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Biomedical subjects

K Messmer

Publications and source records attributed to K Messmer.

At least 361 records · Page 20Linked to original sources
PubMed1989

Prevention of endogenous leukotriene production during anaphylaxis in the guinea pig by an inhibitor of leukotriene biosynthesis (MK-886) but not by dexamethasone.

Leukotriene C4 (LTC4) underwent rapid elimination from the circulating blood and was extensively converted to LTD4 within the vascular space of the guinea pig. To mimic the elimination and metabolism of endogenous LTC4 generated during anaphylaxis, 14,15-3H-labeled LTC4 was infused intravenously over a period of 15 min, leading to a recovery in bile of 85% of the infused LT radioactivity within 2 h. Corresponding to the tracer studies, LTD4 and, to a lesser extent, LTC4 were the predominant endogenous cysteinyl LTs in guinea pig bile. The biliary production rate of endogenous LTD4 increased from 0.3 +/- 0.1 to 6.2 +/- 1.8 pmol x min-1 x kg-1 (p less than 0.001) during anaphylactic shock induced by intravenous injection of OVA (0.2 mg/kg) into sensitized guinea pigs. A novel LT biosynthesis inhibitor (MK-886; 10 mg/kg, i.v., 15 min before antigen challenge) suppressed the antigen-induced cysteinyl LT production by greater than 92% (p less than 0.001). This inhibition of systemic LTC4 formation was associated with a complete protection against lethal anaphylactic shock in animals pretreated in addition with the H1 receptor antagonist pyrilamine. Pretreatment with either the inhibitor of LT synthesis or the histamine receptor antagonist reduced the lethality during anaphylactic shock from 100 to 60 and 78%, respectively. In artificially ventilated, pyrilamine-pretreated animals, the antigen-induced decrease in dynamic lung compliance and the rise in hematocrit were significantly reduced (p less than 0.05) by pretreatment with the inhibitor of LT synthesis. Dexamethasone at high doses (10 mg/kg, i.p., once daily for 7 d, or in a single dose of 10 mg/kg, i.v., 3.5 h before challenge) had no inhibitory effect on LT generation during anaphylaxis in vivo. However, in resident peritoneal macrophages, harvested from these dexamethasone-treated sensitized guinea pigs and stimulated with zymosan, both cysteinyl LT and 6-keto-PGF1 alpha formation were strongly suppressed. These studies indicate an important role of cysteinyl LTs in systemic anaphylaxis in vivo and demonstrate the blockade of anaphylactic LT generation by a novel inhibitor of LT biosynthesis (MK-886) but not by dexamethasone.

Anaphylaxis↗
PubMed1989

Tissue oxygenation after prolonged ischemia in skeletal muscle: therapeutic effect of prophylactic isovolemic hemodilution.

Prolonged ischemia is known to cause severe damage in skeletal muscle and skin as a result of reperfusion failure. Isovolemic hemodilution has been suggested as a modality to reverse microcirculatory disorders by improving flow properties and flow conditions of the blood. The aim of the present study was to investigate whether prophylactic isovolemic hemodilution could improve tissue oxygenation after 4h of pressure induced ischemia in skeletal muscle. In 17 Syrian golden hamsters a dorsal skin fold chamber and two permanent arterial and venous catheters were implanted. Following a recovery period of 48h ischemia was induced for 4h by means of a transparent stamp compressing the tissue within the chamber. In 9 animals (control, hct 43%) measurements of tissue PO2 (platinum multiwire electrode) were performed prior to and 15 min, 2h and 24h after release of ischemia. In 8 animals isovolemic hemodilution with Dextran 60 (hct 29%) was carried out prior to ischemia and measurements of local tissue PO2 were performed as reported for the control group with an additional measurement 30 min after hemodilution. In control animals tissue PO2 decreased significantly (p less than 0.01) from 20.7 +/- 2.4 mmHg prior to ischemia to 8.8 +/- 3.1 mmHg after 15 min of reperfusion; after 24h tissue PO2 was 15.6 +/- 6.1 mmHg. In hemodiluted animals tissue PO2 increased due to hemodilution from 20.9 +/- 1.6 mmHg to 23.5 +/- 2.5 mmHg (p less than 0.05); after 15 min of reperfusion tissue PO2 was 19.8 +/- 6.8 mmHg and remained unchanged for 24h (20.0 +/- 2.5 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

A new experimental model of ARDS and pulmonary hypertension in the dog.

