increase lasted for 48 hr. Concomitantly, there was a modest but significant decrease in haematocrit. Thus, the clearance of desmopressin was on average decreased to approximately one quarter, and the terminal half‐life was prolonged 2–3 times in the patients as compared to previously published values for healthy adults. The single haemostatic dose of desmopressin given to patients with severe renal failure did not cause fluid overload or changes in serum electrolytes.     

An investigation into the effects of aminoguanidine treatment on the plasma and blood of free-fed and dietary-restricted rats.

An investigation has been made into the effect of oral aminoguanidine (50-60 mg kg-1 day-1) on the blood biochemistry of male Wistar rats which either had free access to food or were dietary-restricted (50% of the food consumed by the free access group). In control rats (i.e. without aminoguanidine treatment) three weeks of food restriction caused significant increases in plasma sodium and albumin and the erythrocyte count, haematocrit and haemoglobin. There were reductions in plasma calcium, phosphate, alkaline phosphatase activity, urea, triglycerides, creatinine, glucose and the red cell volume. Similar effects of food restriction were observed in aminoguanidine-treated rats. Aminoguanidine ingestion in free-fed animals caused a reduction in plasma creatinine concentration. In dietary-restricted rats, aminoguanidine ingestion reduced plasma sodium and total plasma proteins (largely as a result of a decline in albumin), and increased plasma urea concentrations. Aminoguanidine was added to plasma of control rats in-vitro to determine whether it interfered with the assay of urea and creatinine. At concentrations of 0.1 to 10 mg mL-1, aminoguanidine had no effect on urea determinations. However, aminoguanidine significantly reduced the apparent concentration of plasma creatinine by between 7 to 81%. The changes in plasma analytes in aminoguanidine-treated rats may be indicative of minor hepatic perturbations or kidney function, but the data also imply that prior nutritional state is a determinant of aminoguanidine effects.     

Isosorbide 5-mononitrate pharmacokinetics in humans

When isosorbide 5-mononitrate was intravenously infused at a rate of 4 mg h ^?1 for 2.5 h to five human subjects, its concentrations in plasma increased slowly to 185 ng ml^?1 ± 5 per cent C.V. at 2.5 h and a steady-state plasma level was not reached during the infusion. When the infusion was discontinued, plasma drug concentrations declined with an elimination half-life of 4.2 h ± 6 per cent C.V. The systemic clearance after the infusion doses was 132 ml min^?1 ± 18 per cent C.V. and the volume of distribution was 48.4 1 ± 16 per cent C. V. After equal oral doses of 10 mg, the peak plasma isosorbide 5-mononitrate concentration of 191 ng ml^?1 ±16 per cent C.V. was reached at 1.1 h ± 30 per cent C.V., and plasma levels declined with a terminal half-life of 4.9 h. The complete systemic availability of isosorbide 5-mononitrate indicated that pre-systemic elimination after the oral doses was negligible. A one-compartment open model appeared adequate to describe the plasma level data after intravenous infusion and oral doses. After single oral doses of 10 mg isosorbide dinitrate, the peak plasma concentration of the 5-mononitrate metabolite of 72 ng ml^?1 ± 27 per cent C. V. occurred at l.7h.41 per cent C.V. Approximately 50 per cent (range 22–68 per cent) of the oral dose of isosorbide dinitrate circulated in plasma as the 5-mononitrate metabolite. The pharmacokinetics of isosorbide mononitrates are markedly different to those of the parent dinitrate and these differences follow from the greater systemic availability and volume of distribution of the mononitrates.     

ROLE OF NITRIC OXIDE IN THE DEVELOPMENT OF CORTICOTROPIN-INDUCED HYPERTENSION IN SHEEP

1. The possibility that altered synthesis of vascular nitric oxide (NO) plays a role in the development of corticotropin-induced hypertension in sheep was examined by determining the effect of concomitant infusion of L-arginine, a precursor of NO, on the development of the hypertension. 2. Corticotropin (5 μg/kg per h) infused over 2 days increased mean arterial pressure (MAP) from 83 ± 4 to 99 ± 4 mmHg in five conscious sheep. Concomitant infusion of L-arginine (60 mg/kg per h) did not alter this response; infusion of L-arginine alone had no effect on blood pressure. 3. The dose of L-arginine (60 mg/kg per h) used blocked the rise in MAP (+16 mmHg) in response to a 5 h infusion of N-nitro-L-arginine (1 mg/kg per h). 4. These findings suggest that disruption of NO synthesis does not play a role in the development of corticotropin hypertension in sheep.     

