Zinc status and interleukin-1 beta-induced alterations in mineral metabolism in rats.

Changes in zinc (Zn) metabolism and interleukin-1 beta (IL-1 beta) release occur as part of the physiological response to tissue injury and trauma. In the present study, the influence of Zn status on the response to continuous low-dose IL-1 beta administration was evaluated. Rats were fed 50 micrograms Zn/g (adequate zinc; AZn) or 5 micrograms Zn/g (marginal zinc; MZn) diets for 14 days. On day 15, rats were infused via osmotic minipumps, with IL-1 beta (2.3 ng/hr) or saline (control, C) and euthanized 1, 3, or 7 days later. In the AZn rats, IL-1 beta infusion resulted in increased plasma copper (Cu) concentrations and ceruloplasmin (Cp) activity, and decreased iron (Fe) concentrations throughout the 7d period. These effects were most pronounced on d1 and d3. A similar trend was observed in the MZn rats, but IL-1 beta-induced increases in plasma Cu and Cp activity were less than in the AZn fed rats. In MZn and AZn IL-1 beta infused rats, plasma Zn was decreased on Day 1, and Day 3, respectively, compared with their respective controls. AZn IL-1 beta-infused rats were characterized by high liver Fe, Zn, and metallothionein (MT) concentrations on Day 1; by Day 7, only MT concentrations remained elevated. Liver MnSOD activity was 13%-29% higher in both the AZn- and MZn-IL-1 beta-infused rats than their respective controls on Day 3 and Day 7, with most significant increase observed on Day 7. These data show that Zn status can influence the response to low-dose IL-1 beta; this influence of Zn should be considered when IL-1 beta is given therapeutically.

Further evaluation of the effects of 7.5% sodium chloride/6% Dextran-70 (HSD) administration on coagulation and platelet aggregation in hemorrhaged and euvolemic swine.

In previous studies, we determined that incubation of high concentrations of the 7.5% saline (HS) component of HSD with human blood, in vitro, significantly prolonged prothrombin time (PT), and reduced platelet aggregation. Considering the rapid plasma volume expansion following HSD infusion, the present study tested the hypothesis that any HS-induced effects on coagulation would have no clinical significance when HSD was infused for the treatment of hemorrhagic hypotension. Conscious, splenectomized pigs, either euvolemic (n = 11) or bled 27 ml/kg over 60 min (n = 9), were treated with the proposed therapeutic dose of 4 ml/kg HSD. Blood samples were withdrawn prior to and at the end of the hemorrhage and 0.5, 1, 2, 3, 4, 24, 48, 72, and 168 hr following HSD infusion, and PT, activated partial thromboplastin time (APTT), and platelet aggregation were determined. HSD did not significantly affect PT, APTT, or platelet aggregation in either group of swine at any time measured. In other studies, HSD did not prolong bleeding times after 1 or 2 hr in euvolemic pigs. These data further support the premise that a single dose of HSD for the prehospital treatment of hemorrhagic hypotension will not adversely affect blood coagulation.

Acute and subacute toxicity of 7.5% hypertonic saline/6% dextran-70 (HSD) in dogs. 1. Serum immunoglobulin and complement responses.

Clinical use of modern dextran solutions has been limited by concerns of anaphylactoid reactions. To assess the short-term antigenic response to 7.5% hypertonic saline in 6% Dextran-70 (HSD), sera were obtained from dogs involved in the acute and subacute toxicology testing of HSD and its individual components, and analyzed for IgG, IgM and C3 complement. In separate studies, beagles were infused i.v. with a single dose of HSD or its components at 20 ml kg-1 (the maximum tolerated dose; MTD), or the MTD daily for 14 days, and serum was obtained prior to and at various times after infusion up to 14 days. In both studies, despite serum dextran concentrations exceeding 2000 mg dl-1, no induction of IgG, IgM or C3 complement concentrations were observed. In addition, serum IgG immunoelectrophoretic patterns were of normal curvature, position and intensity; the immunoprecipitin bands were not displaced, bowed, inhibited or thicker than the normal preinfusion immunoelectrophoretograms. The data suggest that single or multiple HSD i.v. injections, as much as five times the proposed therapeutic level for the treatment of hypovolemia, evoked no increase in antibody titers in dogs. Therefore, therapeutic use of HSD in the treatment of hemorrhagic shock should not be associated with widespread concomitant allergic complications.

The effects of 7.5% NaCl/6% dextran 70 on coagulation and platelet aggregation in humans.

