In vivo microscopy of recirculation and allograft rejection in the rabbit ear-chamber.
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Animals↗
Biomedical subjects
B Gerdin
Publications and source records attributed to B Gerdin.
Small-bowel transplantation in the rat with a nonsuture cuff technique. Technical and immunological considerations.
Small-bowel transplantation (SBT) using an nonsuture cuff technique was carried out on 137 rats. Preparation of the donor graft was carried out according to conventional procedures. Graft perfusion was done at a fixed pressure of 35 cm water. The left renal vessels of the recipient were dissected, the native kidney removed, and the graft was connected to the vessels by a nonsuture cuff technique. Of the animals, 92% survived for at least 5 days posttransplant. Three different combinations were investigated: (1) isografts; (2) semisyngeneic grafts from nontreated Lewis----(Lewis x DA) F1 hybrids; and (3) semisyngeneic grafts from rabbit antilymphocyte globulin (ALG)-pretreated Lewis----(Lewis x DA) F1. In group 1, 80% of the grafts were unaffected after 1 month; flow studies showed slight or no impairment of circulation in the graft. In group 2, the recipients developed clinical signs of graft-versus-host disease (GVHD) after 1 week, and at the end of the 2nd week the animals showed signs of severe illness, leading to death due to GVHD. There was also a higher percentage of complications in this group. In group 3, 65% of the animals died. However, 27% showed intact grafts and no signs of GVDH after 1 month, indicating that antibody pretreatment of the donor may successfully prevent GVHD SBT.
Animals↗
The enhancing effect of cyclosporine A and sulfasalazine on the prevention of rejection in rat cardiac allografts.
Sulfasalazine (SASP) has been used for many years as a disease-modifying agent in inflammatory bowel disease and in rheumatoid arthritis. However, its mode of action is not entirely clear. Evidence has been accumulated which indicates that its efficacy is due to an immunomodulatory effect. In the present communication, we report that SASP has an immunomodulatory capacity in an experimental rat cardiac allograft model. A combination of 100 mg/kg per day of SASP given orally until rejection and 10 mg/kg per day of cyclosporine A (CyA) given orally for 10 days resulted in a significantly increased graft survival time as compared to that in animals given CyA alone.
Animals↗
Is postischaemic water accumulation related to delayed postischaemic hypoperfusion in rat brain?
The effect of reversible cerebral ischaemia on brain oedema development was studied with a gravimetric method. Cerebral blood flow changes after ischaemia were correlated with alterations in brain specific gravity. Forebrain ischaemia (15 min) was induced in rats by reversible bilateral ligation of both carotid arteries plus induction of controlled hypotension to 50 mm Hg. The specific gravity of different brain structures was determined in a Percoll column up to 24 h after ischaemia. In addition, regional cerebral blood flow was measured by 14C-iodoantipyrine autoradiography. Cerebral ischaemia resulted in reduction of cerebral blood flow to less than 1% of normal in cortical structures and the caudatoputamen. One hour after the end of ischaemia blood flows were still reduced to 30-50% of the control level indicative of delayed postischaemic hypoperfusion. Specific gravity in cortex and hypothalamus reached a maximal decrease 10 min after the end of the ischaemia, and was still significantly reduced at 1 h, while it was normal again 6 hrs later. Regression analysis between regional cerebral blood flows and the corresponding specific gravities were made at various time points, but no significant correlations could be established. Other mechanisms, like vasoconstriction, rheologic or metabolic factors may be causative for the delayed postischaemic hypoperfusion.
Animals↗
Inability of flunarizine, lidoflazine or magnesium to counteract delayed hypoperfusion after forebrain ischaemia in the rat.
Local cerebral blood flow (lCBF) was measured autoradiographically 60 min after 15 min of forebrain ischaemia in rats treated with flunarizine (0.1 mg/kg b.w.), lidoflazine (1.0 mg/kg b.w.) or Mg2+ (600 mumol/kg b.w.) before or at the end of the ischaemic period. Incomplete forebrain ischaemia was produced by a combination of common carotid artery occlusion and bleeding to a mean arterial blood pressure of 50 mmHg. During ischaemia lCBFs in cortical areas were less than 1% of preischaemic values. Neither flunarizine, lidoflazine nor Mg2+ influenced lCBF during ischaemia. Sixty minutes after the start of recirculation lCBFs were decreased to between 40 and 60% of the values found in control animals. None of the instituted treatments improved postischaemic cerebral blood flow. The results do not lend support to the view that calcium plays an essential role in the pathogenesis of delayed postischaemic hypoperfusion in the brain in this model.
