Plasma Concentrations Of Thromboxane B2 Research Articles

Effect of PAF receptor antagonism on cardiopulmonary alterations during coinfusion of TNF-alpha and IL-1 alpha in pigs

We examined the possibility that platelet-activating factor (PAF) might be a mediator of cardiopulmonary alterations induced by a 6-h coinfusion of human recombinant tumor necrosis factor (TNF-alpha) and interleukin-1 alpha (IL-1 alpha) in anesthetized pigs. Our hypothesis was tested by pretreating TNF-alpha + IL-1 alpha-infused pigs with WEB 2086 (3 mg/kg from -0.5 to 0 h + 0.75 mg.kg-1.h-1 from 0-6 h), a specific PAF receptor antagonist. Each cytokine was infused intravenously at 0.5 microgram/kg from 0-0.5 h + 5 ng.kg-1.min-1 from 0.5-6 h. WEB 2086 attenuated the early (0.25 h) cytokine-induced increases in mean pulmonary arterial pressure and pulmonary vascular resistance and blocked or markedly attenuated the later occurring (4-6 h) systemic hypertension and increased systemic vascular resistance. WEB 2086 lessened the severity of TNF-alpha + IL-1 alpha-induced hemoconcentration and airway constriction, but did not modify leukopenia, granulocytopenia, or the cytokine-induced increases in plasma concentrations of thromboxane B2, prostaglandin F2 alpha, and 6-ketoprostaglandin F1 alpha. Microscopically, WEB 2086 did not modify the increased number of granulocytes present in lung tissue derived from pigs infused with TNF-alpha + IL-1 alpha. We conclude that PAF occupies a physiological role in modulating TNF-alpha + IL-1 alpha-induced hemoconcentration, the early changes in pulmonary hemodynamics, and the later alterations in systemic hemodynamics.

Evaluation of the dermal effects of cast padding in coaptation casts on dogs

Summary Three configurations of cast padding and no cast padding were evaluated for their effects on skin in dogs. Padding was placed over bony prominences, between bony prominences, and over both areas for full-length padding under short-limb walking casts applied to 1 pelvic limb of Greyhounds. Evaluations were performed by pressure measurement over the calcaneal tuberosity, measurement of skin thromboxane B2 (TxB2) concentrations in skin over bony prominences, and measurement of plasma TXB2 concentrations. Pressure studies were performed to evaluate cutaneous pressures related to no cast padding and various configurations of cast padding. Concentrations of TxB2 in the skin were determined to evaluate the skin inflammatory effects of no padding and the padding configurations, and TXB2 concentrations in the plasma were analyzed to ascertain whether they could be used to predict impending dermal pressure lesions. Flexion of casted limbs revealed the greatest pressure over the calcaneal tuberosity with full-length cast padding. This was followed in decreasing order by no cast padding, padding over the prominences, and padding between the prominences. Compared with all other bony prominences and padding configurations, TXB2 skin concentrations were significantly higher over the calcaneal tuberosity when no padding was used and over the lateral base of metatarsal V when padding was placed between the prominences. Over the calcaneal tuberosity, this was attributed to the sharpness of the prominence and its potential for movement. This high TxB2 concentration corresponded to the high pressure found in the pressure studies. Over the lateral base of metatarsal V, the increase in TxB2 concentration was related to the mass of the prominence and the tendency for localized padding to settle around the area. Although the fully padded cast produced the highest pressure over the calcaneal tuberosity in the pressure measurement studies, this form of padding had the lowest TXB2 skin concentrations over this prominence in the 7- day TXB2 measurement studies. This was attributed to compacting of cast padding over time with resultant decrease in pressure over the bony prominence. There were no significant differences in plasma TxB2 concentrations before and after casting. On the basis of cutaneous pressure measurements and or dermal or plasma TxB2 measurements after short-limb casts had been in place for 7 days, we concluded that absence of cast padding can cause dermal pressure injury over sharp prominences; in some areas, localized cast padding may settle around larger prominences, increase pressure, and potentiate dermal pressure injury; although pressure may be high after applying full-length cast padding, some compacting of the padding occurs, and this provides the best form of padding to prevent dermal pressure injury; and plasma TxB2 concentrations cannot be used to predict impending dermal pressure injury in a coaptation cast.

