Bidirectional peritoneal transport of albumin in continuous ambulatory peritoneal dialysis

The present study was undertaken in order to assess bidirectionalperitoneal kinetics of albumin after simultaneous i.v. and i.p.injection of radioiodinated albumin tracers (¹²⁵I-RISA and ¹³¹I-RISA)in eight clinically stable uraemic patients undergoing continuousambulatory peritoneal dialysis (CAPD). The plasma volume, intravascularalbumin mass (IVM), and overall extravasation rate of albuminwere not significantly different from that found in healthycontrols. Albumin flux from the plasma into the peritoneal cavitywas 3.71 ± 0.82 (SD) µmol/h, which was only 3%of the overall extravasation rate (137 ± 52 µmol/h).Albumin flux from the peritoneal cavity into the plasma wassubstantially lower (0.22 ± 0.07 µmol/h, P<0.01).The net peritoneal accumulation of the albumin from plasma over4 h was 14 ± 3.2 µmol, which was significantlylower than the intraperitoneal albumin mass at the end of thedialysis (54 ± 19 µmol, P<0.01). This indicatesthat only about 25% of the albumin loss during CAPD occurs directlyfrom the plasma. The initial osmotic net filtration was 508± 302 ml. The volume flow equivalent to the albumin fluxwas 6.3 ± 1.5ml/h into the peritoneal cavity and 7.8± 1.9ml/h back into the plasma. Although minor, as comparedto the osmotic net filtration (508 ml), the albumin flux equivalentvolume (31.2 ml) exceeded the steady state filtration (25.2ml) significantly (P<0.01) during the 4 h investigation. In conclusion, albumin flux into the peritoneal cavity is smallcompared to the overall extravasation rate, but our resultssuggest that CAPD loss of albumin predominantly occurs fromthe subperitoneal interstitial space and only to a minor degreedirectly from the plasma. Albumin flux equivalent volume flowis relatively small and most probably represents peritoneallymph drainage.     

Uraemic toxic retention solutes depress polymorphonuclear response to phagocytosis

Previous studies from our laboratory have demonstrated thatthe activity of the hexose mono-phosphate shunt (HMS) pathwayin phagocytosisrelated respiratory burst is disturbed in end-stagerenal disease. To determine whether uraemic solute retentionis responsible for this defect the HMS-path was evaluated bymeasurements of glucose-1-C¹⁴ utilization and determinationof ¹⁴CO₂ production in polymorphonuclear cells (PMNLs), suspendedin normal plasma or uraemic biological fluids. Normal PMNLs,while suspended in normal or uraemic plasma, were stimulatedwith either latex, zymosan or Staph. aureus; CO₂ generation(measured as DPM/10³ PMNL, normal versus uraemic plasma) wasdepressed in uraemic plasma in response to latex (from 43±5to 20±3), zymosan (from 72±8 to 47±4) (P<0.01),and Staph aureus (from 73±17 to 47±8 DPM/10³ PMNL)(P<0.05). The degree of inhibition was similar for each stimulus.To characterize the substances responsible for this defect wefractionated uraemic plasma ultrafiltrate by polarity-basedsemipreparative C₁₈ reversed phase HPLC and found a decreasedresponse to Staph. aureus in the presence of fraction 2 (from102±13 to 23±10 DPM/10³ PMNL, P<0.05), andin fractions 8 and 11 (lowest value in fraction 8, 54±14DPM/10³ PMNL, P<0.05 versus control). The pattern of HPLCelution on a gradient from 100% formiate (pH 4.0) to 100% methanolindicates that there are at least two chemically distinguishablegroups of compounds, one hydrophilic (in fraction 2), and onelipophilic (in fractions 8 and 11). We conclude that uraemicbiological fluids contain factors that inhibit HMS activityrelated to phagocytosis, and that at least two groups of componentswith different characteristics are involved.     