血管紧张素Ⅱ在内皮素诱导的大鼠高血压中的作用

目的探讨血管紧张素Ⅱ在内皮素-1诱导的大鼠高血压中的作用。方法 5～6周雄性SD大鼠随机分为3组:①对照组(1%氯化钠慢性灌注,n=7);②内皮素-1慢性灌注组[2.5pmol/(kg.min),n=7];③内皮素-1+奥美沙坦治疗组(0.01%食物中混入,n=7)。Western blotting检测血浆血管紧张素原和主动脉ACE与AT1受体表达。放射免疫法检测血浆肾素活性、血管紧张素Ⅰ和血管紧张素Ⅱ水平。结果与对照组相比,内皮素-1慢性灌注组大鼠血压明显升高[(121±2)vs(141±2)mmHg,P<0.05)],血浆肾素活性明显增加[(3.1±0.6)vs(8.1±0.8)AngI/(mL.h),P<0.05)],血管紧张素Ⅰ[(45±8)vs(122±28)fmol/mL]及血管紧张素Ⅱ水平[(47±7)vs(94±13)fmol/mL]水平明显升高(P<0.05)。内皮素-1灌注未影响大鼠血浆血管紧张素原以及主动脉ACE和AT1受体表达。AT1受体拮抗剂奥美沙坦降低了内皮素-1慢性灌注引起的大鼠高血压。结论内皮素-1诱导的大鼠高血压与血管紧张素Ⅱ水平增高相关。内皮素-1与血管紧张素Ⅱ共同作用,促进了内皮素-1慢性灌注诱导的大鼠高血压进展。     

INTERACTION OF EXOGENOUS OUABAIN AND CHRONIC MINERALOCORTICOID TREATMENT IN THE KIDNEY OF THE CONSCIOUS SHEEP

1. Ouabain is known to have natriuretic effects only at high doses, and therefore if endogenously produced ouabain has a role in the regulation of sodium excretion, the renal response to ouabain must be increased substantially in certain physiological situations. The aim of this study is to determine whether treatment with the mineralocorticoid, aldosterone, potentiates that natriuretic response to ouabain. 2. Six conscious sheep received renal arterial infusion of either vehicle or aldosterone (3 μg/h). Forty hours after commencement of infusion ouabain was infused into the renal artery at 400 μg/h for 60min. A second infusion of ouabain was administered on the 6th day of aldosterone treatment. 3. In the absence of aldosterone, the effects on sodium excretion produced by ouabain infusion at 400 μg/h into the renal artery were variable and not statistically significant. Ouabain infusion after 40 h of aldosterone treatment increased sodium excretion from 40 ± 14 to 676 ± 69 μmol/min in the second hour following cessation of ouabain infusion (P< 0.001). Ouabain infusion after 6 days of aldosterone treatment increased sodium excretion similarly. Ouabain-stimulated sodium excretion was significantly greater during aldosterone treatment compared to vehicle treatment (P<0.05). In contrast, no enhancement of effect was observed after acute treatment with aldosterone. 4. These results demonstrate potentiation of the natriuretic response to ouabain infusion by chronic mineralocorticoid treatment and suggest a potential role of endogenous digitalislike factor in the physiological control of sodium homeo stasisaldo sterone, endogenous digitalis-like factor, ouabain, sodium excretion.     

EFFECTS OF CHANGING HAEMATOCRIT, VENTRICULAR RATE AND MYOCARDIAL INOTROPY ON THE ACCURACY OF IMPEDANCE CARDIOGRAPHY

1. The accuracy and limitations of the non-invasive impedance cardiograph technique were examined in dogs with electromagnetic flow-transducers mounted on the aortic root over a wide range of physiological conditions of anaemia, heart rate, stroke volume and myocardial inotropy. 2. The in vivo blood resistivity (ρ)-haematocrit relationship is linear and slightly inverse, and is thus opposite to the curvilinear, direct relationship of the bench-derived p-haematocrit relationship. At haematocrit 41%, in vivoρ is 135 ohm. cm (s.e.m. = 1.0, n - 134) and rises only to 143 ohm. cm (s.e.m. = 1.6, n= 134) as haematocrit falls to 26%. 3. When in vivoρ is used in the Kubicek formula for stroke volume (SV) calculation, the instrument is linear and accurate for heart rates over 38–156 min^-1. Thus 82% of all points fall within ±20% of the line of equal value over stroke volumes ranging from 8–46 ml (N = 3, n= 105). The standard error of the estimate for pooled data is ±2% of the mean impedance stroke volume value of 22.2 ml. The instrument tends to overread at heart rates lower than 60 min^-1.     