Dibutyryl cyclic AMP attenuates lung responses induced by endotoxin in conscious sheep.

Dibutyryl cyclic AMP (DBcAMP) could inhibit the production of prostanoids and modulate the pulmonary vascular responses induced by endotoxin. Diffuse lung injury after endotoxemia in sheep is accompanied by the production of prostanoids and an increase in endothelial permeability. To determine whether exogenous DBcAMP could prevent the endotoxin responses, we measured pulmonary hemodynamics, gas exchange, and lung lymph responses to an intravenous infusion of Escherichia coli endotoxin (1.0 micrograms/kg over 30 min) in unanesthetized sheep in the presence and absence of DBcAMP (30 micrograms/kg/min) infused intravenously for 6 h beginning 1 h before endotoxin infusion or for 4.5 h after 30 min of treatment with endotoxin infusion. We also measured circulating leukocytes and lung lymph and plasma concentrations of thromboxane B2 (TXB2) and prostacyclin (6-keto-PGF1 alpha) metabolites by radioimmunoassay. DBcAMP infusion before endotoxin infusion decreased endotoxin-induced pulmonary hypertension and hypoxemia and markedly attenuated the increased lung lymph flow and lymph protein clearance. DBcAMP after endotoxin only attenuated the increased lung lymph flow and lymph protein clearance. DBcAMP treatment both before and after endotoxin infusion blocked endotoxin-induced increases in lung lymph and plasma TXB2 and 6-keto-PGF1 alpha. DBcAMP did not affect the number of circulating leukocytes. Although DBcAMP alone did not affect the pulmonary and systemic hemodynamics and lung lymph balance, the potential that DBcAMP directly modulates the pulmonary vascular responses to endotoxin as a vasodilator could be expected. We conclude that DBcAMP infusion attenuates lung dysfunction caused by endotoxemia, possibly by preventing prostanoid release and modulating the pulmonary vascular responses.

The effects of testosterone on lipids and eicosanoids in cynomolgus monkeys

The effect of testosterone administration on plasma lipoproteins and eicosanoids was studied in 24 male cynomolgus monkeys. We hypothesized that elevated plasma testosterone would unfavorably alter plasma lipids as well as thromboxane A2 (TxA2) and prostacyclin (PGI2), two eicosanoids that have been linked to the increased incidence of atherosclerosis, myocardial ischemia, and thrombosis. To test our hypothesis, half of the monkeys (N = 12) were subjected to 10 wk of testosterone treatment, whereas the remaining monkeys (N = 12) received a sesame oil vehicle. The plasma concentrations of thromboxane B2 (TxB2) and 6-keto-PGF1 alpha, the stable metabolites of TxA2 and PGI2, respectively, were determined. Additionally, assays were conducted on total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Distribution of the HDL subfraction protein was measured by gradient gel electrophoresis. All monkeys exhibited significant increases in TC (P less than 0.001) and low density lipoprotein cholesterol (LDL-C) (P less than 0.001); however, monkeys who received testosterone also displayed significant increases in TxB2 (P less than 0.03) and decreases in HDL-C (P less than 0.03) compared with control monkeys. There was a trend in the HDL-C subfraction data, indicating that testosterone treatment may be associated with a decrease in the larger HDL2b subfraction and a corresponding increase in HDL3c. These results demonstrate that exogenous testosterone adversely alters cardiovascular risk profiles by increasing TXB2 production and decreasing HDL-C. Athletes who use testosterone as an anabolic androgenic steroid may have an increased risk for coronary heart disease.

Association between total cholesterol and thromboxane B2 levels in offspring of parents suffering from premature coronary artery disease.