Survey of Blood Lead and Plasma Aluminium Concentrations in Patients of a Renal Unit

Blood lead and plasma aluminium concentrations have been measuredin patients with end-stage chronic renal failure treated byhaemodialysis (HD) or by continuous ambulatory peritoneal dialysis(CAPD) and in a control group of non-dialysed patients withchronic renal failure (CRF). Data on a group of subjects withnormal renal function is included for comparison. We have foundsignificantly increased mean blood lead and plasma aluminiumconcentrations in all patients with chronic renal failure comparedto a group with normal renal function. All blood lead concentrations were within the accepted safeexposure range of less than 1.8 µmol/l (380 µg/l)).There were significant differences among the patient groups:home HD, 0.60±0.25 µmol/l (124±52 µg/l);hospital HD, 0.39±0.31 µmol/l (81±64 µg/l);CAPD, 0.32±0.17 µmol/l (66±35 µg/l);CRF, 0.38±0.20 µmol/l (79±41 µg/l);normal, 0.24±0.11 µmol/l (50±23 µg/l).Correction of the blood lead results for haemoglobin accentuatesthese differences (i.e. hospital HD, 4.61±3.25 nmol/g(0.96±0.67 µg/g); CRF, 3.05±1.46 nmol/g(0.63±0.30 µg/g); normal, 1.65±0.70 nmol/g(0.34±0.14 µg/g). Plasma aluminium concentrations show a similar pattern: homeHD, 1.09±0.70 µmol/l (29.4±18.9 µg/l);hospital HD, 0.81±0.58 µmol/l (21.9±15.7µg/l); CAPD, 0.34±0.34 µmol/l (9.2±9.2µg/l); CRF, 0.18±0.09 µmol/l (4.9±2.4µg/l); normal, 0.09±0.07 µmol/1 (2.4±1.9µg/l). The duration of dialysis treatment is an important determinantof metal accumulation: there is a significant positive correlationbetween the duration of dialysis treatment and both blood lead:haemoglobinratio (r=0.48, P<0.01) and plasma aluminium (r=0.61, P<0.01)concentrations. There is also a significant negative correlation(r= –0.59, P<0.01) between urine volume and plasmaaluminium for haemodialysis patients, but not for peritonealdialysis patients. Urine volume shows no relationship to bloodlead. Age has no effect on lead accumulation in any of the patientgroups, but there is a significant correlation of age to bloodlead in the normal renal function group (r=0.47, P<0.01).The effect of sex and hypertension on metal concentrations isalso discussed. It is considered probable that the dialysate is a major factorcontributing to the accumulation of both elements. The possiblelong-term clinical significance of these findings remains tobe determined.     

BLOOD CYANIDE AND THIOCYANATE CONCENTRATIONS PRODUCED BY LONG-TERM THERAPY WITH SODIUM NITROPRUSSIDE

Blood cyanide (HCN) or plasma thiocyanate (SCN) concentrations,or both, were measured in 30 patients (ages 11 months-72 yr)receiving sodium nitroprusside (SNP) for 12–314 h. Sequentialmeasurements in three of these patients (infused 5, 12 and 13days) showed that HCN concentrations varied with dose rate,while SCN concentrations increased linearly with increasingSNP dose. The accumulated data confirmed that the rate of administration(0.3–6.5 µg kg^–1 min^–1) determined theplasma HCN concentrations (0–3.8 µmol litre^–1;y = 0.267 x - 0.0733; r = 0.64; n = 51; P< 0.001). Thus,if prolonged exposure to plasma HCN concentrations greater than1 µmol litre^–1 is to be avoided, the maximum safesustained dose rate of SNP will lie near to 4 µg kg^–1min^–1. Likewise, the SCN results (30—880 iimol litre^–1)confirmed the close relationship between plasma concentrationsand the total SNP dose (0.44–32.9 mg kg^–1; y = 24.6x+ 74.9; r = 0.95, n = 51, P < 0.001). Therefore, we suggestthat, to avoid SCN toxicity (plasma SCN > 1.75 µmollitre^–1), in the absence of SCN monitoring, the totalSNP dose should be less than 70 mg kg^–1 in patients withnormal renal function.     

