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P Gresele

Publications and source records attributed to P Gresele.

At least 19 recordsLinked to original sources
PubMed2005

A novel nitric oxide-releasing statin derivative exerts an antiplatelet/antithrombotic activity and inhibits tissue factor expression.

BACKGROUND: NO-releasing statins are new chemical entities, combining HMG-CoA reductase inhibition and slow NO release, that possess stronger anti-inflammatory and antiproliferative activities than the native statins. OBJECTIVE: We evaluated the antithrombotic effects of nitropravastatin (NCX-6550) by assessing its activity on platelet activation and tissue factor (TF) expression by mononuclear cells in vitro and in vivo. METHODS AND RESULTS: In vitro, NCX-6550 inhibited (1) U46619- and collagen-induced platelet aggregation in buffer and plasma; (2) collagen-induced P-selectin expression in whole blood and (3) platelet adhesion to collagen-coated coverslips under high shear stress. These effects were displayed at concentrations of NCX-6550 ranging from 25 to 100 mum, and were totally reverted by the guanylylcyclase inhibitor ODQ (10 microm). Equimolar concentrations of pravastatin had no influence on these parameters of platelet function. LPS- and PMA-induced TF expression by blood mononuclear cells was also inhibited by NCX-6550 (IC50 13 microm), but not by pravastatin, as assessed by functional and immunological assays and by real-time PCR. In a mouse model of platelet pulmonary thromboembolism, induced by the i.v. injection of collagen plus epinephrine, pretreatment with NCX-6550 (24-48 mg kg(-1)) significantly reduced platelet consumption, lung vessel occlusion and mortality. Moreover, nitropravastatin markedly inhibited the generation of procoagulant activity by spleen mononuclear cells and peritoneal macrophages in mice treated with LPS. In these in vivo models too, pravastatin failed to affect platelet activation and monocyte/macrophage procoagulant activity. CONCLUSIONS: Our results show that nitropravastatin exerts strong antithrombotic effects in vitro and in vivo, and may represent an interesting antiatherothrombotic agent for testing in acute coronary syndromes.

Animals↗
PubMed2005

Intraplatelet signaling mechanisms of the priming effect of matrix metalloproteinase-2 on platelet aggregation.

OBJECTIVE: Platelets contain and release some matrix metalloproteinases (MMPs), enzymes involved in the degradation of extracellular matrix, and one of these (MMP-2) exerts a proaggregatory effect. We explored the signal transduction mechanisms activated by MMP-2 in human blood platelets. METHODS AND RESULTS: Recombinant, human MMP-2, added before stimulation with subthreshold doses of different agonists, potentiated platelet activation, calcium influx, IP3 formation, and pleckstrin phosphorylation. Wortmannin and LY29400, two PI3-K inhibitors, suppressed the potentiating effects of MMP-2 and preincubation with MMP-2 enhanced the thrombin-induced association of the p85alpha PI3-K subunit with the cytoskeleton and increased the phosphorylation of PKB. Protein tyrosine kinase inhibitors, MAP kinase inhibitors, PLA2 inhibitors, cyclooxygenase inhibitors and antagonists of the P2Y1 and P2Y12 receptors did not affect the potentiating activity of MMP-2 on platelets. CONCLUSION: Our data show that MMP-2, at a concentration released by activated platelets, facilitates platelet activation acting at the level of a second messenger system common to different agonists and related to the activation of PI3-K. Platelet-released MMP-2 may contribute to platelet activation in vivo.

Androstadienes↗
PubMed2004

Binding and release of cytochrome c in brain mitochondria is influenced by membrane potential and hydrophobic interactions with cardiolipin.