The aim of this study was to establish a stable and reproducible model of pulmonary artery hypertension with concomitant ARDS-like changes of lung function and lung morphology. In eight anesthetized and ventilated dogs, 0.01 ml/kg oleic acid (OA) was given i.v. followed by repetitive injections of 100 microns glass beads (GB) into the right atrium until a mean pulmonary artery pressure of 35-40 mmHg was reached. Mean right ventricular (RVP) and pulmonary artery (PAP) pressures, pulmonary vascular resistance (PVR), lung compliance and resistance, PaO2, intrapulmonary shunt and colloidosmotic pressure (COP) were closely monitored for 150 min. PAP, RVP, and PVR considerably increased subsequent to OA/GB injection, and stabilized at a high level within 70 min, showing only a minimal decrease (PAP, RVP) or no change (PVR) during the following 80 min. A significant decrease of PaO2 and pulmonary compliance as well as an increase of resistance and intrapulmonary shunt were found as early as 30 min after the last embolization and they remained unchanged for 120 min. Reduction of COP suggested transcapillary leakage of macromolecules. Histology revealed an interstitial and intraalveolar edema. We conclude that the combined injection of oleic acid and glass beads provokes microvascular lung injury and results in stable pulmonary artery hypertension with concomitant ARDS-like changes of lung function. Thus, an acute model is provided in the dog allowing for the study of cardiac function in ARDS complicated by pulmonary artery hypertension.

Animals↗
PubMed1989

Microcirculatory therapy in shock.

The normal microvascular perfusion pattern is characterized by temporal and spatial variations of capillary flow. Local driving pressure, arteriolar vasomotion and endothelial cells are key-factors for local regulation of hydraulic resistance and fluid balance between the blood and tissue compartments. In shock, both the central and particularly the local mechanisms controlling microvascular perfusion are impaired. The microvascular perfusion pattern becomes permanently inhomogeneous due to lack of arteriolar vasomotion, changes of flow properties of blood, endothelial cell swelling and blood cell-endothelium interaction. Hence the objectives of primary shock therapy are to reestablish precapillary pressure, arteriolar vasomotion and to open the occluded microvascular pathways in order to reestablish the surface area needed for exchange of nutrients and drainage of waste product. These effects can not be achieved by vasoactive drugs, unless blood volume has been restored and blood fluidity improved by hemodilution. Whereas the necessary hemodilution can be achieved by conventional volume substitutes (colloids, crystalloids) restoration of vasomotion and reopening of narrowed capillaries can be obtained by small volume resuscitation using hyperosmotic/hyperoncotic salt dextran solution. The potential of this new concept for primary resuscitation and treatment of tissue ischemia is presently explored.

Blood Volume↗
PubMed1989

The hairless mouse ear for in vivo studies of skin microcirculation.

The homozygous (hr/hr) hairless mouse ear was introduced in 1980 by Eriksson and coworkers as a model for in vivo studies of the skin microcirculation. Herein we expand on this work, presenting results of in vivo microvascular parameter measurements and morphologic studies in the intact ear. The in vivo measurements include microvascular diameter, RBC velocity, capillary density, and the frequency and amplitude of arteriolar vasomotion. In connection with the in vivo studies, a detailed anatomic description of the overall and vascular anatomy is given. Additionally, the preparation techniques for carrying out these in vivo and morphologic studies in the mouse ear are presented in detail.

Animals↗
PubMed1989

Direct monitoring of nutritive blood flow in a failing skin flap: the hairless mouse ear skin-flap model.

A new experimental skin-flap model is presented in which direct observations of blood flow in individual capillaries can be made from the time of flap creation throughout the entire evolution of the establishment of necrosis. After flap creation, one observes through the microscope that at 1 hour a large area of tissue is nonperfused as a result of the surgical trauma. This is followed by vasodilatation at 6 hours, resulting in an increase in the area of perfused tissue. At 24 hours, the vasodilatation persists, and the red cells that have entered the tissue during the vasodilatation (6 hours) accumulate in the capillaries, this being reflected by an increased area of nonperfused tissue. This increase continues to 72 hours, at which time the perfusion-nonperfusion interface becomes well defined and remains so throughout the 5-day experiment. Analyses of the relationship between early postoperative capillary perfusion and eventual necrosis are presented. Advantages and disadvantages of this model are listed.

