Protective effect of Gelofusine against cRGD-siRNA-induced nephrotoxicity in mice.

Based on successful targeting to the αvß3 integrin of cyclic arginine-glycine-aspartic acid (cRGD), cRGD-conjugated small interfering RNA (siRNA) exhibits tumor targeting and has become a new treatment strategy for solid tumors. However, the nephrotoxicity caused by its renal retention limits its clinical application. Here, we evaluated the protective effect of Gelofusine against cRGD-conjugated siRNA-induced nephrotoxicity in mice. Male Kunming mice (six per group) were either co-injected with Gelofusine and cRGD-siRNA or injected with cRGD-siRNA alone. After administration of these treatments five times, creatinine and blood urea nitrogen (BUN) levels were determined. Hematoxylin-eosin staining (HE staining) and transferase dUTP nick end labeling (TUNEL) analysis were used to compare the difference in renal damage between the groups. Additionally, fluorescence imaging was used to observe the distribution of cRGD-siRNA in vivo. The group co-injected with Gelofusine and cRGD-siRNA displayed lower creatinine and BUN levels than the cRGD-siRNA-alone group and showed less renal damage upon HE staining and TUNEL analysis. Gelofusine decreased the retention time and accelerated the elimination of cRGD-siRNA from the organs, as observed in the fluorescence images. These data indicate that Gelofusine significantly increased the excretion of cRGD-conjugated siRNA and reduced the associated renal damage.

Reduction of renal uptake of 111In-DOTA-labeled and A700-labeled RAFT-RGD during integrin αvß3 targeting using single photon emission computed tomography and optical imaging.

Integrin α(v)ß(3) expression is upregulated during tumor growth and invasion in newly formed endothelial cells in tumor neovasculature and in some tumor cells. A tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 (RAFT-RGD), specifically targets integrin α(v)ß(3) in vitro and in vivo. When labeled with indium-111, the RAFT-RGD is partially reabsorbed and trapped in the kidneys, limiting its use for further internal targeted radiotherapy and imaging investigations. We studied the effect of Gelofusine on RAFT-RGD renal retention in tumor-bearing mice. Mice were imaged using single photon emission computed tomography and optical imaging 1 and 24 h following tracer injection. Distribution of RAFT-RGD was further investigated by tissue removal and direct counting of the tracer. Kidney sections were analyzed by confocal microscopy. Gelofusine significantly induced a >50% reduction of the renal reabsorption of (111)In-DOTA-RAFT-RGD and A700-RAFT-RGD, without affecting tumor uptake. Injection of Gelofusine significantly reduced the renal retention of labeled RAFT-RGD, while increasing the tumor over healthy tissue ratio. These results will lead to the development of future therapeutic approaches.

The choice of the intravenous fluid influences the tolerance of acute normovolemic anemia in anesthetized domestic pigs.

INTRODUCTION: The correction of hypovolemia with acellular fluids results in acute normovolemic anemia. Whether the choice of the infusion fluid has an impact on the maintenance of oxygen (O2) supply during acute normovolemic anemia has not been investigated so far. METHODS: Thirty-six anesthetized and mechanically ventilated pigs were hemodiluted to their physiological limit of anemia tolerance, reflected by the individual critical hemoglobin concentration (Hbcrit). Hbcrit was defined as the Hb-concentration corresponding with the onset of supply-dependency of total body O2-consumption (VO2). The hemodilution protocol was randomly performed with either tetrastarch (6% HES 130/0.4, TS-group, n = 9), gelatin (3.5% urea-crosslinked polygeline, GEL-group, n = 9), hetastarch (6% HES 450/0.7, HS-group, n = 9) or Ringer's solution (RS-group, n = 9). The primary endpoint was the dimension of Hbcrit, secondary endpoints were parameters of central hemodynamics, O2 transport and tissue oxygenation. RESULTS: In each animal, normovolemia was maintained throughout the protocol. Hbcrit was met at 3.7 ± 0.6 g/dl (RS), 3.0 ± 0.6 g/dl (HS P < 0.05 vs. RS), 2.7 ± 0.6 g/dl (GEL, P < 0.05 vs. RS) and 2.1 ± 0.4 g/dl (TS, P < 0.05 vs. GEL, HS and RS). Hemodilution with RS resulted in a significant increase of extravascular lung water index (EVLWI) and a decrease of arterial oxygen partial pressure (paO2), and O2 extraction ratio was increased, when animals of the TS-, GEL- and HS-groups met their individual Hbcrit. CONCLUSIONS: The choice of the intravenous fluid has an impact on the tolerance of acute normovolemic anemia induced by acellular volume replacement. Third-generation tetrastarch preparations (e.g., HES 130/0.4) appear most advantageous regarding maintenance of tissue oxygenation during progressive anemia. The underlying mechanism includes a lower degree of extravasation and favourable effects on microcirculatory function.

