Platelet-activating factor increases vascular resistance in rat hindquarters by thromboxane A2

1995 ◽  
Vol 268 (5) ◽  
pp. H1954-H1958 ◽  
Author(s):  
A. Rizzo ◽  
A. E. Taylor ◽  
M. I. Townsley ◽  
P. Logsdon ◽  
P. L. Khimenko ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Vascular Resistance ◽  
Capillary Permeability ◽  
Platelet Activating Factor ◽  
Thromboxane A2 ◽  
Fold Increase ◽  
Paf Receptor ◽  
Txa2 Receptor ◽  
Txa2 Receptor Antagonist ◽  
Web 2086

The effects of platelet-activating factor (PAF) on vascular resistance and capillary permeability were studied in the isolated rat hindquarter. Six groups were studied (n = 30): control; PAF alone (1.4 microM); and PAF (1.4 microM) pretreated with ibuprofen (30 mg/kg), thromboxane A2 (TxA2)-receptor antagonist (BM-13505, 2 mg/kg), PAF-receptor antagonist (WEB-2086, 5 mg/kg), or dexamethasone (5 mg/kg). The vascular resistance was calculated, and the reflection coefficient (sigma) was determined as an index of capillary permeability. Exogenous PAF caused a threefold increase in vascular resistance peaking at 5 min and a 2.5-fold increase in capillary permeability. The increased vascular resistance caused by PAF alone was significantly attenuated by ibuprofen, BM-13505, and dexamethasone. The PAF-induced permeability was neither attenuated by ibuprofen nor BM-13505. However, both the increased vascular resistance and permeability were blocked and attenuated by WEB-2086 and dexamethasone, respectively. We conclude that TxA2 mediates the PAF-induced increased vascular resistance; however, the increased vascular permeability is independent of the formation of TxA2 in the isolated hindquarter.

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

1993 ◽  
Vol 264 (2) ◽  
pp. L175-L182 ◽  
Author(s):  
K. T. Kruse-Elliott ◽  
M. V. Pino ◽  
N. C. Olson
Keyword(s):  
Vascular Resistance ◽  
Interleukin 1 ◽  
Plasma Concentrations ◽  
Platelet Activating Factor ◽  
Physiological Role ◽  
Systemic Hypertension ◽  
Tnf Alpha ◽  
Pulmonary Hemodynamics ◽  
Paf Receptor ◽  
Web 2086

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.

scholarly journals Attenuation of amiodarone induced lung fibrosis and phospholipidosis in hamsters, by treatment with the platelet activating factor receptor antagonist, WEB 2086

1993 ◽  
Vol 2 (4) ◽  
pp. 279-285 ◽  
Author(s):  
S. N. Giri ◽  
D. M. Hyde ◽  
D. R. Haynam ◽  
M. Casias
Keyword(s):  
Receptor Antagonist ◽  
Group Treatment ◽  
Lung Fibrosis ◽  
Platelet Activating Factor ◽  
Intratracheal Instillation ◽  
Lung Toxicity ◽  
Class Iii ◽  
Paf Receptor ◽  
Histopathological Studies ◽  
Web 2086

