Glomerular responses to platelet-activating factor in the rat: role of thromboxane A2

1989 ◽  
Vol 256 (1) ◽  
pp. F35-F43 ◽  
Author(s):  
K. F. Badr ◽  
D. K. DeBoer ◽  
K. Takahashi ◽  
R. C. Harris ◽  
A. Fogo ◽  
...  
Keyword(s):  
Flow Rate ◽  
Plasma Flow ◽  
Renal Plasma Flow ◽  
Platelet Activating Factor ◽  
Thromboxane A2 ◽  
Wistar Rat ◽  
Cyclooxygenase Inhibitors ◽  
Dependent Manner ◽  
Glomerular Injury ◽  
Dose Dependent

In view of its role as a pro-inflammatory mediator in glomerular injury, we investigated the renal cortical microcirculatory responses to the intrarenal arterial administration of platelet-activating factor (PAF) in the anesthetized euvolemic Munich-Wistar rat. Close arterial administration of PAF led to dose-dependent reductions in renal plasma flow rate (RPF), glomerular filtration rate (GFR), and filtration fraction (FF), in the absence of hypotension or hemoconcentration. Single-nephron (SN) plasma flow rate (QA), SNGFR and SNFF also fell [126 +/- 7 to 101 +/- 6 nl/min (P less than 0.005), 40.6 +/- 2.1 to 21.5 +/- 2.5 nl/min (P less than 0.005), and 0.33 +/- 0.03 to 0.21 +/- 0.03 (P less than 0.025)]. PAF increased pre- and postglomerular arteriolar resistances [2.32 +/- 0.14 to 2.73 +/- 0.19 (P less than 0.005) and 1.32 +/- 0.13 to 1.45 +/- 0.10(10)dyn.s.cm-5 (P less than 0.05)]. PAF infusion also led to a dramatic reduction in the mean value for the glomerular capillary ultrafiltration coefficient, Kf [0.058 +/- 0.012 to 0.020 +/- 0.003 nl.s-1.mmHg (P less than 0.025)]. PAF-induced changes in renal hemodynamics were abolished in the presence of the cyclooxygenase inhibitors, indomethacin and ibuprofen. When administered concomitantly with a thromboxane A2 (TxA2) receptor antagonist, PAF led to significant increases in RPF and GFR. In isolated glomeruli, PAF stimulated the biosynthesis of TxB2 in a dose-dependent manner. Thus PAF depresses rat glomerular function by inducing contraction of arteriolar and mesangial smooth muscle. These effects are likely mediated via the secondary release of TxA2.

Inhibition of platelet-activating factor induced renal hemodynamic and tubular dysfunctions with L-655,240, a new thromboxane–prostaglandin endoperoxide antagonist

1989 ◽  
Vol 67 (4) ◽  
pp. 304-308 ◽  
Author(s):  
R. L. Hébert ◽  
P. Sirois ◽  
G. E. Plante
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Glomerular Filtration ◽  
Plasma Flow ◽  
Filtration Rate ◽  
Renal Plasma Flow ◽  
Platelet Activating Factor ◽  
Urinary Sodium ◽  
Dependent Manner ◽  
Prostaglandin Endoperoxide