Effects of an intraoperative infusion of 4% succinylated gelatine (Gelofusine(R)) and 6% hydroxyethyl starch (Voluven(R)) on blood volume.

BACKGROUND: This study aims to study changes in blood volume after 1 litre infusions of Gelofusine(®) [4% succinylated gelatine in 0.7% saline, weight-average molecular weight (MWw) 30 kDa] and Voluven(®) (6% hydroxyethyl starch in 0.9% saline, MWw 130 kDa) in the presence of increased capillary permeability. METHODS: In this randomized double-blind study, adults undergoing laparoscopic cholecystectomy received 1 litre of Gelofusine(®) (n=12) or Voluven(®) (n=13) over 1 h at the induction of anaesthesia. No other fluids were given. Haematocrit, serum electrolytes, and osmolality were measured before infusion and hourly thereafter for 4 h. Changes in blood volume were calculated from changes in haematocrit. The urinary albumin:creatinine ratio (ACR) was measured before and after operation. RESULTS: Baseline parameters before the two infusions were similar (P>0.050). The urinary ACR increased significantly after operation after Gelofusine(®) (P=0.011) and Voluven(®) (P=0.002), indicating increased capillary permeability. Voluven(®) produced a greater increase in serum chloride concentration (P=0.028) and a larger decrease in strong ion difference (P=0.009) than Gelofusine(®). There were no significant differences in changes in haematocrit (P=0.523) and blood volume (P=0.404) over the study period when the two infusions were compared, nor were there any differences in serum sodium, potassium, bicarbonate, and albumin concentrations (P>0.050). Urine output, sodium concentration, and osmolality were similar after the two infusions (P>0.050). CONCLUSIONS: The blood volume-expanding effects of the two colloids were not significantly different, despite the increase in postoperative urinary ACR and the 100 kDa difference in MWw.

Hypertonic sodium resuscitation after hemorrhage improves hemodynamic function by stimulating cardiac, but not renal, sympathetic nerve activity.

Small volume hypertonic saline resuscitation can be beneficial for treating hemorrhagic shock, but the mechanism remains poorly defined. We investigated the effects of hemorrhagic resuscitation with hypertonic saline on cardiac (CSNA) and renal sympathetic nerve activity (RSNA) and the resulting cardiovascular consequences. Studies were performed on conscious sheep instrumented with cardiac (n=7) and renal (n=6) sympathetic nerve recording electrodes and a pulmonary artery flow probe. Hemorrhage (20 ml/kg over 20 min) caused hypotension and tachycardia followed by bradycardia, reduced cardiac output, and abolition of CSNA and RSNA. Resuscitation with intravenous hypertonic saline (1.2 mol/l at 2 ml/kg) caused rapid, dramatic increases in mean arterial pressure, heart rate, and CSNA, but had no effect on RSNA. In contrast, isotonic saline resuscitation (12 ml/kg) had a much delayed and smaller effect on CSNA, less effect on mean arterial pressure, no effect on heart rate, but stimulated RSNA, although the plasma volume expansion was similar. Intracarotid infusion of hypertonic saline (1 ml/min bilaterally, n=5) caused similar changes to intravenous administration, indicating a cerebral component to the effects of hypertonic saline. In further experiments, contractility (maximum change in pressure over time), heart rate, and cardiac output increased significantly more with intravenous hypertonic saline (2 ml/kg) than with Gelofusine (6 ml/kg) after hemorrhage; the effects of hypertonic saline were attenuated by the ß-receptor antagonist propranolol (n=6). These results demonstrate a novel neural mechanism for the effects of hypertonic saline resuscitation, comprising cerebral stimulation of CSNA by sodium chloride to improve cardiac output by increasing cardiac contractility and rate and inhibition of RSNA.