Therapeutic use of amiodarone (AMD), a Class III antiarrhythmic drug is complicated by the development of lung fibrosis (LF) and phospholipidosis (PL). In the present study, the effectiveness of a PAF antagonist, WEB 2086, against AMD induced LF and PL has been tested in hamsters. The animals were randomly divided into four groups: (1) saline + H2O; (2) WEB + H2O; (3) saline + AMD; and (4) WEB + AMD. Saline or WEB (10 mg/kg i.p.) was given 2 days prior to intratracheal instillation of water or AMD (1.5 μmol/0.25 ml/100 g BW) and thereafter daily throughout the study. Twenty-eight days after intratracheal instillation, the animals were killed and the lungs processed for various assays. The amount of lung hydroxyproline, an index of LF, in saline + H2O, WEB + H2O, saline + AMD, and WEB + AMD groups were 959 ± 46, 1035 ± 51, 1605 ± 85 and 1374 ± 69 μg/lung, respectively. Total lung PL, an index of phospholipidosis, in the corresponding groups were 8.4 ± 0.4, 8.3 ± 0.3, 11.7 ± 0.3 and 9.9 μg/lung. Lung malondialdehyde, an index of lipid peroxidation and superoxide dismutase activity in saline + H2O WEB + H2O, saline + AMD, and WEB + AMD were 93.0 ± 4.3, 93.0 ± 2.7, 138.9 ± 6.0 and 109.0 ± 3.8 nmol/lung and 359.7 ± 13.9, 394.0 ± 22.8, 497.5 ± 19.7 and 425.5 ± 4.9 units/lung, respectively. Administration of AMD alone caused significant increases in all the above indexes of lung toxicity, and treatment with WEB 2086 minimized the AMD induced toxicity as reflected by significant decreases in these indexes. Histopathological studies revealed a marked reduction in the extent and severity of lung lesions in the WEB + AMD group compared with the saline + AMD group. Treatment with WEB 2086 also reduced the acute mortality from 35% in saline + AMD group to 22% in WEB + AMD group. It was concluded that PAF is involved in the AMD induced lung fibrosis and phospholipidosis and that the PAF receptor antagonist may, therefore, be potentially useful in reducing AMD induced lung toxicity.

Implication of thromboxane in frusemide diuresis in rats

1986 ◽  
Vol 71 (6) ◽  
pp. 647-650 ◽  
Author(s):  
T. S. Melki ◽  
M. L. Foegh ◽  
P. W. Ramwell
Keyword(s):  
Receptor Antagonist ◽  
Sodium Excretion ◽  
Loop Diuretic ◽  
Excretion Rate ◽  
Thromboxane A2 ◽  
Diuretic Effect ◽  
Antidiuretic Effect ◽  
Txa2 Receptor ◽  
Txa2 Receptor Antagonist ◽  
Synthase Inhibitor

1. Administration of the thromboxane A2 (TXA2) synthase inhibitor OKY 1581 to rats significantly increased the urine output elicited by the loop diuretic frusemide. 2. The administration of the TXA2 receptor antagonist SQ 29548 significantly increased the diuretic effect of frusemide. 3. Another TXA2 receptor antagonist L-640,035 increased significantly the diuretic effect of frusemide. 4. Both the sodium excretion rate and urine osmolar excretion rate were significantly increased in rats treated with the TXA2 synthase inhibitor OKY 1581 and frusemide. 5. The data suggest that TXA2 is released during frusemide-induced diuresis in rats, and the released TXA2 has an opposing antidiuretic effect.

Differential effects of WEB 2086 and SRI 63-441 on TNF-alpha-induced alterations in cardiopulmonary function

1992 ◽  
Vol 263 (3) ◽  
pp. H761-H770
Author(s):  
K. T. Kruse-Elliott ◽  
J. R. Dodam ◽  
L. W. Johnson ◽  
N. C. Olson
Keyword(s):  
Receptor Antagonist ◽  
Tumor Necrosis ◽  
Platelet Activating Factor ◽  
Tnf Alpha ◽  
Paf Receptor ◽  
Pulmonary Arterial ◽  
Necrosis Factor ◽  
Web 2086 ◽  
Paf Receptor Antagonist