Animals↗
Regulation of spinal cord blood flow in the rat as measured by quantitative autoradiography.
Spinal cord blood flow (SCBF) and its response to alterations in blood gases and to systemic hypotension, haemodilution and barbiturate anaesthesia were measured in 47 rats at the level of Th 7-8 by quantitative autoradiography with [14C]iodoantipyrine ([14C]IAP) as tracer. During normocapnia and normoxia the mean SCBF values in the grey and white matter were 94 +/- 21 and 17 +/- 3 ml min-1 100 g-1, respectively. SCBF was highly dependent on PaCO2. Thus in hypercapnic animals (PaCO2 greater than 9 kPa) SCBF was increased in grey and white matter to 228 +/- 22 and 54 +/- 7 ml min-1 100 g-1, while during hypocapnia (PaCO2 less than 3.9 kPa) it was decreased to 64 +/- 14 and 11 +/- 2 ml min-1 100 g-1, respectively. Mean arterial blood pressure (MABP) was reduced by withdrawal of blood to 80 +/- 8 mmHg in a light hypotension group and to 53 +/- 11 mmHg in a severe hypotension group, compared with 126 +/- 13 mmHg in a control group. There was no significant difference in SCBF between the control group and the hypotension groups, suggesting that autoregulation is maintained down to an MABP of at least 50 mmHg. Normovolaemic haemodilution, with a reduction of the haematocrit from 50 +/- 2 to 33 +/- 3, increased SCBF to 113 +/- 9 ml min-1 100 g-1 in grey matter and to 21 +/- 12 ml min-1 100 g-1 in white matter.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effect of increased hydrostatic pressure on lymphatic elimination of hyaluronan from sheep lung.
The effects of increased hydrostatic pressure on the concentrations of hyaluronan (hyaluronic acid) in lung lymph and serum were investigated in awake sheep with a cannula in the efferent vessel from the caudal mediastinal lymph node. Lung lymph was sampled at base line [left atrial pressure (LAP) 6.5 +/- 1.7 mmHg] and after two increases of LAP to 25.7 +/- 2.2 mmHg (level 1) and 37.0 +/- 5.1 mmHg (level 2). The lung lymph flow increased from 1.9 +/- 0.5 at base line to 9.3 +/- 2.2 and 15.9 +/- 0.7 ml/30 min, and the lymph-to-plasma concentration ratio of total protein decreased from 0.63 +/- 0.02 to 0.32 +/- 0.04 and 0.32 +/- 0.05 at the two elevated levels of LAP, respectively. The hyaluronan concentration in lung lymph was unchanged, and there was a flow-dependent elimination of hyaluronan from the lung that increased from 23 +/- 8 to 87 +/- 19 and 137 +/- 37 micrograms/30 min, respectively. The lung concentration of hyaluronan was 167 +/- 28 micrograms/g fresh lung, and at base line it was calculated that slightly less than 2% of the lung hyaluronan was eliminated by the lymphatic route in 24 h. If extrapolated to 24 h, the elimination rate of hyaluronan seen during elevated LAP would result in lymphatic elimination of 18% of the lung hyaluronan over this time period. Since hyaluronan is responsible for part of the protein exclusion in the extracellular matrix, it is plausible that washout of interstitial hyaluronan contributes to the decrease in albumin exclusion from the interstitium that occurs after an elevation of LAP.
Animals↗
Inflammatory reaction and blood flow in experimental wounds inoculated with Staphylococcus aureus.
Wound healing and granulation tissue formation can be accelerated by inoculation with live pathogenic microorganisms. For further elucidation of this phenomenon the present work was undertaken to study the effects of Staphylococcus aureus microorganisms on the inflammatory reaction and blood flow in developing granulation tissue in rats. Cylindrical hollow sponge implants were used as an inductive matrix for the growth of granulation tissue. In control animals 1 ml of wound fluid was withdrawn from the central dead space of the implant immediately after implantation and replaced with 1 ml of physiological saline. In experimental animals the implants were injected with live staphylococci, 10(2) or 10(5) microorganisms/ml. Wound fluid was analyzed 3, 7, 10 and 14 days after implantation, whereas measurements of local blood flow and albumin extravasation in the granulation tissue were made after 7 days. Implants inoculated with 10(5) organisms developed infection with pus formation while implants contaminated with 10(2) organisms showed no infection. In wound fluid specimens collected from the infected implants correlation between the number of polymorphonuclear leukocytes and prostaglandin E2 concentration was statistically significant. The most prominent finding in contaminated but uninfected implants was an enhanced local blood flow. This may explain some of the mechanisms leading to S. aureus-induced acceleration of wound healing.