Effect of volume loading with 1 liter intravenous infusions of 0.9% saline, 4% succinylated gelatine (Gelofusine) and 6% hydroxyethyl starch (Voluven) on blood volume and endocrine responses: a randomized, three-way crossover study in healthy volunteers.

OBJECTIVE: To study the changes in blood volume and hormones controlling sodium and water homeostasis after infusions of 0.9% saline, Gelofusine (4% succinylated gelatin in 0.7% saline, weight-average molecular weight 30 kD), and Voluven (6% hydroxyethyl starch in 0.9% saline, weight-average molecular weight 130 kD) in healthy volunteers. DESIGN: Randomized, three-way crossover study. SETTING: University teaching hospital. SUBJECTS: Ten healthy adult male volunteers. INTERVENTIONS: Volunteers received 1-L infusions of 0.9% saline, Gelofusine, and Voluven over 1 hr on three occasions. Body weight, hematocrit, serum biochemistry, and plasma concentrations of vasopressin, aldosterone, brain natriuretic peptide, and total renin were measured before infusion and hourly thereafter for 6 hrs. Changes in body water, blood volume, and extravascular fluid volume were calculated. MEASUREMENTS AND MAIN RESULTS: Although changes in body weight (total body water) after the infusions were similar, blood volume expansion by the two colloids was significantly greater than that produced by 0.9% saline (p < .01). At the end of infusions, 68%, 21%, and 16% of the infused volumes of 0.9% saline, Gelofusine, and Voluven, respectively, had escaped from the intravascular space to the extravascular space. Over the 6 hrs, the magnitude and duration of blood volume expansion by the two colloids were similar (p = .70). There were no significant differences in urinary volume, osmolality, and sodium content after the three infusions. Hormonal changes were similar after the three infusions, with the increase in natriuretic peptide being transient. The reduction in aldosterone and total renin concentrations was more sustained. CONCLUSIONS: The effects of Gelofusine and Voluven were similar despite the 100 kD difference in weight-average molecular weight. Excretion of an acute fluid load containing sodium and chloride may be dependent on a sustained suppression of the renin-angiotensin-aldosterone system rather than on natriuretic peptides.

Succinylated gelatin substantially increases en bloc resection size in colonic EMR: a randomized, blinded trial in a porcine model.

BACKGROUND: Succinylated gelatin (SG) is an inexpensive colloid that may combine ease of use with the advantages of a colloid to potentially increase EMR specimen size, leading to a higher rate of en bloc resection. OBJECTIVE: To evaluate the safety, efficacy, and impact on EMR specimen size of SG as a submucosal (s.m.) injectant in comparison with normal saline solution (NS). DESIGN: Randomized, blinded, controlled trial conducted with Animal Ethics Committee approval. SETTING: Academic hospital. SUBJECTS: Ten swine. INTERVENTIONS: Sixty EMRs (30 using SG vs 30 using NS as 3 paired experiments per animal) of the largest possible en bloc snare resection of normal colonic mucosa after s.m. injection of a fixed volume of either SG or NS. MAIN OUTCOME MEASUREMENTS: EMR specimen size, duration of s.m. cushion, duration of procedure, ratio of vertical elevation to lateral spread of injectant, ease of resection, adverse effects, perforation, histopathology of EMR sites in colectomy specimens at necropsy (for inflammatory cell content, depth of ulceration, and vascular or ischemic changes). RESULTS: The mean subject weight was 53 kg. The mean EMR specimen dimensions and surface area were significantly larger with SG (length 37 vs 31 mm, P = .031; width 32 vs 26 mm, P = .022; surface area 9.5 cm(2) vs 6.7 cm(2), P = .044, respectively). The median s.m. cushion duration was 60 minutes with SG versus 15 minutes with NS (P = .005). The median procedure duration with SG was 2.6 minutes vs 2.5 minutes with NS (P = .515). The ratio of vertical elevation to lateral spread of injectant (mean score on a 3-point scale) was 3 with SG versus 2 with NS (P = .228). Ease of resection score (mean score on a 10-point scale) was 8 with SG versus 7 with NS (P = .216). There were no systemic adverse effects, hypersensitivity reactions, or bleeding episodes. There were 2 perforations (treated with clips) with SG and 1 with NS (P = 1.0). Blinded histopathologist assessment of necropsy colectomy specimens did not identify any significant differences between SG and NS EMR sites. LIMITATIONS: Animal study. CONCLUSIONS: SG is safe and results in a 42% increased surface area for en bloc EMR. Given its other favorable properties, it represents a significant step toward defining the ideal EMR solution.