SKELETAL MUSCLE RESTING METABOLISM IN COLD-ACCLIMATED RATS: EFFECT OF AGE, NORADRENALINE AND HYPEROSMOLARITY

1. A myothermic technique has been used to measure the resting metabolism of small bundles of a fast twitch muscle, extensor digitorum longus (EDL), and a slow twitch muscle, soleus (SOL), in 7-week-old rats. At 27°C, mean (± SEM) resting heat rates were 2.33 ± 0.41 and 2.09 ± 0.37 mW/g in EDL and SOL, respectively (n= 16). 2. Seven-week-old rats were cold acclimatized at 4°C for 1–4 weeks and the metabolic rates of the fast and slow twitch muscles were monitored and compared with 7- and 11-week-old controls. There was a 160% increase in metabolic rate from week 7 to week 11, but the increase also occurred in the control group. 3. In accordance with several literature reports, noradrenaline at concentrations of 10”⁷ and 10”⁶ mol/L had no effect on either the control or cold-acclimatized resting heat rate. 4. The osmolarity of the physiological solution bathing the muscle bundles was increased by lOOmosmol using sodium sulphate. Basal metabolism increased by similar amounts (approximately 250%) in both the fast and slow muscle bundles. Periods of cold exposure had no significant effect on the magnitude of the increment. 5. Bumetanide, a potent inhibitor of Na⁺-Cl^? co-transport, produced only a slight reduction in the heat increments caused by hyperosmolar challenge.     

THE EFFECT OF EXPERIMENTAL RENAL FAILURE ON TOLFENAMIC ACID DISPOSITION IN THE DOG

The pharmacokinetic disposition of tolfenamic acid, an NSAID, after a single administration of tolfenamic acid (4 mg kg⁻¹) by the intravenous (IV) route was compared in eight dogs before and after a surgically induced renal failure. Renal impairment was confirmed by a significant increase ( p <0·001) of water intake, urine volume, and urea and creatinine plasma concentration. PAH and inulin clearances decreased after surgery from 15·2±4·2 to 9·5±0·8 mL kg⁻¹ min⁻¹ ( p <0·05) and from 4·37±1·15 to 2·43±0·88 mL kg⁻¹ min⁻¹ ( p =0·067), respectively. After surgery, clearance of TA was significantly ( p <0·001) increased, from 2·22±1·68 to 3·59±1·81 mL kg⁻¹ min⁻¹. There was no modification of the steady-state volume of distribution ( p >0·05) and the mean residence time was significantly decreased from 606±199 to 373±302 min ( p <0·05). No variation of binding to plasma proteins (<99%) was observed. These results suggest that renal insufficiency could increase hepatic metabolism and/or alter the enterohepatic cycle of TA. © 1997 by John Wiley & Sons, Ltd.     

Low doses of recombinant human erythropoietin does not affect C‐terminal FGF23 in healthy men

Recombinant human erythropoietin (rhEpo) can improve human performance, but misuse remains difficult to detect. C‐terminal fibroblast growth factor 23 (cFGF23) was recently demonstrated to increase following injection of a single high dose rhEpo, but the effect of more frequent low doses is unknown. Using a randomized double‐blind placebo‐controlled design, we investigated whether 2 weeks of subcutaneous injections three times a week of 50 IU/kg Eprex (low‐dose) or 20 IU/kg Eprex (micro‐dose) increase cFGF23 levels compared with saline (placebo) injections in 24 healthy males. Venous blood was sampled at day ?3, 0, 1, 3, 11, 14, 18, and 25 of the treatment and analyzed for cFGF23 and erythropoietin concentration ([EPO]). The level of cFGF23 was similar at days ?3, 0, 1, 3, 11, 14, 18, and 25 with the low‐dose (23 ± 4, 26 ± 5, 23 ± 7, 27 ± 6, 25 ± 8, 24 ± 10, 22 ± 5, and 24 ± 7 RU/mL, respectively), micro‐dose (23 ± 6, 25 ± 5, 23 ± 8, 28 ± 9, 27 ± 7, 25 ± 9, 25 ± 5, and 23 ± 6 RU/mL, respectively) and placebo (23 ± 6, 24 ± 6, 26 ± 7, 26 ± 6, 31 ± 6, 31 ± 7, 24 ± 4, and 27 ± 8 RU/mL, respectively) treatment. The correlation coefficient between plasma [EPO] and plasma cFGF23 levels was R² = 0.01 and insignificant. The results demonstrate that cFGF23 is not sensitive to low doses of subcutaneous rhEpo injections in healthy males.     

