PubMed Health⌕ Search

Biomedical subjects

G Remuzzi

Publications and source records attributed to G Remuzzi.

At least 109 records · Page 6Linked to original sources
PubMed1989

Differential inhibition by aspirin of platelet thromboxane and renal prostaglandins in the rat.

Aspirin (ASA) beside inhibiting platelet thromboxane A2 (TxA2) can suppress the formation of renal prostacyclin (PGI2) and prostaglandin E2 (PGE2) which play a crucial role in the control of renal hemodynamics. Previous studies based on urinary PG measurements have suggested that p.o. ASA can spare renal cyclooxygenase. We wanted to establish by direct measurement whether p.o. ASA has a renal sparing effect and to establish to which extent changes in renal cyclooxygenase activity can be predicted measuring urinary excretion of 6-keto-PGF1 alpha and PGE2. Our results showed that in normal rats 10 mg/kg of ASA given p.o. partially inhibits platelet TxA2 formation (measured as serum TxB2) and does not inhibit glomerular and medullary PGI2 and PGE2 synthesis. Higher doses of ASA (30-200 mg/kg) effectively and completely inhibit platelet TxA2 independently if given p.o. or i.v., and also inhibit glomerular and medullary PG synthesis. The kinetics of the effect of ASA on platelet vs. renal cyclooxygenase is different: the inhibition being irreversible in platelets, but rapidly reversible in glomeruli and medulla. Six hours after the administration of 10 and 30 mg/kg i.v. and 30 mg/kg p.o., kidney cyclooxygenase activity recovers completely. This transient inhibition of renal cyclooxygenase is not reflected by urinary excretion of 6-keto-PGF1 alpha and PGE2 (6- and 24-hr collection periods). In conclusion our present results indicate that doses of ASA enough to inhibit platelet TxA2, transiently inhibit glomerular and medullary PGI2 and PGE2. Although the inhibitory effect on platelets is long lasting, the effect on renal cyclooxygenase is transient and rapidly reversible.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Bleeding disorders in uremia: pathophysiology and treatment.

Renal insufficiency is associated with a bleeding tendency. Hemorrhagic manifestations are usually mild (i.e., ecchymoses or purpura) but can be severe in occasional patients who may have gastrointestinal tract or intracranial bleeding. Modern techniques for the management of uremia have definitely reduced the incidence of severe bleeding episodes in patients with renal failure, but hemorrhages still represent a major clinical problem, particularly for patients undergoing surgery or invasive procedures. Although the pathogenesis of uremic bleeding has not been completely elucidated, in the past 10 years a number of studies have contributed substantially to our knowledge of the cause of uremic bleeding tendency and have indicated new therapeutic strategies. The present review will focus mainly on modern concepts of the cause of uremic bleeding and will critically analyze the various therapeutic approaches.

Aspirin↗
PubMed1989

Selective inhibition of platelet thromboxane generation with low-dose aspirin does not protect rats with reduced renal mass from the development of progressive disease.

Rats with extensive renal mass reduction develop hypertension, proteinuria and progressive glomerulosclerosis. Previous studies have demonstrated that these changes are associated with an increased urinary excretion of thromboxane compared with normal rats and that the administration of a thromboxane synthetase inhibitor prevents glomerulosclerosis and progressive renal function deterioration. On this basis it has been speculated that the thromboxane synthetase inhibitor, by inhibiting platelet thromboxane, reduces platelet aggregation and prevents the generation of substances that can influence glomerular functional properties. Because the thromboxane synthetase inhibitor also inhibits thromboxane synthesis by resident glomerular cells and lowers blood pressure in these animals, the question of whether platelet thromboxane is indeed the factor implicated in the development of renal disease after renal ablation remains unanswered. To address this issue the authors administered at different time intervals from the surgical procedure a low-dose of oral aspirin (ASA) to rats with remnant kidney. This approach resulted in selective inhibition of platelet cyclooxygenase leading to an almost complete prevention of platelet thromboxane generation. Low-dose ASA spared renal cyclooxygenase as documented by a lack of significant inhibition of glomerular and urinary 6-keto-PGF1 alpha and did not lower blood pressure. Renal function studies showed that low-dose ASA, despite inhibiting platelet aggregation, had no effect on proteinuria and progressive renal insufficiency irrespectively if administered late (ie, 80 days after surgery) and given daily for all the observation period (ie, 20 days) or earlier in the course of the disease (ie, 40 and 10 days after surgery). Histologic data showed that the degree of glomerulosclerosis and tubulo-interstitial damage was not significantly different in rats with reduction of renal mass alone compared with rats with remnant kidney given low-dose ASA. In conclusion, the present findings indicate that inhibition of platelet aggregation and thromboxane formation does not prevent the progressive glomerulosclerosis that develops in rats with surgical reduction of renal mass. It is suggested that the beneficial results obtained previously in the same model by the use of a thromboxane synthesis inhibitor must be attributed either to an effect on resident glomerular cell thromboxane synthesis or to lowering systemic blood pressure.

