26 research outputs found
The biological activity of acetylated sphingosylphosphorylcholine derivatives
Taking into account their stereochemical similarity with
1-O-alkyl-2-acetyl-sn-glycerol-3-phosphorylcholine (PAF), which is known
to exhibit a diverse spectrum of biological actions, including platelet
aggregating and glycogenolytic activity, the acetylated derivatives of
sphingosylphosphorylcholine and sphingomyelin were synthesized and
tested for their ability to promote washed rabbit platelet aggregation
and glycogenolysis in Tetrahymena pyriformis cells. Sphingomyelin (SPM)
and sphingosylphosphorylcholine (SPC) were subjected to acetylation,
following chromatographic purification and physicochemical
characterization. The synthesized compounds N-acetyl, O-acetyl SPC (NAc,
OAc SPC), N-acetyl SPC (NAc SPC) and O-acetyl SPM (OAc, SPM) were tested
far their biological activity in the washed rabbit platelets and washed
Tetrahymena pyriformis cell systems. These derivatives induced [H-3]
serotonin and ATP release and a monophasic aggregation of washed rabbit
platelets in the concentration range 10(-8)-10(-6) M, However, authentic
PAF-induced washed rabbit platelet aggregation was inhibited at higher
concentrations of the acetylated sphingophospholipid compounds (> 10(-6)
M) and by the PAF-specific receptor(s) antagonists kadsurenone and
triazolam. Platelet desensitization and crossed desensitization
experiments with authentic PAF and the acetylated sphingophospholipids,
suggested interaction with the same receptor(s) as PAF and different
from the ADP or thrombin receptor. The involvement of calmodulin and
protein kinase C in the biological activity of the prepared analogues
was also demonstrated. Besides their action on rabbit platelets, the
PAF-like activity of the acetylated sphingophospholipids was also
demonstrated in a platelet-independent system, by showing that they
stimulate glycogenolysis in washed Tetrahymena pyriformis cells. These
observations indicate that a new class of compounds with PAF-like
activity were synthesized, but their role in the cellular metabolism
remains to be shown. The existence of acetylated sphingophospholipids
with PAF-like activity has so far been reported only in Urtica dioica
MESANGIAL CELL IMMUNE INJURY - EFFECTS OF THROMBOXANE RECEPTOR ANTAGONISM
We assessed the renal hemodynamic changes occurring acutely after glomerular mesangial cell immune injury and the effects of thromboxane receptor antagonism on these changes. A single intravenous proteinuric dose of a monoclonal antibody raised against the rat thymocyte antigen Thy 1.1 (ER4), which is also expressed in rat mesangial cells, induced acute decrements in glomerular filtration rate and in renal blood flow in male Munich-Wistar rats. One hour after administration of 4 to 6 mg/kg of ER4 antibody, glomerular filtration rate and renal blood flow decreased by 80 and 36%, respectively. These decrements were associated with significant increments in basal thromboxane B2 synthesis in isolated glomeruli and no changes in glomerular prostaglandin E2 synthesis. Pretreatment of animals with the thromboxane receptor antagonist SQ-29, 548 (2 mg/kg) significantly ameliorated decrements in glomerular filtration rate and renal blood flow. Pretreatment with a structurally dissimilar thromboxane receptor antagonist, L-670,596 (3 mg/kg) had no effect. Both antagonists at the doses employed abolished the decrements in renal blood flow induced by systemic administration of the thromboxane mimetic U-46619. Whereas the SQ-29,548 antagonist had no effect on glomerular leukotriene B4 and 12-hydroxyeicosate-traenoic acid synthesis, the L-670,596 thromboxane receptor antagonist significantly inhibited glomerular synthesis of these eicosanoids in immunologically injured glomeruli. These observations indicate that in mesangial cell immune injury the protective effect of thromboxane A2 receptor antagonism on glomerular filtration rate and renal blood flow is not solely due to inhibition of the vasoconstrictor effects of thromboxane A2. An effect on the synthesis of arachidonate lipoxygenation products may also play a role