Regulation of nitric oxide synthesis in uraemia

Nitric oxide (NO) is a cell-to-cell mediator involved in theregulation of vascular tone and in the mechanisms of host defence.Since uraemic syndrome is characterized by abnormalities inblood pressure and flow and by impairment of white cell function,we studied the regulation of nitric oxide synthase (NOS) activityby uraemic plasma. We used three different cellular types havingdifferent levels of NOS activity: tEnd. 1 murine endothelialcell line transformed by mT oncogene of polyomavirus had a highNOS activityand expressed endothelial-NOS (eNOS) and inducible-NOS(iNOS) isoforms; human endothelial cells from cord umbilicalvein (HUVEC) had low enzymatic activity and expressed only eNOS;finally, J774 murine macrophage line was characterised by iNOSinduced after treatment with cytokines. We demonstrated thatmost (79%) of end-stage uraemic plasma studied inhibited NOSactivity in tEnd.1 and in cytokine induced -J774, whereas theywere ineffective on HUVEC. Twenty percent of plasma samples(14 of 67) activated NOS activity in tEnd.1 and in J774 cells,but not in HUVEC, suggesting the presence of molecule(s) whichinfluence iNOS. The effect of plasma was not dependent on thetype of haemodialysis treatment. A great number of plasmas frompatients with moderate renal failure also inhibited NOS activityin tEnd.1, suggesting that the accumulation of molecules affectingNOS was caused by the renal failure rather than the haemodialytictreatment. However, the haemodialysis modified the effect of plasmas onNOS activity. Plasma taken after haemodialysis session showeda reduced inhibitory activity in tEnd.1 and in some cases itenhanced NOS activity. Simultaneously, molecules reducing NOSactivity accumulated in the ultrafiltrate. The plasma concentrationof N^G-N^G dimethyl-L-arginine (asymmetrical dimethylarginine,ADMA), an inhibitor of NOS, increased in end-stage uraemic patientsand was reduced by haemodialysis. However, the concentrationsreached in uraemic plasmas were lower than the ADMA ICM₅₀ ontEnd.1 NOS, indicating that this compound contributes with othermolecules to the inhibitory effect of uraemic plasma. Haemodialysisreduced also the enhanced effect exerted by some plasmas onNOS in J774. Therefore, the effect of endstage uraemic plasmaon NOS activity derive from the balance between inhibitors andactivators.     

KETAMINE INFUSIONS: PHARMACOKINETICS AND CLINICAL EFFECTS

The clinical effects and pharmacokinetics of ketamine, administeredas an i.v. infusion, were studied in 31 patients. Anaesthesiawas induced with ketamine 2 mg kg^–1 i.v. and maintainedusing an i.v. infusion of ketamine, supplemented by nitrousoxide. The plasma concentrations of ketamine, nor-ketamine anddehydro-nor-ketamine were analysed using gas-liquid chromatography.The average maintenance dose of ketamine was 41 ± 21µg kg^–1 min^–1, but there was an obvious decreasein the dose required as anaesthesia progressed. This dose gavea stable plasma concentration of ketamine of 9.3 ± 0.8µmol litre^–1. Patients recovered at 2.7 ±0.9 µmol litre^–1. Plasma half-life of ketamine was79 ±8 min. Maximum concentration of nor-ketamine was4.7 ± 2.4 µmol litre^–1 and of dehydro-nor-ketamine3.2 ± 1.9 µmol litre^–1. There were transientincreases (15–30% of pre anaesthetic values) in arterialpressure, heart rate and cardiac output during operation. Nopostoperative respiratory depression was seen.     