Animals↗
PubMed1989

Angiogenesis and hemodynamics of microvasculature of transplanted islets of Langerhans.

Transplantation of isolated islets of Langerhans is frequently followed by early loss of islet function. Because whether this is caused by insufficient vascularization or graft rejection is unknown, angiogenesis and microvascularization of islet grafts were studied in vivo by means of intravital microscopy. After transplantation of syngeneic islets in hamster dorsal skin-fold chambers, 97% (n = 66) of the islets exhibited the first signs of angiogenesis at days 2-4, characterized by sinusoidal sacculations and capillary sprouts. After 10 days, angiogenesis was completed, consisting of a microvascular network similar to those of islets in situ: arterial supply, afferent and efferent capillary loops, and venular drainage. Functional density of microvessels was 700.1 +/- 127.0 cm-1, and erythrocyte velocity was 0.58 +/- 0.35 mm/s. Intracellular insulin was demonstrated immunohistochemically. Electron-microscopic studies revealed normal fine structure of the capillary wall. The model allows in vivo analysis of microvascular phenomena occurring in host-vs.-graft reaction after allogeneic and xenogeneic islet transplantation. Furthermore, it may be used to quantitatively assess immunosuppressive regimens.

Animals↗
PubMed1989

Computer assisted leukocyte adhesion measurement in intravital microscopy.

The pathogenetic role of the leukocytes in the development of postischemic injury is not yet understood. Therefore a model was developed which allows for in vivo quantification of leukocyte-endothelium interaction in the awake animal. The velocity of leukocytes was measured by means of intravital microscopy and interactive digital image analysis. An adhesion coefficient (AC) was calculated which characterizes the degree of the leukocyte-endothelium interaction. A special procedure of automatically taking image samples for the leukocyte velocity measurement reduces observer bias. As shown in a validation experiment, this procedure yields reproducible results and therefore allows to quantify the influence of prophylactic and therapeutic measures on postischemic leukocyte-endothelium interaction.

Animals↗
PubMed1988

Tissue PO2 and functional capillary density in chronically ischemic skeletal muscle.

In order to study changes in functional capillary density and tissue PO2 in chronically ischemic skeletal muscle, a new model, using the Syrian golden hamster was developed. In the hamster dorsal skin fold, which receives its vascular supply from two cranial and two caudal feeding arteries, a double frame chamber was implanted and ischemia was induced in the cranial part by heat coagulation of the cranial arteries outside of the chamber. This technique allows for analysis of microvascular hemodynamics and local tissue PO2 prior to and during a prolonged period of ischemia in skin muscle. As result of ischemia the diameters of the arterioles increased (p less than 0.001) over the whole 11 day observation period. Functional capillary density decreased significantly (p less than 0.01) during the first 7 days, while capillary RBC-velocity was reduced throughout the 11 days of observation. RBC-velocity in collecting venules was diminished significantly throughout the postischemic observation period. The diameters of the collecting venules first increased upon ischemia (p less than 0.001) but were found decreased at 4, 7 and 11 days. Measurements of tissue PO2 demonstrated a marked decrease from a mean PO2 of 20.5 mmHg prior, to 9.5 mmHg following induction of ischemia. The model allows for induction of chronic ischemia and is suitable to study the effect of therapeutic measures on the microcirculation in chronically ischemic skeletal muscle in vivo.

Animals↗
PubMed1988

[Microvascular perfusion of malignant tumors--a therapeutic measure for enhancing the hyperthermia effect?].