Factors influencing the release and anchorage of cytochrome c to the inner membrane of brain mitochondria have been investigated. Metabolic activity of mitochondria caused a decrease in the membrane potential delta psi(m), accompanied by detachment of the protein from the inner membrane. In a model system of cytochrome c reconstituted in cardiolipin (CL) liposomes, phosphate was used to breach the hydrophilic lipid-protein interactions. About 44% cytochrome c was removable when heart CL (80% 18:2n-6) was employed, whereas the remaining protein accounted for the tightly bound conformation characterized by hydrophobic lipid-protein interactions. Cytochrome c release from brain CL liposomes was higher compared to heart CL, consistent with lower polyunsaturated fatty acid content. The release was even higher with CL extracted from metabolically stressed mitochondria, exhibiting more saturated fatty acid profile compared to control (30% vs. 17%). Therefore, weakening of the hydrophobic interactions due to saturation of CL may account for the observed cytochrome c release from mitochondria following metabolic stress. Moreover, mitochondria enriched with polyunsaturated CL exhibited higher delta psi(m), compared to less unsaturated species, suggesting that CL fatty acid composition influences delta psi(m). Mitochondria incorporated exogenous cytochrome c without protease-sensitive factors or delta psi(m). The internalized protein anchored to the inner membrane without producing swelling, as monitored by forward and side light scattering, but produced delta psi(m) consumption, suggesting recovery of respiratory activity. The delta psi(m) decrease is ascribed to a selected mitochondrial population containing the incorporated cytochrome c.

Animals↗
PubMed2003

NCX4016: a novel antithrombotic agent.

Despite great advantages in antithrombotic treatments, important limitations of the presently available drugs encourage the search of more effective agents. Within the cardiovascular system, nitric oxide exerts several activities which may have an antithrombotic potential. Nitroaspirin in vitro inhibits platelet aggregation and adhesion under shear conditions and smooth muscle cell proliferation--all activities not exerted by aspirin. In vivo nitroaspirin exerts antithrombotic properties and prevents restenosis in hypercholesterolemic mice while aspirin is inactive. Nitroaspirin has shown a number of significant advantages over the presently available antiplatelet agents; however, only clinical studies will say whether nitroaspirin represents a step forward in antithrombotic treatment.

Animals↗
PubMed2001

Salicylates inhibit T cell adhesion on endothelium under nonstatic conditions: induction of L-selectin shedding by a tyrosine kinase-dependent mechanism.

Salicylates inhibit T cell adhesion to and transmigration through endothelium by preventing integrin activation induced by contact with endothelial cells. In the present study the effects of aspirin and sodium salicylate on the first steps of T cell adhesion have been analyzed in a nonstatic in vitro system. Salicylates partially reduced adhesion to activated endothelium and, in parallel, L-selectin expression on resting T cells by inducing shedding of the molecule without affecting its mRNA transcript. The role of L-selectin down-regulation in reducing T cell adhesion in this system was supported by the fact that aspirin inhibited T cell adhesion also on plastic-immobilized L-selectin ligand or when alpha(4) integrin-mediated adhesion to endothelium was blocked by specific mAbs. In addition, preincubation of T cells with inhibitors of L-selectin shedding prevented both functional and phenotypic inhibitory effects of salicylates. The decrease in T cell adhesion and L-selectin expression seems to be dependent on intracellular calcium increase and tyrosine kinase activation, because these effects could be reversed by preincubating salicylate-treated T cells with EGTA, genistein, or tyrphostin. Finally, the infusion of aspirin into healthy volunteers induced down-regulation of L-selectin on circulating T cells. These results suggest that salicylates interfere not only with integrin activation, but also with the L-selectin-mediated first steps of T cell binding to endothelium.

Aspirin↗
PubMed2001

Low molecular weight heparins prevent thrombin-induced thrombo-embolism in mice despite low anti-thrombin activity. Evidence that the inhibition of feed-back activation of thrombin generation confers safety advantages over direct thrombin inhibition.