Relationship between plasma thromboxane B2 concentration and serum total cholesterol level was studied in 129 healthy 3 to 18 years old children, 77 girls and 52 boys, without any family history of premature coronary artery disease and in 181 offspring, 105 girls and 76 boys, of parents suffering from acute myocardial infarction before the age of 45. It was identified an enhancement in serum total cholesterol level of endangered children, and an elevated release of thromboxane A2 in affected girls. A significant negative correlation was found between serum total cholesterol concentration and plasma thromboxane B2 level in healthy girls. However, there was no correlation between serum total cholesterol level and plasma thromboxane B2 concentration in the children whose parents had premature coronary artery disease. It appears, from our results, that this in an alteration of thromboxane A2 release of platelets in children of families with high risk of cardiovascular diseases.

Effects of intravenous infusions of diaspirin cross-linked hemoglobin (DCLHb) on sheep.

The purpose of this study was to compare the cardiopulmonary, hematologic, and immunologic responses of unanesthetized sheep to single, "topload", intravenous infusions of either 10 mL/Kg or 40 mL/Kg of Diaspirin Cross-Linked Hemoglobin, 10 mL/Kg or 40 mL/Kg of a Human Serum Albumin (HSA) solution oncotically adjusted with human serum albumin to approximately match the oncotic pressure of the DCLHb, or 10 mL/Kg of Erythrocyte Hemolysate solution prepared in a manner similar to that commonly described in the literature and referred to as "stroma free hemoglobin". Solutions were infused at a rate of 1 mL/Kg/minute and animals were monitored for 72 hours after infusion. These studies demonstrated that in sheep infusion of either DCLHb or HSA solutions was well tolerated and did not produce a significant increase in plasma C3a levels, an increase in the plasma concentration of thromboxane B2, or unexpected fluid shifts. In contrast, infusion of the Erythrocyte Hemolysate produced a greater than 10-fold increase in plasma C3a concentrations, a greater than 6000-fold increase in plasma TxB2 concentration, significant fluid shifts, and changes in a variety of other parameters consistent with induction of a dramatic inflammatory response. These results indicate that appropriately prepared and purified DCLHb solutions do not elicit an inflammatory reaction in sheep.

Effects of hemodialysis on platelet-derived thrombospondin

The effects on platelet-derived thrombospondin (TSP) of hemodialysis with a cellulose membrane were studied in patients during routine hemodialysis and in normal subjects using an ex vivo model. Plasma and platelet-bound TSP were determined pre- and post-dialysis, in blood entering and leaving the dialyzer after 1, 3, 5, 15, and 30 minutes of dialysis, and in blood leaving the ex vivo module after 5, 10, 15, 20, and 25 minutes of perfusion. Plasma concentrations of beta-thromboglobulin (beta TG) and thromboxane B2 (TxB2), and platelet membrane expression of the alpha-granule protein GMP-140, were also measured. Significant increases in plasma concentrations of TSP and beta TG occurred between the inlet and outlet of the dialyzer after 5, 15, and 30 minutes of dialysis, accompanied by a slow, but significant, increase in their arterial plasma concentrations. In contrast, initiation of dialysis was associated with an immediate increase in plasma TxB2 concentration between the inlet and outlet of the dialyzer and an abrupt increase in arterial plasma TxB2 concentration which plateaued at 250% of the pre-dialysis value after five minutes. Transit of platelets through the dialyzer had no effect on platelet-membrane-associated TSP or GMP-140. Plasma TSP and beta TG concentrations at the outlet of the ex vivo module also increased significantly during perfusion, but plasma TSP concentrations were twofold greater than those during hemodialysis. In vitro stimulation of platelets with thrombin and immunoblotting studies of platelet release proteins showed reduced TSP release by platelets of hemodialysis patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostanoid production and pulmonary hypertension after fat embolism are not modified by methylprednisolone