Animals↗
PubMed1989

Renal handling of aspirin in the rat.

Aspirin (ASA), in addition to blocking platelet cyclooxygenase, thus preventing thromboxane A2 formation, can also block renal cyclooxygenase thus inhibiting the renal synthesis of vasodilatory prostaglandins (PGs) which can induce renal function deterioration. The purpose of the present study was to clarify the pharmacological basis of the inhibitory effect of ASA on renal cell cyclooxygenase in the rat. ASA was given to rats either i.v. or p.o. at doses ranging from 10 to 200 mg/kg. After both i.v. and p.o. administration ASA was rapidly detected in plasma as intact molecule. The kinetics were of a dose-dependent type with a disproportionate increase in plasma level increasing the dose. Plasma salicylic acid (SA) concentrations peaked after ASA with a precursor product relationship. ASA levels in kidney homogenates were also determined after i.v. and p.o. ASA. Whereas after i.v. administration ASA was detected in the kidney as intact molecule, no ASA was detected in the kidney after p.o. administration. SA was measurable in the kidney after both i.v. and p.o. ASA with a time course which paralleled the plasma concentrations. Results of isolated kidneys perfused with a medium containing ASA and of kidney homogenates exposed to ASA "in vitro" indicate that ASA is rapidly converted to SA by kidney tissue enzymes. After ASA hydrolysis SA accumulates in the kidney and may protect renal cyclooxygenase from the inhibitor effect of ASA.

Animals↗
PubMed1989

Enhanced glomerular thromboxane A2 mediates some pathophysiologic effect of platelet-activating factor in rabbit nephrotoxic nephritis: evidence from biochemical measurements and inhibitor trials.

Previous studies have shown that platelet-activating factor (PAF) receptor blocking has a protective effect on rabbit nephrotoxic nephritis (NTN). We examined whether arachidonic acid (AA) metabolism is altered in NTN and whether a PAF receptor antagonist has any influence on such changes. Rabbits injected with anti-glomerular basement membrane antiserum in the heterologous phase had a markedly increased glomerular thromboxane B2 (TxB2) production level, whereas no changes have been detected in glomerular 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and prostaglandin E2 (PGE2). During the autologous phase of the disease, the glomerular TxB2 level was even higher than in the heterologous phase. The level of 6-keto-PGF1 alpha was significantly lower than normal, and the level of PGE2 was unchanged in respect to the basal values. The use of L-652,731 (a specific PAF receptor antagonist) reversed the abnormal generation of AA metabolites at glomerular level both in the heterologous and autologous phase of the disease. The effect of L-652,731 on AA metabolism is likely to be an indirect result of the PAF receptor blocking, because L-652,731 given to normal rabbits had no direct effect on glomerular AA metabolism. To assess whether the beneficial effect of L-652,731 in NTN is at least in part mediated by its capability of suppressing the excessive intrarenal synthesis of thromboxane A2 (TxA2), we compared the effect of L-652,731 with that of a selective TxA2-synthase inhibitor (FCE-22178). FCE-22178 ameliorated the morphologic expression of rabbit NTN and reduced function deterioration. The protective effect of L-652,731 on proteinuria in the autologous phase and on glomerular filtration rate in both phases was superior to that of FCE-22178. We conclude that an excessive intraglomerular synthesis of TxA2 occurs in rabbit NTN that can play a role in renal function deterioration. Both a specific PAF receptor antagonist and a TxA2-synthase inhibitor reduced the exaggerated TxA2 synthesis and favorably influenced the evolution of the disease.

Animals↗
PubMed1989

[Von Willebrand factor multimers in systemic scleroderma].