Animals↗
Antiserum-induced neutropenia in the rat: characterization of a rabbit anti-rat neutrophil serum.
A heterologous rabbit anti-rat neutrophil serum (ANS) based on peptone-stimulated peritoneal exudate neutrophils (PMNLs) from Sprague Dawley rats was prepared. Leucoagglutination and indirect immunofluorescence assays revealed high titres of antibodies to rat PMNLs (1/2560), lower titre of antibodies to rat lymphocytes (1/160) and a very low titre against rat platelets (1/20). ANS given intravenously (i.v.) to rats in doses of up to 42 mg of protein/kg b.w. caused transient neutropenia, lasting about 10 min after administration, and thrombocytopenia, lasting about 5 min. Two minutes after an i.v. injection of 21 mg of ANS/kg b.w. there was profound uptake of 51Cr-labelled PMNLs in the lung, increased release of 51Cr to plasma, an increased amount of 51Cr in the spleen and consumption of greater than 98% of total complement (CH50). Two hours later there was high activity of 51Cr in the plasma, spleen and liver, while lung radioactivity had decreased to below baseline and CH50 had recovered to 55% of baseline. An intraperitoneal (i.p.) injection of ANS was followed by prolonged neutropenia with a maximum after 12 h. Simultaneously peripheral mononuclear cells slightly decreased. There was no change in the number of peripheral platelets in the blood or in the plasma concentration of fibrinogen, alpha 2-antiplasmin, plasminogen or plasminogen activators. Intraperitoneal administration of ANS did not affect CH50. It was concluded that the raised ANS had good specificity against rat PMNLs and was able to induce prolonged neutropenia after i.p. injection without affecting the complement of fibrinolytic system.
Agranulocytosis↗
Studies on the role of thromboxane in thrombin-induced pulmonary insufficiency in the rat.
During infusion of thrombin in rats pulmonary arterial pressure rose from 15 +/- 2 to 35 +/- 3 mmHg and mean arterial pressure fell from 120 +/- 6 to 49 +/- 27 mmHg. Plasma thromboxane B2 (TxB2) increased from 0.3 +/- 0.04 to 3.6 +/- 0.5 ng/ml. Ninety minutes later the lung weight and albumin concentration in the lung were increased (2.21 +/- 0.13 g and 22.7 +/- 4.7 mg/g) compared with controls (1.12 +/- 0.14 g and 8.5 +/- 0.9 mg/g). An inhibitor of thromboxane synthetase, Dazoxiben R, reduced the elevated pulmonary arterial pressure and the elevated plasma TxB2 concentration following infusion of thrombin. Ninety minutes after infusion of thrombin, the in vitro synthesis of TxB2 in lung tissue was increased. Dazoxiben and antineutrophil serum reduced this synthesis of TxB2 in vitro. The lung weight (2.18 +/- 0.20 g) and lung albumin concentration (21.4 +/- 3.4 mg/g) was not affected by Dazoxiben. The results indicate that TxA2 is an important mediator of the pressure changes in the early phase after infusion of thrombin and that neutrophils are associated with thromboxane formation in the lung tissue.
6-Ketoprostaglandin F1 alpha↗
Stimulation of wound healing by epidermal growth factor. A dose-dependent effect.
This work was undertaken to study the effects of various doses of locally applied epidermal growth factor (EGF) on developing granulation tissue in rats. Cylindrical hollow sponge implants were used as an inductive matrix for the growth of granulation tissue. In the test groups, the implants were injected daily with a solution containing 0.2, 1, or 5 micrograms of EGF in 0.1% albumin while the implants of the control group were treated correspondingly with the carrier solution only. Analyses of granulation tissue in the sponge cylinders were carried out 7 days after implantation. A stimulatory, dose-dependent effect of EGF on granulation tissue formation was observed: cellularity increased, as evidenced by the elevated amounts of nucleic acids, and accumulation of collagen and glycosaminoglycans was enhanced.
Animals↗
Prophylactic and delayed treatment with indomethacin in a porcine model of early adult respiratory distress syndrome induced by endotoxaemia.