Dose-response effect of Gelofusine on renal uptake and retention of radiolabelled octreotate in rats with CA20948 tumours.

PURPOSE: Peptide receptor radionuclide therapy using ß-emitting radiolabelled somatostatin analogues like DOTA,Tyr3-octreotate shows beneficial results in patients suffering from somatostatin receptor overexpressing tumours. However, after high-dose therapy partial renal reabsorption of radiopeptides may lead to nephrotoxicity. Co-infusion of lysine/arginine lowers renal retention of these radiopeptides without affecting tumour uptake. Recently co-administration of Gelofusine has been described to have a comparable kidney-protecting effect in rats. In the present study optimal dosing of Gelofusine co-administration was studied in tumour-bearing rats. METHODS: Doses of 40, 80, 120 or 160 mg/kg Gelofusine were co-injected with 15 µg DOTA,Tyr3-octreotate, labelled with 3 MBq 111In for biodistribution (24 h post-injection, n = 4 per group) and with 60 MBq 111In for microSPECT imaging experiments at 3, 24 and 48 h post-injection. An additional group of rats received 80 mg/kg Gelofusine plus 400 mg/kg lysine co-injection. Biodistribution studies were performed both in older (475 g) and younger (300 g) rats, the latter bearing CA20948 tumours. RESULTS: Co-injection of 40 mg/kg Gelofusine resulted in 40-50% reduction of renal uptake and retention of 111In-DOTA,Tyr3-octreotate, whereas higher doses further increased the reduction to 50-60% in both groups of rats. Combining Gelofusine and lysine caused 70% reduction of renal uptake. The uptake of radiolabelled octreotate both in somatostatin receptor-expressing normal tissues and tumours was not affected by Gelofusine co-injection. CONCLUSION: In rats co-injection of 80 mg/kg Gelofusine resulted in maximum reduction of renal retention of 111In-DOTA,Tyr3-octreotate, which was further improved when combined with lysine. Tumour uptake of radiolabelled octreotate was not affected, resulting in an increased tumour to kidney ratio.

Effect of replacement fluids saline, gelofusine, and blood on biochemical and hematological parameters in rats subjected to repeated blood sampling.

BACKGROUND: Multiple blood sampling in rat pharmacokinetic (PK) and toxicokinetic studies can result in a pathophysiological response and misleading data interpretation. This study investigated whether these drawbacks can be minimized by replacing withdrawn blood with saline, gelofusine, or donor blood. MATERIAL/METHODS: Rats with cannulated jugular veins were subjected to 12 withdrawals of 250 and 500 microl of blood followed by replacement with the same amount of saline, gelofusine, or donor blood. Red blood cell, hematocrit, hemoglobin, total protein, albumin, glucose, Na, and Cl levels were determined in the drawn blood. RESULTS: Multiple blood sampling caused a time-dependent decrease in red blood cell counts and hematocrit, hemoglobin, total protein, and albumin levels in all the treatment groups, but these effects were significantly alleviated in the blood-treated group. Withdrawal of 500 microl of blood caused more pronounced changes than 250 microl blood withdrawal in the saline- and gelofusine-treatment groups, but not in the blood-treatment group. Plasma glucose and Na remained unchanged in all the treatment groups, while slight changes in Cl levels were observed in the saline- and gelofusine-treatment groups. CONCLUSIONS: Blood sample volume had a crucial impact on the measured parameters, which were least affected in the donor blood-treated group. Regardless of the treatment, up to five 250 microl blood samples can be drawn without causing significant changes in a rat's normal condition. However, for a proper determination of PK profile, more than five blood samples are required and therefore drawn blood should be replaced, preferably with donor blood.

Development and evaluation of peptidic ligands targeting tumour-associated urokinase plasminogen activator receptor (uPAR) for use in alpha-emitter therapy for disseminated ovarian cancer.