PHARMACOKINETICS OF MIDAZOLAM IN ANAESTHETIZED CIRRHOTIC PATIENTS

The pharmacokinetics of midazolam were compared in cirrhoticpatients (n = 10) and control patients (n = 9), during generalanaesthesia. Total plasma clearance was 637 ± 223 mlmin^–1 (mean ± SD) in control patients and 402 ±170 ml min^–1 in cirrhotic patients (P<0.05). The totalvolume of distribution was similar. Elimination half-life was135 ±40 min in controls and 168±30min in cirrhosis(P<0.05). Protein binding was evaluated by equilibrium dialysisin both groups at two concentrations of midazolam: 20 and 500µg litre^–1. No saturation occurred, but the freefraction was 4.9±1.7% in cirrhotic patients, comparedwith 1.9±0.6% in controls (P < 0.01). Despite itsmainly hepatic elimination, midazolam disposition appears tobe only slightly impaired in cirrhotic patients.     

FENTANYL INHIBITS THE UPTAKE OF [3H]NORADRENALINE IN CULTURED NEURONAL CELLS

We have examined how fentanyl modulates [³H]noradrenaline uptakein two cultured neuronal cell preparations, the human neuroblastomaSH-SY5Y and the rat phaeochromocytoma PC12. Fentanyl produceda significant, dose-dependent inhibition of [³noradrenalineuptake at concentrations in excess of 0.1 µmol litre^–1(P <0.05) and 0.3 µmol litre^–1 (P < 0.05)for PC12 and SH-SY5Y cells, respectively. However, these valuesexceed the serum concentration of fentanyl required to produceanalgesia. At the maximum concentration examined (100 µmollitre^–1), fentanyl produced 85–95% inhibition ofuptake. This effect was not antagonized by naloxone, implyinga nonopioid mechanism of action. Imipramine 1 µmol litre^–1reduced [³H]noradrenaline uptake by 65–70% but morphine,in contrast to fentanyl, had no effect (P > 0.1). (Br. J.Anaesth. 1993; 71: 540–543)     

PHARMACOKINETICS OF GLYCOPYRRONIUM IN URAEMIC PATIENTS

We studied the pharmacokinetics of glycopyrronium 11 uraemicpatients undergoing cadaveric renal transplantation and in sevenASA I control patients undergoing general surgery. Glycopyrronium4 µg kg^–1 was given i.v. before induction of anaesthesia.Blood and urine samples were collected for up to 24 h for measurementof glycopyrronium concentrations using a radioreceptor assay.Volume of distribution in the elimination phase (V^ß)was similar in both groups, the elimination half-life was longer (P <0.05), area underthe plasma concentration-time curve (AUC) larger (P <0.01)and plasma clearance (Cl) smaller (P < 0.01) in the uraemicpatients. In 3 h, mean 0.7 (range 0–3) % and 50 (21–82)% of glycopyrronium was excreted in the urine in the uraemicand healthy patients, respectively (P <0.001). The 24-h renalexcretion was 7 (0–25) % in uraernic and 65 (30–99)% in control patients (P <0.001). We conclude that the eliminationof glycopyrronium is severely impaired in uraemic patients.     

Enhanced Gastrointestinal Absorption of Aluminium in Uraemia: Time Course and Effect of Vitamin D

The present study examines the time course of aluminium absorptionin uraemic rats vs controls and investigates the effect of vitaminD. Following an oral load of 410 µmol aluminium there wasa significant increase in the urinary excretion rate of aluminiumas early as 60 min in uraemic rats. Compared with controls thisincrease was significantly greater in uraemic animals and maximumexcretion rates (77±49 vs pre-load 2±1 nmol Al/h)were achieved after 2 h. When vitamin-D-deficient rats with normal renal function werecompared with vitamin-D-replete controls, the latter excreteda significantly greater amount of the oral dose of aluminiumin their urine (727±361 vs 359±l40nmol Al/5d;P<0.02) and the post-load increase in the serum aluminiumconcentration was more pronounced in the vitamin-D-replete animals. Aluminium administered i.v. resulted in similar urinary aluminiumexcretion rates in both groups. In uraemicrats, however, regardlessof their vitamin D status, adminis tration of 1,25(OH)₂D₃ hadno effect on the amount of urinary aluminium excretion afteroral or i.v. loads. These findings suggest that although in rats with normal renalfunction aluminium absorption appears to be partly vitamin Ddependent, 1,25(OH)₂D₃ does not further augment the enhancedgastrointestinal absorption of aluminium in uraemia.     