Bilateral cemented arthroplasty (BCA) in anaesthetized mongrel dogs produces particulate fat and marrow embolism of the lung. Methylprednisolone sodium succinate (MPSS) has been advocated for post-traumatic fat embolism to prevent acute lung injury. We used the BCA procedure to produce acute fat and marrow embolism, and tested the efficacy of MPSS (30 mg.kg-1) in preventing physiological and pathological markers of acute lung injury. Dogs (n = 6) pre-treated with MPSS demonstrated similar acute increases in pulmonary artery pressure (PAP) within one minute of BCA (17.8 +/- 7.3 mmHg) as the untreated (control n = 7) dogs (18.6 +/- 12.6). Pulmonary vascular resistance (PVR) increased to the same degree in both groups (455 +/- 323 and 319 +/- 137 dyne.sec.cm-5) and PaO2 decreased by 18.3 +/- 6.4 mmHg in the control group as opposed to 12.4 +/- 7.7 mmHg in the MPSS group within five minutes of BCA. Circulating arterial and mixed venous plasma concentrations of thromboxane B2 (TxB2) increased within one minute of BCA in both groups with no increase in the transpulmonary gradient. Arterial plasma 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) increased (0.91 +/- 0.29 ng.ml-1 and 0.87 +/- 0.43 ng.ml-1) in both groups one minute after BCA. Mixed venous 6-keto PGF1 alpha plasma concentration also increased, but a significant transpulmonary 6-keto PGF1 alpha gradient was found.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of an ω-3 fatty acid-enriched ration on in vivo responses of horses to endotoxin

SUMMARY Because certain inflammatory processes are dependent on the fatty acid composition of the cellular membrane, dietary manipulations that replace ω-6 fatty acids with ω-3 fatty acids may modify inflammatory responses. We investigated the effect of supplemental dietary linseed oil, containing the ω-3 fatty acid, α-linolenic acid, on in vivo responses of horses to endotoxin. One group of horses (n = 6) was fed a control pelleted ration (0% linseed oil), and another group of horses (n = 6) was fed an 8% linseed oil pelleted ration. After 8 weeks of consuming these rations, all horses were given 0.03 μg of Escherichia coli 055:B5 endotoxin/kg of body weight, infused over 30 minutes. Horses were monitored over 24 hours. Compared with baseline values within each ration group, endotoxin infusion caused significant (P < 0.05) increase in rectal temperature, heart rate, and plasma concentration of thromboxane B2, 6-keto-prostaglandin F1α, and fibrinogen and significant (P < 0.05) decrease in total WBC count. Compared with baseline values within each ration group, endotoxin infusion failed to cause significant changes in prothrombin, activated partial thromboplastin, thrombin, or whole blood recalcification times, serum concentration of fibrin degradation products, pcv, or plasma total protein concentration. Before and after endotoxin infusion, horses given the linseed oil ration had longer mean whole blood recalcification time and activated partial thromboplastin time than did horses fed the control ration.

Effect of LY171883 on endotoxin-induced lung injury in pigs

We evaluated the role of sulfidopeptide leukotrienes as mediators of endotoxin-induced respiratory failure in pigs. Escherichia coli endotoxin (055-B5) was infused intravenously into anesthetized 10- to 14-wk-old pigs at 5 micrograms/kg the 1st h followed by 2 micrograms.kg-1.h-1 for 3 h in the presence and absence of LY171883, a specific leukotriene D4 (LTD4)/LTE4 receptor antagonist. Endotoxin caused hemoconcentration, granulocytopenia, decreased cardiac index, systemic hypotension, pulmonary hypertension, increased pulmonary vascular resistance, bronchoconstriction, hypoxemia, increased permeability of the alveolar-capillary membrane, pulmonary edema, and increased plasma concentrations of thromboxane B2 (TxB2), prostaglandin F2 alpha (PGF2 alpha), and 6-keto-PGF1 alpha. LY171883 did not modify endotoxin-induced cardiopulmonary and hematologic abnormalities, except for a modest attenuation of pulmonary hypertension (at 1 h) and increased pulmonary vascular resistance (at 1-2 h). Ex vivo stimulation of whole blood with calcium ionophore caused large increases in plasma concentrations of TxB2, PGF2 alpha, and LTB4. These increases were not significantly modified in blood derived from pigs treated with LY171883, indicating no inhibition of cyclooxygenase or 5-lipoxygenase. We conclude that LTD4 and LTE4 are not important mediators of endotoxin-induced lung injury in anesthetized pigs, although they may contribute modestly to pulmonary vasoconstriction.