The continuous infusion or bolus injection of the platelet-activating factor (PAF) is associated with profound hypotension, marked reductions of renal plasma flow, glomerular filtration, and urinary sodium excretion. All these effects are inhibited by blocking PAF receptors. To examine further the potential mediators of PAF on renal function, we utilized L-655,240 (6 mg/kg, intravenously), a thromboxane–prostaglandin endoperoxide antagonist, to study the systemic and renal response to PAF (0.8 μg/kg, intravenously) in the anesthetized dog, using clearance methodology. PAF decreased blood pressure from 115 ± 7 to 54 ± 4 mmHg (1 mmHg = 133.3 Pa), renal plasma flow from 105 ± 6 to 74 ± 56 mL/min, and glomerular filtration from 43 ± 3 to 32 ± 1 mL/min. PAF also reduced urine volume from 1.1 ± 0.2 to 0.4 ± 0.1 mL/min, and urinary sodium from 158 ± 7 to 86 ± 7 μequiv./min. L-655,240 alone had no significant effect on blood pressure, renal plasma flow, and filtration rate, at any dose. However, the 6-mg/kg dose resulted in a slight elevation of diuresis, from 1.1 ± 0.2 to 1.9 ± 0.1 mL/min, and urinary sodium, from 134 ± 13 to 212 ± 19 μequiv./min. All doses of L-655,240 blocked the effect of PAF on blood pressure. However, the two lower doses of this antagonist (1 and 3 mg/kg) failed to prevent the PAF-induced fall of renal plasma flow and filtration rate, and attenuated the effect on urinary sodium in a dose-dependent manner. These results indicate that the renal vasoconstriction and antinatriuretic effects of PAF are probably mediated by thromboxane A2 and (or) prostaglandin endoperoxides in the dog. L-655,240 represents therefore a potent inhibitor of PAF-induced renal dysfunctions, and may be of significant interest to explore further the physiology and pathophysiology of PAF.Key words: platelet-activating factor, renal function, lipid mediators, thromboxane antagonist, shock.

scholarly journals Effects of esculentoside A on turnour necrosis factor production by mice peritoneal macrophages

1992 ◽  
Vol 1 (6) ◽  
pp. 375-377 ◽  
Author(s):  
Fang Jun ◽  
Zheng Qin Yue ◽  
Wang Hong Bin ◽  
Ju Dian Wen ◽  
Yi Yang Hua
Keyword(s):  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Inflammatory Mediator ◽  
Platelet Activating Factor ◽  
Peritoneal Macrophages ◽  
Dependent Manner ◽  
Anti Inflammatory ◽  
Dose Dependent ◽  
Necrosis Factor ◽  
Inflammatory Effect

Esculentoside A (EsA) is a saponin isolated from the roots of Phytolacca esculenta. Previous experiments showed that it had strong anti-inflammatory effects. Tumour necrosis factor (TNF) is an important inflammatory mediator. In order to study the mechanism of the anti-inflammatory effect of EsA, it was determined whether TNF production from macrophages was altered by EsA under lipopolysaccharide (LPS) stimulated conditions. EsA was found to decrease both extracellular and cell associated TNF production in a dose dependent manner at concentrations higher than 1 μmol/l EsA. Previous studies have showed that EsA reduced the releasing of platelet activating factor (PAF) from rat macrophages. The reducing effects of EsA on the release of TNF and PAF may explain its anti-inflammatory effect.

Direct effects of endothelin in the rat kidney

1990 ◽  
Vol 258 (2) ◽  
pp. F397-F402 ◽  
Author(s):  
T. Katoh ◽  
H. Chang ◽  
S. Uchida ◽  
T. Okuda ◽  
K. Kurokawa
Keyword(s):  
Renal Artery ◽  
Rat Kidney ◽  
Renal Plasma Flow ◽  
Urine Volume ◽  
Fractional Excretion ◽  
Left Renal Artery ◽  
Dependent Manner ◽  
Direct Effects ◽  
Dose Dependent

In the present study, we tested the direct effects of endothelin (ET) on rat kidney in vivo. ET was infused into the left renal artery of anesthetized rats at a rate of 0.5, 5, 20, or 40 pmol/h. ET reduced ipsilateral urine volume (V), clearance of inulin (CIN), and clearance of p-aminohippuric acid (CPAH) in a dose-dependent manner. Thus ET at 20 pmol/h did not change V but decreased renal plasma flow (RPF) and glomerular filtration rate (GFR) by 27.6 +/- 14.3 and 30.8 +/- 10.4%, respectively, in the ipsilateral kidney. ET at 0.5 pmol/h was without effect and at 5 pmol/h had only minor effects on CIN and CPAH of ipsilateral kidney. At 40 pmol/h, ET reduced ipsilateral V, GFR, and RPF by 52.3 +/- 21.4, 58.4 +/- 14.5, and 72.5 +/- 10.6%, respectively. Filtration fraction and fractional excretion of Na remained unchanged during ET infusion. ET, 40 pmol/h, infused into the renal artery together with atrial natriuretic peptide (ANP) at a rate of 12 pmol/h reduced the ipsilateral V, GFR, and RPF by 33.2 +/- 6.3, 26.1 +/- 6.0, and 27.2 +/- 7.1%, respectively, decrements less than those with ET alone. When a calcium-channel blocker nicardipine was infused at a rate of 2.5 micrograms/h into the renal artery together with ET, 20 pmol/h, there was little change in the ipsilateral V, RPF, and GFR; ET, 40 pmol/h, with nicardipine did not change V and decreased GFR and RPF by 25.9 +/- 5.6 and 23.1 +/- 10.8%, respectively, decrements less than those without nicardipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Unsaturated fatty acids and cyclooxygenase inhibitors: effects on pial arterioles