PURPOSE: Among gynecologic malignancies, ovarian cancer has the highest mortality due to rapid peritoneal dissemination. Treatment failure particularly arises from failure to eliminate disseminated cells. Our aim was to develop peptidic radioligands targeting tumour cell-associated urokinase receptor (uPAR, CD87) for alpha-emitter therapy for advanced ovarian cancer. METHODS: DOTA-conjugated, uPAR-directed ligands were synthesised on solid-phase. Binding of peptides to human cells expressing uPAR was assayed by flow cytofluorometry or, in case of (213)Bi-labelled peptides, by measuring cell-bound radioactivity. Bio-distribution of the (213)Bi-labelled peptide P-P4D was analysed in nude mice 28 days after intraperitoneal inoculation of OV-MZ-6 ovarian cancer cells in the absence or presence of the plasma expander gelofusine. RESULTS: uPAR-selective ligands were developed based on published high-affinity uPAR-binding peptides. For preparation of N-terminally cross-linked divalent ligands, a novel solid-phase procedure was developed. Specific binding of (213)Bi-labelled peptides to monocytoid U937 and OV-MZ-6 cells was demonstrated using the natural ligand of uPAR, pro-uPA, or a soluble form of uPAR, suPAR, as competitors. The pseudo-symmetrical covalent dimer (213)Bi-P-P4D displayed superior binding to OV-MZ-6 cells in vitro. Accumulation of (213)Bi-P-P4D in tumour tissue was demonstrated by bio-distribution analysis in nude mice bearing intraperitoneal OV-MZ-6-derived tumours. Gelofusine reduced kidney uptake of (213)Bi-P-P4D by half. CONCLUSION: Ovarian cancer cells overexpressing uPAR were specifically targeted in vitro and in vivo by (213)Bi-P-P4D. Kidney uptake of (213)Bi-P-P4D was distinctly reduced using gelofusine. Thus, this radiopeptide may represent a promising option for therapy for disseminated ovarian cancer.

Molecular imaging of reduced renal uptake of radiolabelled [DOTA0,Tyr3]octreotate by the combination of lysine and Gelofusine in rats.

AIM: In peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues, kidney uptake of radiolabelled compound is the major dose-limiting factor. We studied the effects of Gelofusine (20 mg) and lysine (100 mg) and the combination of both after injection of therapeutic doses of radiolabelled [DOTA0,Tyr3]octreotate (60 MBq 111In or 555 MBq 177Lu labelled to 15 microg peptide) in male Lewis rats. METHODS: Kidney uptake was measured by single photon emission computed tomography (SPECT) scans with a four-headed multi-pinhole camera (NanoSPECT) at 24 h, 5 and 7 days p. i. and was quantified by volume of interest analysis. For validation the activity concentration in the dissected kidneys was also determined ex vivo using a gamma counter and a dose calibrator. RESULTS: Gelofusine and lysine both reduced kidney uptake of [177Lu-DOTA0,Tyr3]octreotate significantly by about 40% at all time points. The combination of Gelofusine and lysine resulted in a 62% inhibition of kidney uptake (p < 0.01 vs. lysine alone). A weak but significant dose-response relationship for Gelofusine, but not for lysine, was found. In a study with [111In-DOTA0,Tyr3]octreotate, conclusions drawn from NanoSPECT data were confirmed by biodistribution data. CONCLUSIONS: We conclude that rat kidney uptake of radiolabelled somatostatin analogues can be monitored for a longer period in the same animal using animal SPECT. Gelofusine and lysine had equal potential to reduce kidney uptake of therapeutic doses of [177Lu-DOTA0,Tyr3]octreotate. The combination of these compounds caused a significantly larger reduction than lysine or Gelofusine alone and may therefore offer new possibilities in PRRT. The NanoSPECT data were validated by standard biodistribution experiments.

[Effect of hydroxyethyl starch 130/0.4 on S100B protein level and cerebral oxygen metabolism in open cardiac surgery under cardiopulmonary bypass].