In scleroderma endothelial cell damage plays an early and pivotal role in the pathogenesis of sclerotic lesions. In our study we determined whether or not plasma from 11 consecutive patients with scleroderma contained a subset of larger than normal (supranormal) multimers of von Willebrand factor which are potent inducers of platelet aggregation and adhesion. Supranormal multimers were found in all patients, but in none of the normal controls. Supranormal multimers may contribute to the pathogenesis of systemic sclerosis by inducing platelet aggregation and enhancing adhesion to subendothelium.

Adult↗
PubMed1989

Development of a mass spectrometric method to quantitate platelet activating factor in mouse urine.

Platelet activating factor (PAF) is a lipid mediator of inflammation released by a variety of stimulated inflammatory cells. It may be involved in immune glomerulonephritis. Thus, its measurement in urine could give information on the mechanism of this disease. We present here a method to measure PAF in mouse urine, using gas-liquid chromatography-mass spectrometry (GLC-MS) in the selected ion recording (SIR) mode. Before instrumental analysis, the extracted and purified samples were hydrolyzed and derivatized with pentafluorobenzoyl chloride. Different experimental conditions are presented and discussed to corroborate the analytical findings. PAF levels in mouse urine were 2.08 +/- 0.46 ng/24 h. This procedure might represent a new experimental tool to establish the possible role of PAF as mediator of tissue damage in renal disease.

Animals↗
PubMed1989

Age-related nephropathy and proteinuria in rats with intact kidneys exposed to diets with different protein content.

Tubulointerstitial damage and glomerular sclerosis are findings commonly observed in the experimental models of adriamycin and puromycin aminonucleoside nephrosis. It has been suggested that in such models proteinuria might be an important mediator of tubulo-interstitial damage which in turn may determine the progression of the disease favoring the development of glomerulosclerosis. The objective of the present investigation was to establish the temporal relationship between proteinuria, tubulo-interstitial damage and glomerulosclerosis in aging rats with intact kidneys exposed to diets with different protein content. There were six groups of rats studied. Animals of groups 1, 5, and 6 (N = 10) were fed diets containing 20, 35, and 6% protein, respectively, for 20 months and sacrificed at the end of the experimental period. Rats in groups 3 and 4 (N = 6) exhibited marked and mild proteinuria, respectively, after 14 months of maintenance on standard diet, and followed for two additional months after the onset of proteinuria with the aim of evaluating the pattern of renal damage after a relatively short period of proteinuria. Rats in group 2 (N = 10) were fed standard diet and sacrificed before (5 months) and at the onset of proteinuria (10 months). Protein excretion and plasma creatinine were measured for each animal every month. Pathologic examination was performed by light and electron microscopy. At the onset of proteinuria neither renal structural nor functional abnormalities were detected. After 20 months, rats fed standard diet developed tubulo-interstitial damage (score: 1.29 +/- 1.05) and focal glomerular sclerosis (percentage of glomeruli with focal segmental glomerular sclerosis: 16.70 +/- 16.40). A significant correlation was found between the degree of tubulo-interstitial damage and the percentage of glomeruli with focal glomerular sclerosis (r = 0.99, p less than 0.01). Development of tubulo-interstitial damage and focal glomerular sclerosis were correlated with heavy and sustained proteinuria. The high protein diet significantly worsened proteinuria (at month 20: 247.08 +/- 101.73 mg/day), tubulo-interstitial changes (score: 1.99 +/- 0.70), focal glomerular sclerosis (percentage of glomeruli with focal segmental glomerular sclerosis: 21.50 +/- 9.44) and was associated with deteriorating renal function (at month 20, plasma creatinine: 1.20 +/- 0.50 mg/dl).(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1989

Tumor necrosis factor induces glomerular damage in the rabbit.