LONG-TERM INCREASES IN RENAL SYMPATHETIC NERVE ACTIVITY AND HYPERTENSION

1. Essential hypertensive patients have been characterized by increased sympathetic nerve activity, increased peripheral vascular tone, decreased plasma volume and normal cardiac output when compared with normotensive subjects. Bilateral renal denervation reduces the magnitude or delays the onset of the blood pressure response in numerous models of experimental hypertension regardless of the aetiology of the elevation in arterial pressure. 2. Using a servocontrolled intrarenal infusion system, we have elevated intrarenal noradrenaline concentration via intermittent renal artery infusion without decreasing renal blood flow as a method of simulating selective elevation of renal sympathetic outflow. 3. Chronic intrarenal adrenergic stimulation increased arterial pressure within 24 h and this hypertension persisted for 28 consecutive days. The elevated arterial pressure was not associated with sustained increases in plasma renin activity, aldosterone, circulating catecholamines, arginine vasopressin or significant renal vasoconstriction. Urinary sodium excretion was chronically elevated and the dogs remained in negative sodium balance for the duration of the intrarenal noradrenaline infusion. 4. After 2 weeks of elevated intrarenal neurotransmitter coupled with hypertension, renal vascular reactivity to further adrenergic stimulation was significantly increased because the hypertension was maintained during continual reductions in the daily dosage of neurotransmitter allowed to be infused by the servocontroller. After only 28 days of noradrenaline infusion, renal vascular hypertrophy developed in vessels from 150–300 μm. 5. We conclude that selective and intermittent increases in intrarenal adrenergic neurotransmitter are sufficient to elicit chronic hypertension in the absence of volume expansion. This intrarenal neuroadrenergic hypertension is closely associated with the haemodynamic parameters which characterize a major subset of human essential hypertensives.     

HAEMODYNAMIC, RENAL AND HORMONAL RESPONSES TO ENALKIREN IN FOUR PATIENTS WITH POST-SURGICAL OLIGURIA

1. The haemodynamic and hormonal responses of four patients with acute post-surgical oliguria (urine output <0.5 mL/kg perh) were measured in response to the renin inhibitor enalkiren. Enalkiren was infused at 0.01 up to 0.1 mg/kg perh for up to 4h. 2. Enalkiren infusion was associated with a progressive fall in blood pressure, clinically significant in three of the four patients. Systemic vascular resistance fell in proportion to blood pressure fall. Cardiac output and pulse rate remained unchanged. Effective renal plasma flow rose in all four cases (236 ± 19 to 327± 38). There was no change in urine flow rate, or urinary sodium excretion. 3. Plasma renin activity (ng angiotensin I/mL perh) fell from 1.9 ± 0.5 to 0.02 ± 0.01 (P<0.04), plasma angiotensin II (pg/mL) fell from 104 ± 93 to 7.7 ± 1.5, and plasma aldosterone (ng/dL) fell from 32 ± 8 to 21 ± 9 (P= 0.03) at the highest infusion dose. 4. Enalkiren inhibited plasma renin activity with reduced plasma angiotensin II and aldosterone concentrations. This was associated with vasodilation, reduced blood pressure and maintained cardiac output. There was no beneficial effect on renal function in these patients with post-surgical oliguria.     

Disposition Kinetics of Intravenous Halofantrine-HCl in an Animal Model

Abstract

The disposition kinetics of intravenous halofantrine-HCl was studied in beagle dogs. In a dose-ranging study, three dose levels of halofantrine, 2.5 mg/kg, 5 mg/kg, and 10 mg/kg, were administered intravenously by infusion pump over 10 min or 2 h. the mode of intravenous administration of halofantrine was well tolerated by all animals. the 5 mg/kg dose infused over a period of 10 min produced adequate blood and plasma levels for pharmacokinetic analysis. therefore, this dose and infusion rate was employed in the definitive study.

The disposition of halofantrine followed a tri-exponential decline. the mean (± SD) elimination clearance is 15.7 ± 4.3 L/h for blood and 12.9 ± 2.6 L/h for plasma; while the steady-state volume of distribution for blood and plasma are 275.7 ± 165.9 L and 402.0 ± 205.6 L respectively. the terminal elimination half-lives in blood and plasma are 111.3 ± 72.1 h for blood and 192.8 ± 104.5 h for plasma.