The effects of prophylactic and delayed treatment with indomethacin were evaluated in a porcine model of early adult respiratory distress syndrome (ARDS) induced by endotoxaemia. Spontaneously breathing pigs under ketamine anaesthesia were infused i.v. with E. coli endotoxin (10 micrograms . h-1 . kg-1) over 6 h. Twenty animals received endotoxin without treatment. Eight animals were pretreated with indomethacin i.v., 5 mg . kg-1 in 30 min, followed by further infusion at a rate of 2 mg . h-1 . kg-1. Ten animals received the same dosage of indomethacin beginning 2 h after the start of endotoxin infusion. Pretreatment with indomethacin inhibited the endotoxin-induced impairment in pulmonary gas exchange, but did not prevent pulmonary oedema. The pulmonary hypertension was counteracted. Oxygen delivery did not improve, because of a marked reduction in cardiac output (Qt). Systemic vascular resistance (SVR) increased markedly, and mean arterial pressure (MAP) was higher. Survival was improved. Delayed indomethacin treatment prevented a further deterioration in pulmonary gas exchange and restored it towards the baseline level. The pulmonary oedema was not counteracted, while the pulmonary hypertension was reduced. O2 delivery was not restored, owing to the greater decrease in Qt compared with the untreated endotoxin group. SVR increased considerably, and MAP was better maintained. Survival was not improved. These results indicate that cyclo-oxygenase inhibitors might benefit pulmonary gas exchange in human ARDS. Drugs which interfere with arachidonate metabolism will probably be of great importance in the prophylaxis, in particular, and also in the treatment of ARDS.
Anesthesia, General↗
Effect of carotid artery occlusion and ganglionic blockade on regional blood flows and intestinal damage after haemorrhagic hypotension in the rat.
The effects of cerebral ischaemia by carotid artery occlusion and of a ganglionic blocking agent (Arfonad) on cardiac output and regional blood flows were studied after 15 min of haemorrhagic hypotension (mean arterial pressure 50 mmHg) in the rat. The microsphere technique was used for blood flow determinations. Animals subjected to haemorrhagic hypotension and simultaneous carotid artery occlusion (group BC) exhibited a stronger immediate vasoconstrictor response than animals subjected to haemorrhagic hypotension only (group B) and more blood had to be withdrawn to achieve stable hypotension at 50 mmHg (2.6 +/- 0.1 vs. 2.2 +/- 0.4 ml per 100 g body weight (body wt); P less than 0.05). However, group B showed the same decrease in cardiac output as group BC, but the blood flows of the kidneys, spleen, intestine, liver and skin were less deranged at the end of the hypotensive period. Groups B and BC exhibited similar intestinal ischaemic mucosal damage, measured as leakage of [125I]albumin. When induction of haemorrhagic hypotension was combined with ganglionic blockade administration (Arfonad) and carotid artery occlusion (group ABC), significantly less blood had to be withdrawn than in groups BC (1.6 +/- 0.2 vs. 2.6 +/- 0.1 ml per 100 g body wt; P less than 0.05). The blood flows of the kidneys, small intestine, liver, spleen and skin were less compromised in group ABC. In addition, group BC had more profound metabolic acidosis and were more haemoconcentrated than group ABC; moreover, group BC, tended to be hypoglycaemic and showed intestinal mucosal damage, whereas neither of these effects occurred in group ABC.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Selective actions of calcium antagonistic drugs on the haemodynamics and regional organ blood flow in rats.
Six substances, all of which influence calcium utilization by smooth muscle, namely nimodipine (50 micrograms/kg), flunarizine (1 mg/kg), verapamil (0.2 mg/kg), lidoflazine (1 mg/kg), magnesium (600 mumol Mg++/kg), and manganese (180 mumol Mn++/kg), were given intravenously to rats and their effects on regional blood flows and on cardiac output were determined by the radioactive microsphere technique. All compounds caused a temporary fall in mean arterial blood pressure. Cardiac output was decreased by manganese, and minute work by nimodipine, manganese and lidoflazine. Nimodipine increased blood flow in the liver, skeletal muscle and heart and decreased that in the stomach, ileum, colon, kidney, spleen and skin; manganese increased flow in the duodenum, jejunum, liver and myocardium and decreased that in the stomach, ileum, colon, spleen and skin; flunarizine increased flow in the liver, heart and brain; and magnesium increased flow in the liver, spleen and brain. Lidoflazine and verapamil, although leading to haemodynamic alterations, had no selective effect on organ blood flow. Selective actions by calcium effector drugs can provide information on mechanisms of calcium flux in various types of vascular smooth muscle, and show that it is possible to tailor combinations of anti-calcium agents with optimal effects on a given organ.