Tumor necrosis factor (TNF) is a polypeptide hormone produced by activated macrophages detectable in the circulation of experimental animals given endotoxin. Recent evidence strongly suggests that many of the deleterious effects of endotoxin in experimental animals are mediated by TNF. Because endotoxemia in experimental animals and humans is associated with glomerular damage the present investigation was designed to establish whether TNF directly induces glomerular functional and structural changes. Twenty-three rabbits were given human recombinant TNF at the doses of 0.08, 0.8, and 8.0 micrograms/kg/h as a continuous 5-hour intravenous infusion. Animals were killed at the end of the infusion. All rabbits given 0.8 and 8.0 micrograms/kg/h TNF developed anemia (Ht value decrease at 5 hours: 0.8 microgram/kg/h, 15%; 8.0 micrograms/kg/h, 16%); leukopenia (leukocyte count decrease at 5 hours: 0.8 micrograms/kg/h, 47%; 8.0 micrograms/kg/h, 59%); thrombocytopenia (platelet count decrease at 5 hours; 0.8 micrograms/kg/h, 45%; 8.0 micrograms/kg/h, 57%). Rabbits given 8.0 micrograms/kg/h also had renal failure (serum creatinine from 1.02 +/- 0.15 to 1.64 +/- 0.34 mg/dl). By light microscopy only occasional polymorphonuclear leukocytes in the glomerular capillaries were detectable in rabbits infused with 0.08 micrograms/kg/h TNF, whereas with 0.8 micrograms/kg/h TNF the presence of inflammatory cells in the glomerular capillaries was the prominent finding. With 8.0 micrograms/kg/h TNF beside leukocyte accumulation, fibrin was detected in the glomerular capillary lumens of two of eight animals. Electron microscopy found dose-dependent glomerular endothelial cell damage in animals given TNF with fibrinlike material in the capillary lumens. Glomerular changes induced by TNF were remarkably similar to those previously found in animals given endotoxin. Thus, TNF is likely to be the mediator of endotoxin-induced glomerular damage and can be regarded as a new mediator of macrophage-dependent damage in glomerulonephritis.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Metabolism of arachidonic acid in isolated glomeruli from pig kidney.

Arachidonic acid metabolism in isolated glomeruli from pig kidney was investigated. Arachidonic acid metabolism via cyclooxygenase was studied by three different methodological approaches: radioimmunoassay (RIA), high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). By all these techniques, the major prostaglandins (PG) formed by pig glomeruli appeared to be 6-keto-PGF1 alpha and PGF2 alpha, the former being the most abundant. RIA and GC-MS also detected lower amounts of thromboxane B2 (TxB2) and PGE2. This emphasises the similarity with human glomeruli, in which the main cyclooxygenase product has indeed been reported to be 6-keto-PGF1 alpha. The lipoxygenase activity in isolated pig glomeruli, as studied by HPLC, generated 15-HETE, 12-HETE and 5-HETE. These data demonstrate that isolated glomeruli from pig kidney possess cyclooxygenase as well as lipoxygenase activity. Since a marked functional similarity exists between human and pig kidney, the pig can be regarded as a good model for studying the influence of arachidonic acid metabolites on glomerular pathophysiology.

Animals↗
PubMed1988

Plasma infusion for hemolytic-uremic syndrome in children: results of a multicenter controlled trial.

The results of a controlled trial to ascertain the usefulness of plasma infusion for the treatment of hemolytic-uremic syndrome (HUS) are reported. Criteria for admission were (1) observation within 8 days from first symptoms, (2) dialysis treatment required, and (3) no special treatments and no more than 25 ml blood/kg previously received. Children were subdivided according to age (less than or more than 3 years) and then randomly assigned to treatment with plasma or symptomatic therapy. Thirty-two children ranging in age from 4 months to 6 years entered this study; 17 received plasma (P+ group) and 15 only symptomatic therapy (P- group). The mean follow-up period was 16 months in both groups. Surgical renal biopsy was performed 29 to 49 days after onset in 11 P+ and 11 P- children, and 33 histologic findings were semiquantitatively evaluated. No death occurred in either group. No differences were found in blood pressure, proteinuria, or hematuria at the end of the follow-up period; in no case were severe arteriolar lesions found. There were no significant differences for the scores of the individual histologic measurements; on electron microscopy, no vascular changes were observed in seven children of the P+ group, whereas in five of seven of the P- group, thickening of the lamina rara interna and arteriolar damage were present. The ability of plasma to stimulate prostacyclin (PGI2) production, measured as its stable derivative 6-keto-PGF1 alpha, was within the normal range for all patients. In our patients with predominant glomerular involvement who were treated in a very early phase of HUS, infusions of plasma did not significantly influence the short- and medium-term clinical outcome and were not effective in severe HUS when given later in the course of the disease. A longer follow-up is needed to ascertain whether the presence of endothelial damage, demonstrated by electron microscopy in children who were not given plasma, is of clinical relevance.

Biopsy↗
PubMed1988

Influence of antacid administrations on aspirin absorption in patients with chronic renal failure on maintenance hemodialysis.