Excellent uricosuric efficacy of benzbromarone in cyclosporin-A-treated renal transplant patients: a prospective study

Patients on cyclosporin A (CsA) often develop hyperuricaemiaand gout. In transplant patients the use of uricosuric drugsfor treating hyperuricaemia may be preferable to allopurinolbecause of the known interaction of the latter with azathioprine.We therefore prospectively studied the uricosuric efficacy of100 mg benzbromarone (Bbr;Desuric®) daily in 25 CsA-treatedrenal transplant patients with stable graft function and hyperuricaemia(>359 µmol/l for females, >491 µmol/l formales). Benzbromarone decreased plasma uric acid from 579±18µmol/l to 313±24 µmol/l (mean±SEM;P<0.001) and thereby normalized plasma uric acid in 21 of25 patients. The remaining four patients had creatininc clearancesbetween 21 and 25 ml/min, the lowest of the entire study group.Mean fractional clearance of uric acid increased from 5.4±0.4%to 17.2±1.0% (P<0.001). The relative decrease of plasmauric acid closely correlated with baseline creatinine clearance(r=0.67; P<0.001). CsA trough values were not influenced.None of the patients experienced any significant side-effects.As an unexpected find-ing, urinary uric acid excretion increasedfrom 2082 ± 175 µmol7sol;24 h to 3233 ±232µmol/24 h after 4 weeks' treatment with benzbromarone. In conclusion, benzbromarone normalized plasma uric acid inall CsA-treated renal transplant recipients with a creatinineclearance >25 ml/min. Due to its excellent efficacy and lackof significant side-effects, benzbromarone appears to be preferableto allopurinol in CsA-treated renal transplant recipients witha creati nine clearance over 25 ml/min.     

Influence of Haemodialysis Membranes on {beta}2-Microlobulin Kinetics:In Vivo and In Vitro Studies

Amyloidosis of the ß₂-microglobulin (ß₂M)type is a recently recognised complication of dialysis. We studiedplasma and ultrafiltrate ß₂M in 36 chronic haemodialysispatients. Long-term dialysis with standard cuprophan membranein non-oliguric patients and with the AN69 polyacrylonitrilemembrane in oliguric patients resulted in lower plasma ß₂Mconcentrations (means±SD, 24.4±6.6 and 33.0±8.2µg/ml, respectively) than with cuprophan in oliguric patients(47.0±13.2 µg/ml, P<0.01). In acute studies, plasma ß₂M (corrected for haemoconcentration)increased, although not significantly, during cuprophan dialysis(n=10) from 40.6±12.2 to 44.8±7.6 µg/mland decreased during AN69 dialyis (n=10) from 39.4±18.0to 24.3±7.1 µg/ml (P<0.02). After 15 min ultrafiltration,ß₂M sieving coefficient in vivo was 0.33 for AN69but near zero for cuprophan. Total mass transfer of ß₂Macross the AN69 membrane during a 4-h dialysis was 142 ±45.8 mg(n=7). AN69, but not cuprophan, membrane fragments incubatedin vitro with normal or uraemic plasma exhibited avid [125-I]ß₂M binding (respectively 12.9% vs 0.47% and 6.09%vs 0.06% of total ß₂M bound at 30 mim, n=6, P<0.001for both). No in vitro generation of ß₂M from wholenormal or uraemic blood could be demonstrated during incubationwith either membrane. In conclusion, at least in some patients, standard cuprophandialysis promotes retention and possibly tissue release of ß₂Min vivo, whereas AN69 dialysis leads to ß₂M removaldue to both transmembrane transfer and, to a lesser extent,membrane binding.     