Animals↗
Permeability-increasing ability of PAF-acether in rat skin.
Platelet-activating factor (PAF-acether), a phospholipid compound with effects on several cells, e.g., platelets and polymorphonuclear leukocytes (PMNs), was examined for its effect on microvascular permeability in rat skin. It was found to increase microvascular permeability, measured as exudation of [125I]human serum albumin, in amounts exceeding 1 pmol, and was more than 1000 times as potent as histamine. The effect was independent of cell infiltration, as no accumulation of PMNs, measured as the amount of myeloperoxidase in the skin, occurred and as the response was unaltered in animals rendered neutropenic due to treatment with an antiserum against PMNs.
Animals↗
Hemorrhagic shock in the dog. I. Correlation between survival and severity of shock.
A prerequisite elucidating the pathomechanism of hemorrhagic shock are reproducible experimental models, leading to a predictable outcome. Two concepts have been reported to be a good predictor for the outcome both employing a fixed hypotension level: total oxygen deficit and shed blood volume uptake. To correlate these two models we subjected 31 dogs to a standardized hemorrhagic shock procedure. Besides determination of acid-base status, hematocrit, mean arterial pressure, and cardiac output, these two parameters were measured continuously. Seventeen dogs survived the shock procedure, 14 died within 24 h. During shock, neither oxygen deficit nor any other parameter mentioned above correlated with the final outcome of the shock state. The only significant difference between surviving and non-surviving animals during this period was the amount of uptake. The non-surviving dogs exhibited a higher uptake volume, indicating an incipient collapse of the microcirculation. Terminating the duration of hypotension at an uptake volume of 5% of the maximum shed blood, all animals survived, while after an uptake volume of 15% about 50% of the dogs died. Using uptake volumes of various degrees in a hemorrhagic shock model as the endpoint of the hypotensive stress, it seems possible to produce reliable survival rates.
Animals↗
Hemorrhagic shock in the dog. II. Studies on central hemodynamics and regional blood flow.
Oxygen consumption, hemodynamics, and regional blood flow (with the radioactive microspheres technique) were determined in 12 anesthetized dogs subjected to hemorrhagic shock. The animals were kept in hypotension at 40 mmHg, until 15% of the maximum shed blood had been infused to keep arterial pressure stable, whereafter all the shed blood was retransfused. Cardiac output (CO) decreased to 33% and 25% of preshock values in survivors (S) and nonsurvivors (NS), respectively, and after retransfusion it was significantly higher in S. After retransfusion, NS showed a higher arterial pCO2 than S adding a respiratory component to the metabolic acidosis that occurred during and after hemorrhage. Blood flow to the brain was not impeded during shock, but as CO decreased the fraction delivered to the brain was increased 2.6-3.3-fold. Myocardial blood flow decreased to about 28% of preshock values immediately after hemorrhage, and increased to about 54% at the end of hemorrhage. After retransfusion S had a higher myocardial flow than NS. The flow to the gut paralleled the decrease in CO during hemorrhage and immediately after retransfusion NS exhibited an overperfusion in ileum and colon compared to the preshock values. Kidney blood flow fell progressively during the course of hypotension, similarly in S and NS. After retransfusion it was normalized in S but not in NS. The preshock flow to pancreas was significantly higher in S than in NS, but during and after shock the blood flow did not differ between S and NS.
Animals↗
Effect of anti-inflammatory drugs on xanthine oxidase and xanthine oxidase induced depolymerization of hyaluronic acid.
The inhibitory effect of various anti-inflammatory drugs on the xanthine oxidase derived depolymerization of hyaluronic acid was studied. The depolymerization was assayed by repeated viscosity measurements. By using a low xanthine oxidase activity, the decrease in viscosity with time followed first order reaction kinetics and was therefore suitable for kinetic analysis. The xanthine oxidase activity was monitored by assay of O2-consumption with a Clark-electrode and by assay of urate production. We present evidence that salicylic, acetylsalicylic, gentisic and azodisalicylic acid and sulfasalazine inhibit the production of oxygen-derived free radicals by xanthine oxidase. We found that sulfapyridine, 5-aminosalicylic acid, allopurinol, mannitol, glucuronic acid and N-acetylglucosamine in addition to the earlier studied drugs, paracetamol, ibuprofen, benoxaprofen and gentisic acid exert their effect via scavenging of free radicals. These drugs had very little effect on the enzyme activity.
Anti-Inflammatory Agents↗