In order to investigate the possible interaction between oral aspirin and antacids in uremic patients on chronic hemodialysis, we administered to 5 uremic patients: (1) aspirin alone; (2) aluminum-magnesium hydroxide with aspirin; (3) aluminum-magnesium hydroxide followed (two hours) by aspirin; (4) calcium carbonate simultaneously with aspirin; and (5) calcium carbonate followed (two hours) by aspirin. In all the occasions, aspirin was given two hours after a standard lunch. Both antacid preparations induced comparable changes in aspirin mean peak plasma concentration (Cmax), if given simultaneously with aspirin, whereas no difference was found in other pharmacokinetic parameters. When antacids were followed (two hours) by aspirin, both Cmax and time of maximum concentration (Tmax) were significantly altered in respect to the value with aspirin alone. No changes in the time course of post aspirin serum thromboxane B2 were detected when aspirin and antacids were administered simultaneously, but the inhibition of serum thromboxane B2 was delayed when antacids were followed (two hours) by aspirin. These results indicate that the administration of antacids to uremic patients interferes with absorption of oral aspirin. This interference can be minimized if aspirin and antacids are given simultaneously.

Absorption↗
PubMed1988

Catecholamine receptor binding in rat kidney: effect of aging.

Binding to several receptors was compared in kidneys from 3- and 24-month-old rats. In crude membrane preparations of aged rat kidneys, the number of beta 2-adrenergic receptors was significantly reduced but the number of total beta-adrenoceptors was unchanged. The high-affinity alpha 1-adrenoceptor component was significantly reduced in old rats, whereas the low-affinity component was unchanged. The number of alpha 2-adrenoceptors showed a non-significant decrease. 3H-spiperone binding sites were similar in young and old rats. For each receptor binding the KD values were the same in young and old animals. The D1 dopamine receptor was significantly reduced in old rats. In our experiments, age-related changes of specific binding sites in the kidney were selective for some receptors studied and did not seem to be due to general aging-induced membrane modifications. Moreover, the renal and central receptors were sensitive to aging differently in the same animal model.

Aging↗
PubMed1988

Increased urinary excretion of thromboxane B2 and 2,3-dinor-TxB2 in cyclosporin A nephrotoxicity.

Cyclosporin A (CsA) administration to rats is associated with a selective increase in urinary excretion of immunoreactive thromboxane B2 (i-TxB2), the stable breakdown product of TxA2. The exaggerated synthesis of TxA2 may play a role in the reduction of glomerular filtration rate (GFR) observed both in animals and humans undergoing CsA treatment. The present study was designed to get further insight into the origin of the abnormal i-TxB2 urinary excretion. Rats given orally CsA (50 mg/kg/day) for 30 days had a significant increase in the urinary excretion of both 2,3-dinor-TxB2 and TxB2 measured by technique of capillary column gas chromatography-negative ion chemical ionization mass spectrometry (HRGC-NICIMS). Urinary TxB2 is more likely to reflect the renal synthesis of the parent compound, whereas 2,3-dinor-TxB2 is considered to reflect the amount of TxB2 formed in the circulation. Experiments in isolated perfused kidney (IPK) taken from animals given CsA for 30 days showed a lower percentage increase in urinary TxB2 over vehicle treated animals. Moreover in IPK the ratio 2,3-dinor-TxB2/TxB2 was lower than in vivo. The amount of i-TxB2 detectable in serum of animals given CsA was not different from that of control animals. In contrast, isolated glomeruli taken from rats given CsA had an increase in their TxA2 synthesis measured as i-TxB2 in the supernatants. Ultrastructural studies on kidney specimens from animals given CsA showed a focal glomerular endothelial damage together with a marked infiltration of blood borne cells of monocyte-macrophage type in the glomerular tuft. In contrast, kidney specimens taken from IPK preparations were devoid of inflammatory cells. In vitro CsA did not interfere with platelet arachidonic acid (AA) metabolism as shown by a normal i-TxB2 generation in vitro by rat platelet-rich plasma (PRP) exposed to CsA and then challenged with AA or ADP. Similarly isolated glomeruli and isolated proximal tubules from normal rats when challenged with CsA in vitro converted AA into TxA2 normally. It is suggested that the cause of the increased urinary excretion of 2,3-dinor-TxB2 is the consequence of intrarenal platelet and macrophage activation, probably triggered by the endothelial damage. The parallel increase in the urinary excretion of unmetabolized TxB2 is likely to reflect a concomitant activation of resident renal cell AA metabolism induced by CsA.