OBJECTIVE: To observe the effect of hydroxyethyl starch (HES) 130/0.4 on S100B protein level and cerebral metabolism of oxygen in open cardiac surgery under cardiopulmonary bypass (CPB) and to explore whether it has the protective effect of 6%HES130/0.4 as priming solution on cerebral injury during CPB and explore the probable mechanism. METHODS: Forty patients with atrioseptal defect or ventricular septal defect scheduled for elective surgical repair under CPB with moderate hypothermia were randomly divided into two equal groups: HES 130/0.4 group (HES group) in which HES 130/0.4 (voluven) was used as priming solution and gelatin group (GRL group) in which gelofusine (succinylated gelatin) was used as priming solution. ECG, heart rate (HR), blood pressure (BP), mean arterial pressure (MAP), central venous pressure (CVP), arterial partial pressure of oxygen (P(a)O(2),), arterial partial pressure of carbon dioxide (P(et)CO(2)) and body temperature (naso-pharyngeal and rectal) were continuously monitored during the operation. Blood samples were obtained from the central vein for determination of blood concentrations of S100B protein at the following time points: before CPB (T(0)), 20 minutes after the beginning of CPB (T(1)), immediately after the termination of CPB (T(2)), 60 minutes after the termination of CPB (T(3)), and 24 hours after the termination of CPB (T(4)). The serum S100B protein levels were measured by ELISA. At the same time points blood samples were obtained from the jugular vein and radial artery to undergo blood gas analysis and measurement of blood glucose, based on which the cerebral oxygen metabolic rate/cerebral metabolic rate of glucose (CMRO(2)/CMR(GLU)) was calculated. RESULTS: Compared with the time point of immediately before CPB (T(0)), The S100B protein level of the 2 groups began to increase since the time point T(1), peaked at the time point T(2), began to decrease gradually since the time point T(3), and were still significantly higher than those before CPB at the time point T(4) (all P < 0.01), and the S100B protein levels at different time points of the HES group were all significantly lower than those of the GEL group (all P < 0.01). The S(jv)O(2) and CMRO(2)/CMR(GLU) levels of both groups increased at the time point T(1), decreased at the time points T(2) and T(3), and then restored to normal at the time points T(4). In the GEL group there were no significant differences in the levels between any 2 different time points, however, in the HES group S(jv)O(2) and CMRO(2)/CMR(GLU) levels at T(1) was significantly higher than those at the other time points (P < 0.05 or P < 0.01). CONCLUSION: S100B protein increases significantly in open cardiac surgery under CPB. HES130/0.4 lowers the S100B protein levels from the beginning of CPB to one hour after the termination of CPB with the probable mechanism of improving the cerebral metabolism of oxygen. 6%HES130/0.4 as priming solution may play a protective role in reduction of cerebral injury during CPB and open cardiac surgery.

Does calcium cause the different effects of Gelofusine and Haemaccel on coagulation?

BACKGROUND: Gelofusine (which does not contain calcium) has a greater effect on coagulation than Haemaccel (which contains 6.25 mmol/l of calcium). This in vitro study was performed to assess whether calcium might be the cause of the different effects on coagulation. METHODS: Three solutions were compared; (a) Gelofusine, (b) Gelofusine with calcium added to 6.25 mmol/l, and (c) Haemaccel. Thromboelastography (Sonoclot) was used to examine whole blood coagulation, with time to peak clot weight as the primary outcome measure. RESULTS: There was no significant difference between the Gelofusine containing solutions. Both Gelofusine solutions gave a greater impairment of coagulation than the Haemaccel solution. CONCLUSIONS: The different effect of Gelofusine on coagulation compared with Haemaccel does not seem to be related to the different calcium contents of the solutions.

Hemodynamic and hormonal effects of neutral endopeptidase inhibitor SCH 39370 in sheep.

Whole body clearance of atrial natriuretic factor is due to both receptor uptake and enzymatic degradation initiated by neutral endopeptidase 24.11. The effects of neutral endopeptidase inhibition have been studied in seven sodium-replete sheep using SCH 39370, a specific and potent inhibitor of neutral endopeptidase, in the presence or absence of exogenous hormone [rat ANF-(101-126), 2.4 pmol/kg/min for 2 hours]. SCH 39370 alone (2.5 mg/kg bolus) increased plasma atrial natriuretic factor and plasma cyclic GMP levels, lowered arterial pressure for periods beyond changes in plasma atrial natriuretic factor or cyclic GMP, and suppressed both plasma aldosterone and cortisol levels when compared with vehicle injections. The effects of SCH 39370 were similar to or exceeded those of atrial natriuretic factor infusions, which induced significantly greater increases in plasma atrial natriuretic factor (p = 0.01). Neither agent alone was natriuretic. When SCH 39370 and atrial natriuretic factor were given together, plasma cyclic GMP but not atrial natriuretic factor levels were increased (p = 0.013) compared with atrial natriuretic factor infusion alone, and the half-life was prolonged (p = 0.002) in the presence of SCH 39370. The hypotensive response was greater than that induced by atrial natriuretic factor alone (p = 0.03) but not different from SCH 39370 alone. Inhibitory effects of SCH 39370 on aldosterone levels were similar in the presence of absence of exogenous atrial natriuretic factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypothermic perfusion of rabbit kidneys with solutions containing gelatin polypeptides.