Role of platelet-activating factor and eicosanoids during endotoxin-induced lung injury in pigs

We hypothesized that platelet-activating factor (PAF) and eicosanoids might be important mediators of endotoxin-induced respiratory failure in pigs. Escherichia coli endotoxin (055-B5) was infused intravenously into anesthetized 10- to 14-wk-old pigs at 5 micrograms/kg the 1st h, followed by 2 micrograms.kg-1.h-1 for 3 h in the presence and absence of SRI 63-675, a specific PAF receptor antagonist. During phase I (i.e., 0-2 h), endotoxin caused pulmonary hypertension and hypoxemia, decreased cardiac index, increased pulmonary vascular resistance, and increased plasma concentrations of thromboxane B2 (TxB2), prostaglandin (PG)F2 alpha, and 6-keto-PGF1 alpha. These phase I effects were attenuated or blocked by SRI 63-675 (10 mg/kg before endotoxin + 3 mg.kg-1.h-1 during endotoxemia). During phase II endotoxemia (i.e., 2-4 h), the PAF receptor antagonist blocked endotoxin-induced pulmonary edema and hypoxemia and increased relative permeability index of the alveolar-capillary membrane. SRI 63-675 also blocked the endotoxin-induced increases in plasma and bronchoalveolar lavage fluid concentrations of leukotriene B4 (LTB4). Ex vivo stimulation of whole blood with calcium ionophore caused large increases in plasma concentrations of TxB2 and LTB4. These increases were not significantly modified in blood derived from pigs treated with SRI 63-675, indicating no inhibition of cyclooxygenase or 5-lipoxygenase and suggesting that the in vivo effects were PAF receptor mediated. We conclude that PAF plays an important role in the release of eicosanoids during endotoxemia and in mediating, either directly or indirectly, endotoxin-induced lung injury in anesthetized pigs.

Sustained-release nifedipine (nifedipine-L) suppresses plasma thromboxane B 2 and 6-keto prostaglandin F 1 α in both young male smokers and nonsmokers

Sustained-release nifedipine (nifedipine-L) (40 mg twice a day) was administered orally to healthy young adult male smokers and nonsmokers for 10 days, and its effects on platelet aggregation, beta-thromboglobulin and platelet factor 4 levels, and plasma thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha (6-Keto-PGF1 alpha) concentrations were studied. The plasma nifedipine-L concentration in smokers (46.0 +/- 7.4 ng/ml) was significantly lower than that in nonsmokers (88.2 +/- 1.2 ng/ml). Nifedipine-L did not affect platelet aggregation induced by adenosine diphosphate, collagen, or epinephrine in either smokers or nonsmokers. The plasma beta-thromboglobulin level on the tenth day of nifedipine-L administration in nonsmokers was lower than that in smokers, but there were no significant differences either with or without nifedipine-L or between nonsmokers and smokers. Nifedipine-L had no effect on the concentration of platelet factor 4 in either smokers or nonsmokers. On the other hand, nifedipine-L significantly decreased the plasma TxB2 and 6-keto-PGF1 alpha concentrations in both smokers and nonsmokers. Thus we concluded that nifedipine-L suppressed the production of plasma TxB2 from platelets and also subsequently suppressed the production of 6-keto-PGF1 alpha and that this action was not affected by cigarette smoking.

Vascular permeability and coagulation during Rickettsia riekettsii infection in dogs

SUMMARY The vascular permeability of the ocular fundus, alterations in the coagulation system, and plasma concentrations of thromboxane B2 (txb2) and 6-keto-prostaglandin F1α, (6-keto-pgf1α) were studied in dogs following intradermal inoculation with 5 × 105 tcid50 of Rickettsia rickettsii. Twenty-four to 48 hours after the onset of fever and rickettsemia, multifocal areas of retinal vasculitis were evident, which corresponded to areas of altered vascular permeability demonstrated by fluorescein angiography. The number and intensity of retinal vessels with sodium fluorescein leakage peaked during the second week after inoculation, and retinal vascular permeability remained altered during the third week of infection, well past the phase of clinical and clinicopathologic recovery. Development of retinal vasculitic foci was associated with thrombocytopenia, increased concentrations of circulating fibrinogen, and slight prolongation of activated partial thromboplastin time. Increased concentrations of fibrin/fibrinogen degradation products were detected in 4 of 9 dogs. Despite the degree of vascular endothelial damage evident on fluorescein angiographic and histologic studies in these dogs, plasma txb2 and 6-keto-pgf1α concentrations were not increased.