Animals↗
PubMed1988

Sex related differences in glomerular ultrafiltration and proteinuria in Munich-Wistar rats.

Munich-Wistar rats (MWF/Ztm), originally selected for high number of superficial glomeruli, were used to correlate abnormal urinary protein excretion with glomerular hemodynamics and glomerular morphology. Two animal groups were used, one of male and one of female rats. They were kept periodically in metabolic cages to determine urinary protein excretion. All animals were fed standard rat chow. In male animals protein excretion, evaluated at seven weeks of age, was already significantly higher than in females (17 +/- 11 vs. 8 +/- 3 mg/24 hr), and then progressively increased averaging 291 +/- 51 mg/24 hr at week 21. In females urinary protein excretion was within the normal range up to week 18 and averaged 25 +/- 13 mg/24 hr at week 21. Body and kidney weight at the end of the experimental period were significantly higher in males than in females. Whole kidney inulin clearance (CIn) and single nephron glomerular filtration rate (SNGFR) were significantly higher in male than in female rats, while mean glomerular capillary hydraulic pressure (PGC) and transcapillary hydraulic pressure difference (delta P) were comparable. Single nephron glomerular plasma flow (QA) and afferent and efferent arteriolar resistance were comparable in male and female rats. The calculated glomerular ultrafiltration coefficient (Kf) was significantly higher in male than in female MWF/Ztm rats. No significant differences were detected between the two groups in the total number of glomeruli, and in glomerular size. These findings indicate that male MWF/Ztm rats develop spontaneous proteinuria, which progressively increases with the age.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Dose-effect and pharmacokinetics of estrogens given to correct bleeding time in uremia.

Conjugated estrogens have a significant and long-lasting effect in shortening bleeding time in patients with end-stage renal disease. The studies so far available indicate that repeated estrogen administrations are necessary to short bleeding time in uremia in a dose range of 95 to 325 mg. With the present study we wanted to establish whether single or repeated doses are required to induce a significant shortening of bleeding time in uremia, and the minimum cumulative dose of conjugated estrogens necessary to control bleeding time for a prolonged period of time, and to check whether the prolonged effect of estrogens on bleeding time in uremia is due to an accumulation of the drug or its metabolites in the blood. Fifteen uremics on chronic hemodialysis were studied. A pilot study carried out in five uremic patients indicated that single or repeated estrogen infusions of 0.3 mg/kg did not significantly influence bleeding time values. Therefore the subsequent studies have been carried out using daily infusion of 0.6 mg/kg. A single estrogen infusion of 0.6 mg/kg shortened bleeding time in all patients. The effect was transient and bleeding time returned to pre-infusion values within 72 hours. A 50% decrease of bleeding time or a shortening of bleeding time more than 30 to 15 minutes or less was obtained in all patients with four or five infusions (0.6 mg/kg) spaced 24 hours apart. The effect lasted for 14 days. At day 25 from the last infusion all the patients had bleeding time values comparable with the pre-infusion ones.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Role of platelet-activating factor in primary hemostasis.

To determine whether platelet-activating factor (PAF) has a physiological role in the process of primary hemostasis in the rabbit, we measured skin bleeding times in animals given orally a specific PAF-receptor antagonist L-652,731. One hour after the administration of L-652,731 (20 or 40 mg/kg), a significant prolongation of bleeding time was observed. Parameters known to interfere with the process of primary hemostasis were not altered by PAF-receptor antagonist. In addition, no changes were observed in platelet count and vessel wall arachidonic acid metabolism, as revealed by serum thromboxane B2 levels, vascular 6-ketoprostaglandin F1 alpha generation, and by aspirin experiment. The fact that aspirin alone did not induce prolongation of bleeding time in rabbits is probably due to the simultaneous inhibition of platelet thromboxane A2 and vascular prostacyclin. [3H]PAF binding to washed platelets of rabbits given L-652,731 showed a significant reduction in maximum number of detectable binding sites in comparison with values found in the same animals before the L-652,731 administration. The results suggest that the bleeding-time prolongation observed after L-652,731 administration results from its ability to selectively inhibit PAF bioactivity. Thus locally released PAF appears to exert a physiological role in the process of platelet plug formation that follows a skin incision in the rabbit.

Animals↗