Effect of L-carnitine administration on erythropoietin use in thalassemic minor haemodialysis patients.

Sir, We read with great interest the recent letter by Arduini etal. [1], on the effect of L-carnitine (LC) on erythrocyte survivalin haemodialysis patients. In the same issue, there is a paperby Hothi et al. [2] showing that plasma free-carnitine (FC)levels fell from 26.54 ± 2.99 to 15.6 ± 2.34 µmol/l(P < 000.1) in nocturnal haemodialysis (NHD). A similar reductionin plasma acyl-carnitine (AC) levels was observed (from 13.22± 1.34 to 6.24 ± 1.20 µmol/l (P < 0.001)).The AC : FC ratio improved from 0.51     

Adequacy of dialysis and nutritional status in CAPD

Urea kinetic modelling (UKM) was used to assess adequacy ofdialysis in 50 CAPD patients. Nutritional status was assessedfrom the measurement of visceral protein status (total protein,albumin, transferrin, immunoglobulins, complement), somaticprotein status (anthropometry), and dietary intake (1 week weigheddietary inventory and normalized protein catabolic rate (NPCR)from UKM). Morbidity was assessed from the peritonitis and admissionhistory. Mean Kt/V (corrected to x3 weekly dialysis) was 0.66 ±0.02. Dietary protein intake estimated from the NPCR (1.08±0.03g kg^–1 day^–1) correlated well (r=0.72, P<0.001)with that estimated from the dietary inventory (1.10±0.04g kg^–1 day^–1). There was a strong correlation betweenKt/V and NPCR corrected for actual weight (r=0.65, P<0.001),but when NPCR was corrected for IBW this correlation was weaker(r=0.35, P<0.05). Patients were divided by Kt/V into twogroups (>0.65, n=22 and <0.65, n=28). There were no significantdifferences in the indices of visceral protein status betweenthe two groups. Weight, height, BMI, fat free mass and arm musclearea were significantly greater in the group Kt/V<0.65. Residualrenal function (creatinine clearance) was higher in the groupKt/V>0.65 (3.8±0.7 versus 1.9±0.5 1/24 h, P<0.05)and plasma creatinine less (913±51 versus 1265±51µmol/l, P<0.001). Hb, potassium, bicarbonate, phosphate,alkaline phosphatase, PTH, and blood pressure were not different.Neither was there any difference between the two groups in anyof the indices of morbidity.     

Plasma Adhesion and Inflammation Markers: Asymmetrical Dimethyl-L-Arginine and Secretory Phospholipase A<Subscript>2</Subscript> Concentrations before and after Laparoscopic Gastric Banding in Morbidly Obese Patients

Background The aim of this study was to examine the relationship between subclinical inflammation and weight loss by laparoscopic adjustable gastric banding (LAGB). Methods Plasma concentrations of intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), sensitive C-Reactive Protein (sCRP), asymmetrical dimethyl-L-arginine (ADMA), Secretory Phospholipase A2 (sPLA2), and metabolic markers, such as homeostatic model assessment – insulin resistance (HOMA-IR) and body mass index (BMI) were determined in morbidly obese patients (n = 18, BMI 48.6 ± 1.7 kg/m²) at baseline and 1 month after operations. Baseline levels in patients were also compared with age-matched controls (n = 20, BMI 21.3 ± 1.8 kg/m²). Plasma ICAM-1,VCAM, sCRP and ADMA, and sPLA₂ concentrations were determined by enzyme-linked immunoassay methods and colorimetric method, respectively. Results Plasma sCRP, ICAM-1, ADMA and sPLA₂ concentrations and HOMA-IR were significantly higher in morbidly obese patients than in controls (for each, P < 0.01). Plasma VCAM-1 concentration was not changed in obese patients. HOMA-IR was significantly correlated with ICAM-1, ADMA and sPLA₂ in the obese group at baseline (for each, P < 0.01). There was a significant correlation between plasma sCRP and plasma glucose,VCAM-1, ICAM-1, ADMA and sPLA₂ concentrations (for each, P < 0.01). 1 month after LAGB, mean body weight loss was 13.2 ± 6.3 kg, and plasma sCRP and ADMA concentrations and HOMA-IR and BMI were significantly decreased (for each, P < 0.01). However, these levels cannot be decreased to the levels of the controls. Conclusion Obesity and insulin resistance appear to be associated with low-grade inflammation and endothelial dysfunction. Insulin resistance and endothelial dysfunction were improved by weight loss after LAGB.     