Rabbit kidneys were perfused with a solution of extracellular electrolyte composition, made hypertonic with glucose and containing the gelatin polypeptide preparation Haemaccel (Hoechst) as the only colloid. Perfusions were carried out at 5 and 10 C for 19 hr, and function was tested by autografting. All of the kidneys perfused at the higher temperature showed immediate life-sustaining function after transplantation and contralateral nephrectomy, whereas only one graft of five perfused at the lower temperature showed any function. The suitability of the Haemaccel solution as a vehicle for introducing the cryoprotective agent glycerol was tested by perfusing kidneys for 4 hr with a solutiont containing 2% glycerol; the function of these organs was similar to that of kidneys transplanted without perfusion. Ultrastructural examination of kidneys perfused for 24 hr at 10 C showed excellent structural preservation, but measurements of water and ion contents and the penetration of marker molecules in nonmetabolizing kidneys showed 2.8% Haemaccel to be somewhat less effective than 6% bovine serum albumin in stabilizing these values. The Haemaccel perfusate is considered to be highly suitable for the introduction and removal of cryoprotective agents, and the results of hypothermic preservation by continuous perfusion are encouraging.

Effect of low molecular weight heparin, dextran and their combinations on experimental venous thrombosis in rabbits.

An experimental model based on the combination of endothelial damage and flow reduction was used to induce jugular vein thrombosis in rabbits. The effect on thrombosis of a low molecular weight heparin (LMWH [Fragmin]), dextran 70, placebo and their combination was studied in a double-blind fashion with actual doses used in clinical thromboprophylaxis. Saline and polygeline were used as placebo in the control group. Four groups with 120 isolated vein segments in 60 animals were studied for presence of thrombus formation, occlusive thrombi and thrombus weights. Dextran reduced the thrombus weights (p = 0.048) and the formation of occlusive thrombi (p = 0.01), but not the formation of thrombi when compared with the placebo control group. Similarly, LMWH reduced the thrombus weights (p = 0.046), the formation of thrombi (p = 0.007) and occlusive thrombi (p = 0.0001). Compared with the LMWH group the group treated with the combination of LMWH and dextran was found to reduce the frequency of occlusive thrombi (p = 0.03) and numerically, but not significantly, further reduce the overall frequency of thrombosis (p = 0.18) and thrombus weights (p = 0.11). The results are consistent with an augmentation of the antithrombotic effect of LMWH by dextran 70. The need for further evaluation of the combined efficacy of LMWH and dextran is apparent from this study.

Phagocytic reticuloendothelial function after hemorrhage and resuscitation: modulation by different fluids.

Although the efficacy of colloid resuscitation fluids in restoring cardiovascular status in hemorrhagic shock is accepted, the effect they have on the activity of the reticuloendothelial system (RES) is less clear. As interaction with the RES may be important in determining susceptibility to infections after resuscitation the effects of three such fluids, hydroxyethyl starch, Haemaccel, and fresh autologous blood on RES function after a 40% hemorrhage have been investigated in BALB/C mice. The mice, anesthetized with isoflurane, were bled over a 10 min period, left hypovolemic for 30 min, and then resuscitated with their shed blood or the same volume of asanguineous fluid. Normothermia was maintained throughout the experiments. Whole body phagocytic activity was assessed at 1, 6, 24, 48, and 72 h after the end of hemorrhage by measuring the clearance rate (K) of intravenously injected 51Cr-labeled sheep red blood cells. No significant change in K was found at any time in animals resuscitated with shed blood. However, significant increases in K were found 48 h after resuscitation with Haemaccel. Hepatic uptake of sheep red blood cells was significantly increased at 48 and 72 h in Haemaccel-resuscitated animals compared with hydroxyethyl starch or shed blood resuscitation, whereas spleen uptake decreased at 72 h. Lung uptake was not affected at any time with any fluid. The same volume of Haemaccel had no significant effect either on K or on organ uptake when given to normovolemic animals. The changes in organ uptake after hemorrhage and resuscitation with Haemaccel were partially prevented if animals were resuscitated with Haemaccel plus autologous red cells.