1982 ◽  
Vol 242 (4) ◽  
pp. H629-H632
Author(s):  
W. I. Rosenblum
Keyword(s):  
Fatty Acids ◽  
Unsaturated Fatty Acids ◽  
Eicosatrienoic Acid ◽  
Inhibitory Effect ◽  
Cyclooxygenase Inhibitors ◽  
Dependent Manner ◽  
Double Bonds ◽  
Pial Arterioles ◽  
Dose Dependent

Cerebral surface arterioles of the mouse were constricted in a dose-dependent manner by three different unsaturated fatty acids each with one of its double bonds in the n-6 position: arachidonate, linoleic, and 11,14,17-eicosatrienoic acid (ETA) in doses of 10-200 micrograms/ml. The constriction was transient, and its magnitude was significantly reduced by pretreatment of the mice with intraperitoneal injections of indomethacin (5 mg/kg), aspirin (100 mg/kg), or sodium 2-amino-3-(4 chlorobenzyl)-phenylacetate (AHR-6293, 100 mg/kg). The inhibitory effect of these cyclooxygenase inhibitors suggests that this enzyme is involved in the response to these fatty acids and is in keeping with suggestions in the literature stating that such unsaturated fatty acids may interact with cyclooxygenase even when they cannot form prostaglandin (PG) endoperoxides, The PG endoperoxide formed by arachidonate or the analogous hydroperoxy compounds formed by linoleic or 11,14,17 ETA, may then alter cerebrovascular tone by production of reactive, O2-containing species. Alternate explanations for the data are also proposed.

Platelet-activating factor increases platelet-dependent glycoconjugate secretion from tracheal submucosal gland

1989 ◽  
Vol 257 (6) ◽  
pp. L373-L378 ◽  
Author(s):  
T. Sasaki ◽  
S. Shimura ◽  
K. Ikeda ◽  
H. Sasaki ◽  
T. Takishima
Keyword(s):  
Platelet Activating Factor ◽  
Thromboxane A2 ◽  
Submucosal Gland ◽  
Thromboxane Receptor ◽  
Significant Stimulation ◽  
Submucosal Glands ◽  
Dose Dependent Fashion ◽  
Thromboxane Receptor Antagonist ◽  
Dose Dependent ◽  
Thromboxane A2 Analogue

Using isolated glands from feline trachea, we examined the effect of platelet-activating factor (PAF) on radiolabeled glycoconjugate release and glandular contraction by measuring induced tension in the absence or presence of platelets. PAF alone did not produce any significant glandular contraction nor any significant change in glycoconjugate release from isolated glands. In the presence of purified platelets containing no plasma, PAF (10(-8) to 10(-5) M) produced significant glycoconjugate secretion in a dose-dependent fashion, but it produced no significant glandular contraction. PAF-evoked glycoconjugate secretion was time dependent, reaching a peak response of 277% of control 15-30 min after the exposure of isolated glands to 10(-5) M PAF in the presence of platelets and returning to 135% of controls at 2 h. Platelets alone did not produce any significant stimulation in glycoconjugate release. CV-3988, a known PAF antagonist, inhibited the secretory response to PAF. Methysergide, a known antagonist to receptors for 5-hydroxytryptamine, did not alter PAF-evoked glycoconjugate secretion. Both indomethacin and SQ 29,548, a thromboxane receptor antagonist, abolished the PAF-evoked glycoconjugate secretion from isolated submucosal glands. Epithiomethanothromboxane A2, a stable thromboxane A2 analogue, produced a significant increase in glycoconjugate secretion in a dose-dependent fashion. These findings indicate that PAF increases glycoconjugate release in the presence of platelets and that the increase is dependent on some aspect of platelet function, namely thromboxane generation.