Interleukin-1{beta} induces the formation of nitric oxide in isolated juxtaglomerular cells: influence on renin secretion

Renin secretion may be modulated by nitric oxide (NO). We studiedwhether interleukin-lß (IL-1ß) induces endogenousNO synthesis in mouse juxtaglomerular cells (JGC) in primaryculture, and whether endogenous NO or NO applied exogenouslyvia sodium nitroprusside (SNP) influences renin secretion. JGCseeded on culture plates were stimulated by IL-1ßor by SNP. Cyclic guanosine 3', 5'-monophosphate (cGMP) in thecell supernatant was determined as indicator for NO effects.Stimulation of JGC with IL-1ß or SNP increased cGMPin the supernatant significantly. The NO synthase inhibitorsN^G-nitro-L-arginine or N^G-monomethyl-L-arginine, or the NO scavengeroxyhaemoglobin prevented the IL-1ß-induced increaseof cGMP. The biological activity of NO was shown in a bioassayby the vasodilatory effect of the effluent from an IL-1ß-stimulatedJGC column on a precontracted rat aortic ring and was preventedby oxyhaemoglobin and methylene blue. Renin activity of JGCwas detected in the culture supernatants and the cells. Spontaneousrenin secretion into the cell supernatant was 26±1%oftotal activity. Melittin or forskolin concentration dependentlyincreased renin secretion up to 90 ±2%. Incubation ofJGC with IL-1ß in the absence or presence of NO inhibitorsdid not alter spontaneous or stimulated renin secretion. SNP(30 µM) had a dual effect on renin secretion. After 1h of incubation, it inhibited basal renin secretion, whilstit had a stimulatory effect after 20 h of incubation. Melittin-or forskolin-stimulated renin secretion was not influenced bySNP. In summary, IL-1ß stimulates NO synthesis inJGC. Endogenous NO was without influence on renin secretion,whereas high concentrations of exogeneously applied NO had adual effect on renin secretion.     

METABOLIC CHANGES DURING DOPAMINE INFUSION IN DOGS

The effects were investigated, in 12 dogs, of the infusion ofdopamine 10 or 30 µg kg^–1 min^–1 on circulatingglucose, glycerol, lactate and potassium concentrations. Bothdoses of dopamine produced an initial increase in blood glucoseconcentration (P < 0.05) followed by hypoglycaemia (P<0.05).Lipolysis was stimulated as shown by an increase in plasma glycerolconcentrations with dopamine 10 µg kg^–1 min^–1(P<0.05) and dopamine 30 µg kg^–1 min^–1(P<0.01). Blood lactate concentrations increased slightlyin both groups, but this was significant (P < 0.05) onlyin the dogs infused with dopamine 10 µg kg^–1min^–1.Dopamine had no significant effect on the plasma potassium concentration.     