We hypothesized that platelet-activating factor (PAF) and cyclooxygenase products might be important mediators of the cardiopulmonary effects induced by tumor necrosis factor (TNF-alpha) in anesthetized pigs. A 6-h infusion of human recombinant TNF-alpha caused hypoxemia, leukopenia, thrombocytopenia, decreased cardiac index (CI), increased pulmonary vascular resistance (PVR) and increased mean pulmonary arterial (Ppa) and intratracheal (Pt) pressures. Administration of the PAF receptor antagonist SRI 63–441 or indomethacin blocked the early (0.25–0.5 h) and attenuated the later increases in PVR and Ppa; indomethacin also attenuated the increase in Pt and hypoxemia associated with TNF-alpha infusion. WEB 2086 did not attenuate the TNF-alpha-induced alterations in CI, PVR, Pt, or PaO2. The in vivo specificity of SRI 63–441 and WEB 2086 was tested by infusing exogenous PAF, prostaglandin (PG) F2 alpha, U-46619 [thromboxane (Tx)A2 receptor mimetic], or arachidonic acid (AA) before and during administration of SRI 63–441 or WEB 2086. Both antagonists blocked the cardiopulmonary effects induced by exogenous PAF. SRI 63–441, but not WEB 2086, significantly attenuated the increased PVR caused by PGF2 alpha, U-46619, and AA. We conclude that SRI 63–441 is a less specific PAF receptor antagonist in vivo compared with WEB 2086 and that cyclooxygenase products, but not PAF, contribute significantly to the cardiopulmonary responses induced by exogenously infused TNF-alpha in pigs.

scholarly journals Human platelets secrete chemotactic activity for eosinophils

Blood ◽  
1993 ◽  
Vol 81 (1) ◽  
pp. 49-55 ◽  
Author(s):  
JA Burgers ◽  
RC Schweizer ◽  
L Koenderman ◽  
PL Bruijnzeel ◽  
JW Akkerman
Keyword(s):  
Receptor Antagonist ◽  
Adenosine Triphosphate ◽  
Platelet Activating Factor ◽  
Thromboxane A2 ◽  
Adenosine Diphosphate ◽  
Human Platelets ◽  
Chemotactic Activity ◽  
Platelet Factor ◽  
Storage Pool ◽  
Web 2086

Abstract Thrombin-stimulated platelets liberate factors that induce chemotaxis of eosinophils and raise their cytosolic Ca2+ content ([Ca2+]i). The sources of this activity are the dense- and alpha-granules because inhibition of prostaglandin endoperoxide/thromboxane A2 formation and the platelet-activating factor receptor-antagonist WEB 2086 have no effect. Platelets from patients with Storage-Pool Deficiency show about 60% of the normal chemotactic activity with little effect on [Ca2+]i, whereas completely degranulated platelets fail to affect eosinophils. In concentrations secreted by the platelets, adenosine diphosphate (ADP), and platelet factor 4 have no effect, whereas adenosine triphosphate (ATP) induces a strong chemotactic response and increases [Ca2+]i. However, apart from ATP other modulating factors must be involved as platelet releasates induce more chemotaxis than ATP alone. Thus, platelets secrete factors that activate eosinophils and may contribute to inflammatory and allergic processes.

scholarly journals Human platelets secrete chemotactic activity for eosinophils

Blood ◽  
1993 ◽  
Vol 81 (1) ◽  
pp. 49-55
Author(s):  
JA Burgers ◽  
RC Schweizer ◽  
L Koenderman ◽  
PL Bruijnzeel ◽  
JW Akkerman
Keyword(s):  
Receptor Antagonist ◽  
Adenosine Triphosphate ◽  
Platelet Activating Factor ◽  
Thromboxane A2 ◽  
Adenosine Diphosphate ◽  
Human Platelets ◽  
Chemotactic Activity ◽  
Platelet Factor ◽  
Storage Pool ◽  
Web 2086

Thrombin-stimulated platelets liberate factors that induce chemotaxis of eosinophils and raise their cytosolic Ca2+ content ([Ca2+]i). The sources of this activity are the dense- and alpha-granules because inhibition of prostaglandin endoperoxide/thromboxane A2 formation and the platelet-activating factor receptor-antagonist WEB 2086 have no effect. Platelets from patients with Storage-Pool Deficiency show about 60% of the normal chemotactic activity with little effect on [Ca2+]i, whereas completely degranulated platelets fail to affect eosinophils. In concentrations secreted by the platelets, adenosine diphosphate (ADP), and platelet factor 4 have no effect, whereas adenosine triphosphate (ATP) induces a strong chemotactic response and increases [Ca2+]i. However, apart from ATP other modulating factors must be involved as platelet releasates induce more chemotaxis than ATP alone. Thus, platelets secrete factors that activate eosinophils and may contribute to inflammatory and allergic processes.

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