Characterization of the role of CaMKI-like kinase (CKLiK) in human granulocyte function

Blood ◽  
2005 ◽  
Vol 106 (3) ◽  
pp. 1076-1083 ◽  
Author(s):  
Sandra Verploegen ◽  
Laurien Ulfman ◽  
Hanneke W. M. van Deutekom ◽  
Corneli van Aalst ◽  
Henk Honing ◽  
...  
Keyword(s):  
Respiratory Burst ◽  
Critical Role ◽  
Neutrophil Migration ◽  
Platelet Activating Factor ◽  
Dependent Manner ◽  
Functional Responses ◽  
Effector Functions ◽  
C Terminus ◽  
Human Granulocytes ◽  
Dose Dependent

AbstractActivation of granulocyte effector functions, such as induction of the respiratory burst and migration, are regulated by a variety of relatively ill-defined signaling pathways. Recently, we identified a novel Ca2+/calmodulin-dependent kinase I-like kinase, CKLiK, which exhibits restricted mRNA expression to human granulocytes. Using a novel antibody generated against the C-terminus of CKLiK, CKLiK was detected in CD34+-derived neutrophils and eosinophils, as well as in mature peripheral blood granulocytes. Activation of human granulocytes by N-formyl-methionyl-leucyl-phenylalanine (fMLP) and platelet-activating factor (PAF), but not the phorbol ester PMA (phorbol 12-myristate-13-acetate), resulted in induction of CKLiK activity, in parallel with a rise of intracellular Ca2+ [Ca2+]i. To study the functionality of CKLiK in human granulocytes, a cell-permeable CKLiK peptide inhibitor (CKLiK297-321) was generated which was able to inhibit kinase activity in a dose-dependent manner. The effect of this peptide was studied on specific granulocyte effector functions such as phagocytosis, respiratory burst, migration, and adhesion. Phagocytosis of Aspergillus fumigatus particles was reduced in the presence of CKLiK297-321 and fMLP-induced reactive oxygen species (ROS) production was potently inhibited by CKLiK297-321 in a dose-dependent manner. Furthermore, fMLP-induced neutrophil migration on albumin-coated surfaces was perturbed, as well as β2-integrin-mediated adhesion. These findings suggest a critical role for CKLiK in modulating chemoattractant-induced functional responses in human granulocytes.

Effects of Platelet-Activating Factor on Leukocyte Adhesion in the Guinea Pig Aorta

1985 ◽  
Vol 43 ◽  
pp. 684-685
Author(s):  
Mary Kay Melden ◽  
Ronald G. Van Valen ◽  
Robert N. Saunders ◽  
Dean A. Handley
Keyword(s):  
Blood Vessel ◽  
Guinea Pig ◽  
Intravenous Injection ◽  
Leukocyte Adhesion ◽  
Platelet Activating Factor ◽  
Dependent Manner ◽  
Cardiac Effects ◽  
Small Vessels ◽  
Dose Dependent

Platelet-activating factor (PAF) is a potent mediator of immune anaphylaxis. In a dose-dependent manner, PAF can induce such effects as thrombocytopenia, neutropenia, hypotension, bronchoconstriction, hemoconcentration, and negative inotropic cardiac effects. By intradermal or intravenous injection, PAF has been shown to induce blood vessel hyperpermeability resulting in extravasation of plasma, leukocyte adhesion and subsequent diapedesis. However, most studies of endothelial-leukocyte interactions have been limited to small vessels. We have examined the effects of PAF on endothelial structure and leukocyte involvement in the guinea pig aorta.