Hypoxic regions of malignant tumors are poorly vascularized; they appear to be more susceptible to hyperthermia in vivo than tumor cells in vitro after an exposure to heat. In an attempt to explain this discrepancy, changes of microcirculatory flow in the tumor have been proposed as key mechanism for destroying adjacent tumor cells in particular. This study was conducted to define the impact of the microcirculation on tumor destruction after local hyperthermia. A transparent chamber was implanted in the dorsal skin fold and two permanent indwelling catheters placed in carotid artery and jugular vein of 45 Syrian golden hamsters. 48 h later, 4 X 10(4) cells of the amelanotic melanoma A-Mel-3 were implanted into the s.c. tissue covered by the chamber. 5 days later, at a tumor diameter of 3 mm, the microcirculation of this tumor was studied using intravital microscopy, a platinum multiwire electrode, television as well as micropuncture techniques for the determination of local PO2, microcirculatory blood flow and microvascular pressure. Measurements were taken at 30 degrees C and 15 min after reaching a tumor temperature of 35 degrees and 42.5 degrees C. When heating up the melanoma to 35 degrees C, an increase in capillary perfusion by 35% was noted. With an apparent maximum of capillary perfusion, there was no change in arteriolar pressure but a significant drop in venular pressure from 11.0 +/- 1.1 to 7.4 +/- 0.6 mmHg resulting in an increase of the arteriolo-venular pressure gradient while the systemic pressures were unchanged. At a tumor temperature of 42.5 degrees C, prestasis and stasis became apparent in capillaries and collecting venules. This was accompanied by a rise in capillary and venular pressure by 5 mmHg. At the same time, pronounced tissue hypoxia was present in the tumor with more than 50% of the values within the hypoxic range between 0 and 5 mmHg. Despite tissue hypoxia, the constriction of all tumor arterioles became evident 15-30 min after reaching a tumor temperature of 42.5 degrees C. The deterioration of tumor oxygenation was associated with damage of tumor cells such as swelling and destruction of mitochondria which was seen under the electron microscope. After 40 min at 42.5 degrees C, the attenuation of the endothelial lining around the entire vascular perimeter was seen in tumor capillaries.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Quantitative analysis of microcirculatory disorders after prolonged ischemia in skeletal muscle. Therapeutic effects of prophylactic isovolemic hemodilution.

Reperfusion injury following prolonged ischemia is thought to be caused primarily by microvascular failure. The aim of the present study was to investigate whether prophylactic isovolemic hemodilution with Dextran 60 (hct 30%) could improve microvascular perfusion after 4 h of pressure-induced ischemia in skeletal muscle. In 28 Syrian golden hamsters (6-8 weeks/60-80 g b. wt.) a dorsal skinfold chamber and permanent arterial and venous catheters were implanted under Nembutal anesthesia (50 mg/kg b. wt.). Following a recovery period of 48 h pressure-induced ischemia was applied to the skeletal muscle within the skinfold chamber by means of a transparent stamp. Quantitative analyses of microhemodynamics were performed in the awake animal prior to and 15 min, 1, 2, 4 and 24 h after ischemia using vital fluorescence microscopy. In non-treated animals, functional capillary density decreased after 4 h of ischemia to 30% of the initial values (P less than 0.001); after 24-h reperfusion only 50% of the initially perfused capillaries were reperfused (P less than 0.001). The heterogeneity of functional capillary density increased after ischemia to a maximum of 2.19 +/- 0.94 as compared to 0.48 +/- 0.11 prior to ischemia. Capillary RBC-velocity suffered a marked reduction in the early reperfusion phase and did not recover up to the 24-h observation time. In contrast, prophylactic isovolemic hemodilution was associated with only a small and reversible reduction of functional capillary density after 4-h ischemia. At 24-h reperfusion 90% of the initially perfused capillaries were reperfused. Capillary RBC-velocity was reduced in the early reperfusion phase, but returned to normal values within 24 h. Thus, prophylactic isovolemic hemodilution resulted in a marked reduction of microvascular reperfusion failure in skeletal muscle. A hematocrit lower than normal prior to ischemia provides better conditions for capillary reperfusion after prolonged ischemia.

Animals↗
PubMed1988

Hemodilution--possibilities and safety aspects.

Normovolemic hemodilution is an essential part of the overall strategy to avoid exposure of patients to the hazards of homologous blood transfusions. It includes beneficial effects on the flow properties and flow conditions of blood. A hematocrit of 30% can be regarded as an optimal compromise between the fluidity and the oxygen content of the blood. Compensatory responses such as increased cardiac output and stroke volume occur following hemodilution. In patients with compromised coronary reserve the degree of hemodilution that is tolerated has to be carefully considered. Therefore specific selection criteria for patients to be preoperatively hemodiluted are needed. For reasons of safety, efficiency and practicability colloid solutions rather than crystalloid solutions should be used for intentional hemodilution.

Hemodilution↗