Effects of a thromboxane A2 synthetase inhibitor on ventricular fibrillation threshold during coronary artery occlusion and reperfusion.

The effects of a new thromboxane A2 synthetase inhibitor (DP-1904) on electrical stability of the heart were tested in anesthetized, open chest dogs. The incidence of spontaneous ventricular arrhythmias, ventricular refractory period and ventricular fibrillation threshold (VFT) during ligation of the left anterior descending coronary artery (LAD) for 180 min and after reperfusion were measured as indices of stability. Ventricular fibrillation and ventricular tachycardia occurred spontaneously after ligation of LAD in 56% of 9 control dogs and 29% of 7 dogs which received intravenous DP-1904 (100 mg) before ligation of LAD (n.s.). In the control group, the ventricular refractory period decreased in the ischemic region; consequently, the difference in refractory period duration between the ischemic and non-ischemic regions (i.e., dispersion) increased 30 min after coronary ligation (7 +/- 9 ms vs 32 +/- 17 ms, p less than 0.05). The dispersion at 30 min after coronary ligation, though, was not affected in the DP-1904 treated group (2 +/- 4 ms vs 10 +/- 9 ms, n.s.). The VFT (determined with pulse trains) decreased from 28 +/- 5 mA to 15 +/- 11 mA (p less than 0.05) 30 min after coronary ligation in the control group, but was not affected (30 +/- 0 mA vs 27 +/- 4 mA) in the DP-1904 group. The plasma concentration of thromboxane B2 decreased after DP-1904 administration (baseline vs 30 min after coronary ligation: 475 +/- 165 pg/ml vs 165 +/- 74 pg/ml, n = 3, p less than 0.05), while the concentration of 6-keto-prostaglandin F1 alpha increased gradually. In conclusion, DP-1904 prevents a decline in electrical stability in the ischemic region of the canine heart during coronary occlusion.

Combination therapy with low-dose aspirin and ticlopidine in cerebral ischemia.

We compared combination therapy with low-dose aspirin plus ticlopidine to therapy with aspirin alone or ticlopidine alone in patients suffering transient ischemic attack or cerebral infarction. In 17, 24, and 23 patients, respectively, 300 mg/day aspirin, 200 mg/day ticlopidine, and 81 mg/day aspirin plus 100 mg/day ticlopidine were administered orally. Aspirin alone markedly inhibited platelet aggregation induced by arachidonic acid, partially inhibited platelet aggregation induced by adenosine diphosphate, and did not inhibit platelet aggregation induced by platelet activating factor. Ticlopidine alone inhibited platelet aggregation induced by adenosine diphosphate and platelet activating factor, but did not inhibit platelet aggregation induced by arachidonic acid. Combination therapy with aspirin plus ticlopidine markedly inhibited platelet aggregation induced by all three agonists. Plasma concentrations of beta-thromboglobulin and platelet factor 4 remained unchanged by aspirin alone, were slightly reduced by ticlopidine alone, and were markedly reduced by aspirin plus ticlopidine. Plasma concentration of thromboxane B2 was reduced by aspirin alone or with ticlopidine, but not by ticlopidine alone. The level of 6-ketoprostaglandin F1 alpha was reduced only by aspirin alone. Bleeding time was significantly prolonged by aspirin alone and by ticlopidine alone, although the greatest prolongation was produced by aspirin plus ticlopidine. Our results indicate that the combination of aspirin plus ticlopidine is a potent antiplatelet strategy, although the clinical importance of the changes observed need to be determined by a properly designed and controlled prospective study.