Effects of interleukin 5-induced pulmonary eosinophilia on airway reactivity in the guinea pig

1996 ◽  
Vol 270 (3) ◽  
pp. L368-L375 ◽  
Author(s):  
C. M. Lilly ◽  
R. W. Chapman ◽  
S. J. Sehring ◽  
P. J. Mauser ◽  
R. W. Egan ◽  
...  
Keyword(s):  
Substance P ◽  
Guinea Pig ◽  
Guinea Pigs ◽  
Airway Hyperresponsiveness ◽  
Histological Grade ◽  
Platelet Activating Factor ◽  
Inflammatory Cells ◽  
Dependent Manner ◽  
Interleukin 5 ◽  
Dose Dependent

Administration of interleukin 5 (IL-5) to guinea pigs by tracheal injection was associated with increased recovery of eosinophils and neutrophils from bronchoalveolar lavage (BAL) fluid. The number of eosinophils recovered from BAL fluid increased in a dose-dependent manner from 9 +/- 2 X 10(3)/ml to a plateau of 143 +/- 29 X 10(3)/ml after the administration of recombinant human IL-5 (rhIL-5). Tracheal administration of recombinant guinea pig IL-5 (gpIL-5) also increased eosinophil recovery but was less potent than rhIL-5. Histological analysis confirmed the presence of inflammatory cells in the lung; there were higher grades of inflammation in airway than in parenchymal tissue after gpIL-5 administration. In addition, the histological grade of airway inflammation was greater 24 and 72 h after gpIL-5 administration than it was 6 days after administration. Airway hyperresponsiveness is reported to occur in guinea pigs exposed to rhIL-5 by intraperitoneal cellular production. It is surprising that airway infiltration with eosinophils induced by the topical application of IL-5 was not associated with hyperresponsiveness to substance P, histamine, or platelet-activating factor in intact animals or to methacholine in tracheally perfused lungs. Furthermore, the microvascular leakage induced by substance P was not altered by rhIL-5 administration. These findings indicate that the presence of eosinophils alone is not sufficient for the expression of airway hyperresponsiveness. Our ability to separate eosinophil recruitment and retention in the tissues from airway hyperresponsiveness indicates that these two processes are distinct and that the presence of eosinophils in lung tissue, by itself, is not sufficient to alter airway contractile responses.

15-HETE-substituted diglycerides selectively regulate PKC isotypes in human tracheal epithelial cells

1999 ◽  
Vol 277 (3) ◽  
pp. L457-L464 ◽  
Author(s):  
Stephen E. Alpert ◽  
Ronald W. Walenga ◽  
Atashi Mandal ◽  
Nicole Bourbon ◽  
Mark Kester
Keyword(s):  
High Performance ◽  
Neutral Lipids ◽  
Platelet Activating Factor ◽  
Dependent Manner ◽  
Western Blots ◽  
Tracheal Epithelial Cells ◽  
Tracheal Epithelial ◽  
Layer Chromatography ◽  
Dose Dependent

Human tracheal epithelial (TE) cells selectively incorporate their major lipoxygenase product, 15-hydroxyeicosatetraenoic acid (15-HETE), into the sn-2 position of phosphatidylinositol (PI) (S. E. Alpert and R. W. Walenga. Am. J. Respir. Cell Mol. Biol. 8: 273–281, 1993). Here we investigated whether 15-HETE-PI is a substrate for receptor-mediated generation of 15-HETE-substituted diglycerides (DGs) and whether these 15-HETE-DGs directly activate and/or alter conventional diacylglycerol-induced activation of protein kinase C (PKC) isotypes in these cells. Primary human TE monolayers incubated with 0.5 μM 15-[3H]-HETE or 15-[14C]HETE for 1–2 h were stimulated with 1 nM to 1 μM platelet-activating factor (PAF) for 30 s to 6 min, and the radiolabel in the medium, cellular phospholipids, and neutral lipids was assessed by high-performance liquid and thin-layer chromatography. PAF mobilized radiolabel from PI in a dose-dependent manner (22 ± 5% decrease after 1 μM PAF) without a concomitant release of free intra- or extracellular 15-HETE. 14C-labeled DGs were present in unstimulated TE monolayers incubated with 15-[14C]HETE, and the major 14C band, identified as sn-1,2-15-[14C]HETE-DG, increased transiently in response to PAF. Western blots of freshly isolated and cultured human TE cells revealed PKC isotypes α, βI, βII, δ, ε, and ζ. In vitro, cell-generated sn-1,2-15-[14C]HETE-DG selectively activated immunoprecipitated PKC-α and inhibited diacylglycerol-induced activation of PKC-α, -δ, -βI, and -βII. Our observations indicate that 15-HETE-DGs can modulate the activity of PKC isotypes in human TE cells and suggest an intracellular autocrine role for 15-HETE in human airway epithelia.