DECAY OF NITROPRUSSIDE. II: IN VIVO

Clinical experience suggests that nitroprusside (SNP) concentrationsdecay more rapidly in vivo than in vitro. Plasma concentrationsof SNP were measured therefore in 20 patients at the end ofan infusion, with mean arterial pressure (MAP) and cyanide (HCN)concentrations. Plasma SNP concentrations (20–243 µglitre^–1; mean = 123.5 µg litre^–1), were relatedto infusion rate (r = 0.66, P < 0.001), and declined rapidlyto a mean (SD) of 7.7 (4.5) µg litre^–1 in 15 min.The decay of SNP correlated closely with the increase in arterialpressure (mean MAP vs log mean plasma SNP concentrations: r= –0.993, P < 0.001), and was probably biphasic: mean(SD) = 0.89 (0.62) min, T^ß= 14.3 (12) min. Mean plasmaHCN and mean plasma SNP concentrations decreased together (r= 0.955, P < 0.001), thus confirming that in vivo decompositionof the drug is the source of HCN.     

RELATIONSHIP BETWEEN DECAY OF PLASMA CONCENTRATION OF FAZADINIUM AND RECOVERY FROM ITS NEUROMUSCULAR BLOCKING EFFECT

The relationship of the time-course of the decay of plasma concentrationof fazadinium and neuromuscular block has been investigatedafter i.v. administration ofO.75mgkg^–1 to six anaesthetizcdpatients. The phar acokinctic of fazadinium were analysed accordingto a two-compartment open model. A significant correlation wasfound between the plasma concentration of fazadinium and thetwitch height (TH) values during recovery from the block (P<0.001). The mean total plasma concentrations for 25,50and75%THrecoverywere: 1.90±0.17; 1.44±0.l8and 1.08±0.l2µgm^–1,respectivcly.Elapsed time between fazadinium administrationand the Th recovery to 50% (0-TH and the recovery period TH_25–75were 47±4mm and 25±2mm, respectively. Plasma logdecay rate of fazadinium during TH_25–75 period (K_{app 25–75})was: 0.0249±0.0032min^–1. Significant correlations(P<0.01) were observed between the elimination rate constant(k₁₀ ) of the pharmacokinetic model, K_{app 25 –75} (P<0.01)and the pharmacodynamic parameters: time interval 0-TH₅₀ andrecovery rate TH _25-73. These results showed that part of theindividual pharmacodynamic variation had its origin in the interindividualpharmacokinenc variation.     

PTH/PTHrP receptor mRNA is down-regulated in epiphyseal cartilage growth plate of uraemic rats

PTH/PTHrP receptor mRNA is down-regulated in epiphyseal cartilagegrowth plate of uraemic rats. Growth retardation, hypocalcaemia,hyperphosphataemia, and skeletal resistance to the action ofPTH are well known features of advanced chronic renal failure(CRF). It has been suggested that the downregulation of renaland skeletal PTH receptors (PTH/PTHrP-R) could play an importantrole in the occurrence of these abnormalities. In the presentstudy, four uraemic (4 weeks after 5/6 nephrectomy) and fourcontrol (sham-operated) rats were analysed for PTH/PTHrP-R mRNAexpression at the proximal femoral and tibial growth platesby in situ hybridization. Uraemic rats had plasma biochemicalabnormalities of advanced CRF including high creatinine, phosphate,and PTH, and low calcium and calcitriol levels. The femoraland tibial bones of uraemic animals were shorter in length thanthose of control rats, and had reduced width and cellularityof the epiphyseal cartilage growth plate. Mean (±SD)tibia growth plate width was 152±30 µm in uraemicrats, compared with 170±35 µm in control rats.The difference was mostly due to a marked reduction of the zoneexpressing PTH/PTHrP-R (mature chondrocytes) which was 30±5µm in tibias from uraemic versus 44±10 µmin tibias from control rats. The hybridization signals of PTH/PTHrP-Rper individual cell were quantified on dark field images usinga computer-assisted image analysis system. The number of grainsin PTH/PTHrP-R positive cells was also decreased in uraemicrats, 103±13 compared with 123±14 arbitrary units(dark pixel density)/cell in control rats (P 0.005). In conclusion,these data indicate that rats with severe CRF and secondaryhyperparathyroidism have reduced epiphyseal cartil age PTH/PTHrP-RmRNA expression. This alteration may be relevant in the pathogenesisof growth retardation in uraemia.