Eicosanoid Release as Laboratory Indicator of Biocompatibility

Biocompatibility evaluation of extracorporeal devices requires the establishment of sensitive indicators of blood cells/surface interactions. Among others, arachidonic acid derivatives, such as prostaglandins and thromboxanes, play an important role in the cell control systems. Hence, the release of eicosanoids during blood exposure to dialyzer membranes was investigated. Experiments included in vitro incubation of human blood with flat membranes (FM), as well as ex vivo perfusion of hollow fiber membranes (HFM) with blood from healthy volunteers in single-pass fashion. In both models, a significant release of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) was detected. In addition, the amount of eicosanoid release depended on the type of membrane tested. After a 10-min FM incubation with fresh blood, plasma concentrations of TXB2 and PGE2 were pronounced by polycarbonate when compared to Cuprophan and polyacrylonitrile. During 10 min of open loop perfusion of HFM, polymethylmethacrylate was the most active biomaterial, whereas the reactivity of Cuprophan was significantly lower. Among HFM, Hemophan was by far the less active. These results indicate that the release of eicosanoids represents a sensitive parameter of blood cells/membrane reactivity. Thus, the question arises as to whether or not the extracorporeal process of cyclooxygenase activity could contribute to the clinical side effects of chronical hemodialysis.

Significance of prostaglandin E2 in acute necrotising pancreatitis in rats.

Acute necrotising pancreatitis in rats was induced by injecting 5% sodium taurocholate into the pancreatic duct. Prostaglandin E2 (100 micrograms/kg subcutaneously twice) decreased the mortality rate from 100% to 60% (NS). When treatment with prostaglandin E2 was combined with simultaneous administration of either dazmegrel (UK 38,485, 50 mg/kg bodyweight) or Sibelium (Flunarizine R 14,950, 0.2 mg/kg body weight) a significant decrease in the mortality rate (p less than 0.05) was recorded. Dazmegrel is a selective thromboxane A2 synthetase inhibitor and prevents the formation of thromboxane A2. Flunarizine (a calcium entry blocker) decreases thromboxane A2 formation and also inhibits the effects of raised thromboxane A2 concentrations. As plasma thromboxane B2 (the stable metabolite of thromboxane A2) concentrations increase and the plasma prostaglandin E2 concentrations decrease in acute necrotising pancreatitis in rats, the results of the present study indicate that these prostaglandins play a role in the pathophysiology of the disease. It is suggested that restoration of the balance in prostanoid concentrations will have a beneficial effect on the course of acute necrotising pancreatitis.

Influence of dietary cis and trans fats on DMH-induced colon tumors, steroid excretion, and eicosanoid production in rats prone to colon cancer.

The effect of geometrical isomerism of dietary fats on colon tumorigenesis was studied in male and female rats of a strain prone to colon cancer (Wistar-Furth-Osaka). The rats were fed purified diets containing either partially hydrogenated corn oil (trans fat) or high-oleic safflower (cis fat) at the 5% level for one week and received a single oral dose of 1,2-dimethylhydrazine. The difference in the fatty acid composition of dietary fats was confined solely to the geometry of octadecenoate. An appropriate level of linoleic acid (2% of total energy) was supplied. After about 60 weeks, neither fat-type nor sex-dependent differences in the incidence of colon and small intestinal tumors was observed. The fecal excretion of neutral but not acidic steroids was higher in male rats fed the trans fat than in those fed the cis fat, but the composition remained almost unchanged. Aortic production of prostacyclin and the plasma concentration of thromboxane B2 were not influenced by dietary fats, although these were significantly higher in females, irregardless of the fat source. Thus, trans fat behaved much like the cis fat in various parameters, except for steroid excretion.

Inhibitory effect of acetylsalicylic acid on platelet function in patients with completed stroke or reversible ischemic neurologic deficit.