The combination solution of 7.5% NaCl/6% dextran 70 (HSD) administered IV gives hemodynamic improvement in the treatment of hemorrhagic hypotension. Since earlier dextran solutions were reported to interfere with blood coagulation, the effects of HSD on the prothrombin time (PT), the activated partial thromboplastin time (APTT), platelet aggregation, and platelet concentration were studied. The HSD mixed with human plasma (1:5 and 1:10) slightly prolonged PT, but had no effect on the APTT, compared with saline controls. The HSD also decreased human platelet aggregation at the 1:5 dilution. In separate mixing studies, the hypertonic saline component of HSD was associated with the prolongation of PT and decreased platelet aggregation. The data from these studies indicate that at its proposed therapeutic dose, HSD is expected to have minimal effect on blood coagulation.

Effects of hypertonic saline (7.5%)/dextran 70 on human red cell typing, lysis, and metabolism in vitro.

The introduction of a 7.5% hypertonic saline/6% dextran 70 (HSD) solution into clinical trials for the treatment of hypovolemic states, and the past concerns regarding the possible interference of dextran with blood serology, prompted us to investigate the effects of HSD on human red-cell typing and stability. HSD was evaluated with fresh and 35-day stored CPDA-1 red cells from 12 healthy donors. A 1:5 mixture of HSD to blood in vitro had no effect on ABO, Rh, and MN typing in both fresh and stored blood. HSD produced no significant lysis with fresh cells and a minimal level with stored blood. No evidence of metabolic or morphologic changes was seen after HSD treatment. The results of this study suggest that the clinical use of HSD for the treatment of hemorrhagic shock will not affect blood group determinations or red-cell stability from stored blood which may be infused after the HSD-treated patient is transported to a hospital.

Dextran concentrations in plasma and urine following administration of 6% dextran-70/7.5% NaCl to hemorrhaged and euvolemic conscious swine.

Dextran metabolism was investigated in ten hemorrhaged and seven euvolemic conscious swine. Chronically instrumented, splenectomized swine were subjected to a progressive fixed-volume hemorrhage (27 ml/kg over 45 min). Resuscitation with 4 ml/kg of a 7.5% NaCl/6% dextran 70 (HSD) solution was begun 5 min later. Blood and urine samples were drawn before and during hemorrhage, and at 15, 60, and 120 min following intravenous HSD infusion. Hemorrhage significantly reduced cardiac output (CO) and mean arterial pressure (MAP) and eliminated urinary flow. HSD administration to hemorrhaged pigs returned CO and MAP to control values and improved urinary flow. Creatinine clearance returned to prehemorrhage values. These parameters were not affected by HSD in nonhemorrhaged animals. Plasma dextran concentrations were 20-30% higher in hemorrhaged pigs compared with euvolemic swine. In additional studies, plasma t1/2 for dextran was 9.4 hr in hemorrhaged pigs (n = 3) compared to 10.8 hr in euvolemic animals (n = 2). These data show that HSD ameliorates the effects of hemorrhage on cardiovascular and renal function and suggest that plasma clearance of dextran may be affected by hemorrhage.

Massive myoglobinuria precipitated by halothane and succinylcholine in a member of a family with elevation of serum creatine phosphokinase.

Massive myoglobinuria developed in a patient given halothane and IV succinylcholine, Marked elevations of serum CPK were found in the patient and several family members. Myopathic changes in electromyogram and lack of neuromuscular symptoms and physical findings prompted the diagnosis of familial nonprogessive muscular dystrophy. Other hereditary muscular diseases were eliminated by medical workup. It is recommended that patients with known myopathy or unexplained elevations of serum CPK not receive the combination of halothane and succinylcholine.

The spectrophotometric determination of human serum carboxypolypeptidase with angiotensin converting enzyme-like activity.

1. A colorimetric method was developed for the direct chemical assay of human carboxypeptidase A (carboxypolypeptidase; EC 3.4.12.2) with angiotensin converting enzyme-like activity in serum or plasma, with the substrate analogue glycyl-L-histidylglycine and the angiotensin converting enzyme substrate angiotensin I (A-I). This method was based on the spectrophototometric determination of histidylglycine and histidyl-leucine, products of the hydrolysis of glycyl-L-histidylglycine and A-I respectively. omicron-Phthalaldehyde reacted with the imidazole moiety of nu-terminal histidyl peptides to produce a yellow chromophore. 2. A large number of inhibitors were tested for their effects on carboxypolpeptidase activity. The hydrolysis of Gly-His-Gly and A-I was inhibited by histidyl-leucine and angiotensin II, both products of the hydrolysis of A-I. Bothrops jararaca venom extract, EDTA, rho-chloromercuribenzoate, 8-hydroxyquinoline and 2,3-dimercaptopropanol, previously reported as converting enzyme inhibitors, also inhibited carboxypolypeptidase activity. 3. Angiotensin converting enzyme activity in the serum of sixty-six adults ranged from 10 to 37 nmol of glycyl-L-histidylglygine hydrolysed in 10 min by 10 mu1 of serum at 37 degrees C and pH 7-25.