Halofantrine was observed to be a low extraction drug with hepatic extraction ratio of approximately 0.25 and, is highly distributed in the peripheral compartments. It has a short mean residence time of about 0.3 h in the central compartment and there was evidence of preferential concentration of desbutyl-halofantrine in red blood cells. the implications of these in malaria therapy with halofantrine is unknown.     

The fate of intravenously infused gelatin

The fate of i.v. infused gelatin was studied by measuring the rise in the level of total hydroxyproline (HP) in some organs of the rat following the infusion of a 5% autoclaved gelatin solution (1 ml/100 g body weight). The results obtained showed that HP levels were consequently increased in all of the organs studied, then the levels were generally normalised during the 3rd day post infusion. Small concentrations of HP were still retained by the kidneys and blood plasma, at the end of the first week after infusion. The rat ratio HP/creatinine (HP/C index), which increased from 0.33 to 3.78 during the first 24 h post infusion, declined gradually to the base-line level after 4 weeks, during which time 94% of the HP infused could be accounted for in the urine. Most of the HP was excreted in the bound form.     

THE EFFECT OF GRADED HAEMORRHAGE ON ERYTHROPOIETIN PRODUCTION IN THE IMMATURE OVINE FOETUS

1. Basal and haemorrhage-stimulated erythropoietin (Epo) and ACTH levels were measured in the chronically cannulated immature ovine foetus (less than 125 days) by radio immunoassay (RIA). 2. Basal erythropoietin levels were found to be higher than those previously reported in the late gestation (greater than 130 days) ovine foetus, but were lower than those observed in the neonatal lamb. 3. In control foetuses (Protocol 1) the small degree of haemorrhage associated with the sampling procedure increased the plasma Epo values from 11.4 +/- 3.0 (n = 5) mU/mL to 23.8 +/- 4.3 mU/mL at 24 h (mean +/- s.e.m.). There was a significant monotonic increase with time (F = 16.4; d.f. 1,19; P = 0.001). An initial haemorrhage of approximately 10% blood volume (Protocol 2) increased plasma Epo values from 7.3 +/- 2.3 to 24.2 +/- 7.1 mU/mL (n = 3). 4. Haemorrhage of 20% fetal blood volume (Protocol 3) produced an increase in plasma Epo from 9.3 +/- 1.7 to 54.7 +/- 15.5 mU/mL at 6 h and to 57.6 +/- 7.3 mU/mL at 24 h (n = 5). By repeated measures ANOVA, the effect of the 20% haemorrhage was significant when compared with the control group (F = 7.32, d.f. 2,16, P = 0.006). There was a significantly greater decrease in haematocrit (F = 6.7, d.f. 2,20, P = 0.004) and haemoglobin (F = 5.0, d.f. 2,20, P = 0.013) in animals of Protocol 3 than in those of Protocol 1. 5. Fetal blood gases and plasma adrenocorticotropic hormone (ACTH) did not alter with haemorrhage, indicating the tolerance of the foetus to this degree of haemorrhage.     

RELATIONSHIP BETWEEN THE SUPPRESSIVE ACTIONS ON INTESTINAL ABSORPTION AND ON cGMP PRODUCTION FOR THE NATRIURETIC PEPTIDE FAMILY IN DOGS

1. The aim of this study was to investigate whether the suppressive effects of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) on net intestinal absorption were related to guanosine 3′,5′-cyclic monophosphate (cGMP) production in the intestine. 2. We measured the plasma cGMP concentration of the arterial, jejunal and ileal venous blood after intravenous infusions of natriuretic peptides (97 pmol/ kg per min for 30 min) in anaesthetized dogs. 3. The infusion of ANP increased cGMP concentration of the aortic blood by 49.9 ± 9.0 (pmol/mL), BNP by 71.8 ± 12.3 and CNP by 5.5 ± 1.3. The increases in cGMP after ANP and BNP were larger than after CNP. The infusion of ANP increased jejunal arteriovenous differences in cGMP concentration by 69.9 ± 3.5 (pmol/mL) and ileal arteriovenous differences by 8.7 ± 3.2. In BNP infusion, the jejunal and ileal arteriovenous differences in cGMP concentration tended to increase by 15.6 ± 5.8 (pmol/mL) and by 14.8 ± 6.6 but neither were significant. CNP infusion did not change the jejunal and ileal arteriovenous differences in cGMP concentration. 4. These results suggest that, while the actions of ANP on intestinal absorption may be mediated by cGMP, those of BNP and CNP are not.