scholarly journals Biosynthesis of platelet-activating factor (PAF) in human polymorphonuclear leucocytes. The role of lyso-PAF disposal and free arachidonic acid

1990 ◽  
Vol 268 (1) ◽  
pp. 91-98 ◽  
Author(s):  
M D C Garcia ◽  
S Fernandez-Gallardo ◽  
M A Gijon ◽  
C Garcia ◽  
M L Nieto ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Arachidonic Acid ◽  
Phospholipase A2 ◽  
Platelet Activating Factor ◽  
Inhibitory Effect ◽  
Eicosatetraenoic Acid ◽  
Polymorphonuclear Leucocytes ◽  
Maximal Effect ◽  
Dependent Manner ◽  
Dose Dependent

Theophylline and 1-methyl-3-isobutylxanthine (MIX), compounds that block eicosanoid formation and modulate phospholipase A2 activity, inhibited in a dose-dependent manner the formation of both leukotriene B4 (LTB4) and platelet-activating factor (PAF) by human polymorphonuclear leucocytes (PMN) in response to ionophore A23187. Theophylline and MIX lacked any inhibitory effect on acetyl-CoA: lyso-PAF acetyltransferase activity, which is the rate-limiting step for PAF biosynthesis in PMN. The effect of theophylline and MIX on PAF formation could be reversed by incubating the cells in the presence of 1-10 microM exogenous lyso-PAF. Incubation of PMN homogenates in the presence of unsaturated non-esterified fatty acids resulted in dose-dependent inhibition of the acetyltransferase. This effect was linked to the presence of a free carboxyl group, since both arachidonic acid methyl ester and palmitoyl-arachidonoyl phosphatidylcholine lacked inhibitory activity. This inhibitory effect was also dependent on the number of double bonds, since arachidonic acid (C20:4) and eicosapentaenoic acid (C20:5) displayed maximal effect. Kinetic analysis showed that the effect of arachidonic acid was consistent with competitive inhibition, with a Ki value of about 19 microM. Oxidative metabolites of arachidonic acid showed a lesser inhibitory effect with the following order of potency: arachidonic acid greater than 15-HETE (15-hydroxy-6,8,11,14-eicosatetraenoic acid) greater than LTB4 greater than 5-HETE (5-hydroxy-6,8,11,14-eicosatetraenoic acid) greater than lipoxin A4. Examination of enzymes involved in CoA-dependent acylation revealed a low activity of both arachidonoyl-CoA synthetase and arachidonoyl-CoA: lyso-PAF arachidonoyltransferase. These data indicate a strong influence on PAF biosynthesis of the products of the phospholipase A2 reaction, with lyso-PAF disposal being a critical event for PAF formation, and unsaturated fatty acids acting as feed-back inhibitors. The conversion of arachidonic acid via oxidative metabolism into less active inhibitors of acetyl-CoA:lyso-PAF acetyltransferase seems to be an additional mechanism of modulation of this enzyme activity, linked to the function of lipoxygenases. Finally, the enzyme activities involved in arachidonoyl-CoA-dependent acylation of lyso-PAF show a low efficiency in capturing arachidonic acid.

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