The purpose of our study was to investigate the effects of different doses of acetylsalicylic acid on platelet aggregation. Among inpatients of the National Taiwan University Hospital, 236 cases of completed stroke and seven cases of reversible ischemic neurologic deficit that were diagnosed by computed tomography of the brain and that had not ingested acetylsalicylic acid or acetylsalicylic acidlike drugs for greater than 2 weeks before admission were selected for this study. Thromboxane B2 and 6-keto-PGF1 alpha were measured by radioimmunoassay, threshold concentration of adenosine diphosphate was measured by Born's method, and circulating platelet aggregates were measured by the method of Wu and Hoak. Various single doses of acetylsalicylic acid (75, 300, or 600 mg) or 300 mg acetylsalicylic acid every 6 hours for four doses or one dose of 300 mg acetylsalicylic acid with 75 mg dipyridamole significantly suppressed the mean plasma thromboxane B2 concentrations and elevated the mean adenosine diphosphate threshold concentrations. Abnormal plasma thromboxane B2 concentrations, adenosine diphosphate threshold concentrations, or circulating platelet aggregate ratios were significantly normalized after administration of these regimens. The effects were not significantly different among treatment groups. Forty milligrams of acetylsalicylic acid seemed to have less platelet-inhibitory effect. A single dose of 75 mg acetylsalicylic acid significantly inhibited platelet hyperfunction and effectively corrected the abnormal plasma thromboxane B2 concentrations, adenosine diphosphate threshold concentrations, and circulating platelet aggregate ratios. Higher doses did not enhance the inhibitory effect. In addition, this single dose of acetylsalicylic acid did not significantly suppress plasma 6-keto-PGF1 alpha. We conclude that 75 mg acetylsalicylic acid per day is adequate to inhibit platelet hyperfunction.

Dietary supplementation with omega-3 polyunsaturated fatty acids in patients with stable coronary heart disease: Effects on indices of platelet and neutrophil function and exercise performance

It has been suggested that omega-3 polyunsaturated fatty acids (PUFAs) may alter the course of coronary artery disease by influencing platelet and neutrophil function, arachidonic acid metabolism, and circulating lipid concentrations. To examine this hypothesis, placebo or omega-3 PUFAs as Max-EPA (equivalent to 3.2 g of eicosapentaenoic acid and 2.2 g of docosahexaenoic acid daily) was administered to eight patients with stable coronary artery disease and positive exercise stress test results in a randomized, double-blind, crossover fashion over a 12-week period. With Max-EPA administration, platelet aggregation threshold to epinephrine was increased in only two patients, but neutrophil aggregation and chemotaxic functions decreased consistently (both p <- 0.01 compared with preceding placebo phase) in all eight. Serum and platelet-rich plasma thromboxane B2 concentrations decreased 40 percent and 28 percent, respectively (both p ≤0.05). Neutrophil leukotriene B4 formation decreased 23 percent (p ≤0.01) and synthesis of leukotriene B5 became apparent in all subjects. Serum triglyceride concentrations fell 52 percent (p <-0.05) without significant change in total cholesterol, high-density lipoprotein-cholesterol, or low-density lipoprotein-cholesterol concentrations. Systolic blood pressure and the double product (heart rate × systolic blood pressure) were lower (p <-0.05) at the end of the Max-EPA phase than in the preceding placebo phase. Heart rate, systolic blood pressure, and the double product were also lower (p <-0.05) at three as well as at six minutes of an exercise stress test, indicating a significant reduction in myocardial oxygen demand. Despite these alterations in platelet and neutrophil function, arachidonic acid metabolism, serum triglyceride concentrations, and myocardial oxygen demand, there were no significant changes in subjective parameters of coronary artery disease during the Max-EPA phase (angina frequency 3.7 versus 2.8 episodes per week, nitroglycerin consumption 3.0 versus 1.9 tablets per week, both p = NS). Similarly, exercise times to ST-segment depression (6.5 versus 4.1 minutes) and to onset of angina (5.4 versus 5.0 minutes) were not altered by administration of Max-EPA. Thus, short-term dietary supplementation with omega-3 PUFAs to patients with stable coronary artery disease does not appear to alter subjective or objective parameters of myocardial ischemia.