BACKGROUND AND OBJECTIVES: Thrombin-induced thromboembolism in mice is a model in which the feed-back clotting activation produced by the injected enzyme greatly contributes to fibrin accumulation in lungs and to mortality. Using this model we have previously shown that activated human protein C (aPC), by interrupting endogenous clotting activation at a high level (factors Va and VIIIa), prevents mortality inducing only a minor hemostatic impairment. With the same model we have now compared the antithrombotic and prohemorrhagic effects of two low molecular weight heparins (LMWHs), reviparin and tinzaparin, which are expected to inhibit preferentially the positive feed-back triggered by thrombin (anti Xa activity), with those of unfractionated heparin (UFH) and PEG-hirudin, which inhibit mainly or exclusively thrombin activity (anti IIa activity). DESIGN AND METHODS: Pulmonary thromboembolism was induced in mice by i.v. injection of bovine thrombin (1,000U/kg). Drugs (from 0.12 to 1.2 mg/kg) were given as bolus injection 2 min prior to thrombin challenge and mortality was assessed within 15 min. The bleeding time was assessed by a tail tip transection model. Activated partial thromboplastin time (aPTT), thrombin clotting time (TcT), fibrinogen assay and anti Xa activity determination were performed in citrated plasma from saline- or drug-treated animals. RESULTS: All drugs protected mice from thrombin-induced mortality in a dose-dependent way. At comparable antithrombotic dosages, the anti IIa activity generated in plasma (assessed by TcT) was highest with UFH, intermediate with tinzaparin and very low with reviparin. Accordingly, the fibrinogen drop, which is caused mainly by the injected thrombin, was prevented by the heparins to an extent that was fairly well related to their anti IIa activity. aPTT and bleeding time, used as measures of hemorrhagic risk, were markedly more prolonged by UFH than by reviparin. Tinzaparin, instead, had an intermediate effect. Interestingly, PEG-hirudin, at equipotent antithrombotic dosages, caused a prolongation of bleeding time comparable to that observed with UFH. INTERPRETATIONS AND CONCLUSIONS: Our data show that, in our model, drugs acting at a high level of the blood clotting cascade, like LMWHs with a high anti Xa/anti IIa ratio, display a better antithrombotic/prohemorrhagic profile than drugs acting prevalently on thrombin.

Animals↗
PubMed2001

Thrombin activatable fibrinolysis inhibitor (TAFI) does not inhibit in vitro thrombolysis by pharmacological concentrations of t-PA.

TAFI (thrombin activatable fibrinolysis inhibitor) is a plasma procarboxypeptidase that upon activation inhibits the fibrinolytic process by removing the C-terminal lysines from partially degraded fibrin. The generation of activated TAFI (TAFIa) has been suggested to represent a mechanism of thrombus resistance to thrombolytic therapy. However, the ability of TAFI to inhibit fibrinolysis by pharmacological concentrations of t-PA has not been properly investigated. We used an in vitro model consisting of 125I-fibrin blood clots submerged in autologous defibrinated plasma. Upon addition of t-PA (125-5,000 ng/ml) and CaCl2 (25 mM), samples were incubated at 37 degrees C, and clot lysis was measured at intervals from the radioactivity released into solution. The role of TAFI was assessed either by neutralizing the generated TAFIa with the specific inhibitor PTI (50 microg/ml) or by enhancing TAFI activation through the addition of recombinant soluble thrombomodulin (solulin, 1 microg/ml). In our clot lysis model, activation of TAFI amounted to about 20% of inducible carboxypeptidase activity. Addition of PTI, however, produced a significant increase in the extent of lysis only at concentrations of t-PA equal to or lower than 250 ng/ml. When solulin was added to the plasma surrounding the clot, about 70% of TAFI was activated within 15 min. Under these conditions, inhibition of clot lysis was very marked in samples containing 125 or 250 ng/ml of t-PA, but negligible in those containing pharmacological concentrations of the activator (1,000 and 5,000 ng/ml). Additional experiments suggest that loss of fibrin-dependence by elevated concentrations of t-PA may be one of the mechanisms explaining the lack of effect of TAFIa. Our data indicate that, under our experimental conditions, clot lysis by pharmacological concentrations of t-PA is not influenced by TAFIa even after maximal activation of this procarboxy-peptidase.

Animals↗
PubMed2001

Treatment of intermittent claudication with mesoglycan--a placebo-controlled, double-blind study.

OBJECTIVE: To assess the effect of treatment with mesoglycan, a sulphated polysaccharide compound, on the walking capacity of patients with stage II peripheral arterial disease. METHODS: Non-diabetic outpatients with intermittent claudication, duplex ultrasound evidence of peripheral atherosclerosis, ankle/arm index <0.80, systolic ankle pressure >50 mmHg, and absolute walking distance (AWD) between 100 and 300 m (standardised treadmill test) were eligible. After a 5-week run-in on single-blind placebo, patients were randomised to double-blind treatment with mesoglycan, 30 mg/day intramuscularly for 3 weeks followed by 100 mg/day orally for 20 weeks, or matching placebo. All patients received low-dose aspirin and lifestyle instructions. Clinical response was defined as an AWD increase at Week 23 >50% over baseline. Health-related quality of life and ischaemic events were assessed as secondary efficacy variables. RESULTS: 242 patients were randomised and 237 were assessed for clinical response. Patients achieving clinical response were 59/118 with mesoglycan (50.0%) and 31/119 with placebo (26.1%; p <0.001). Geometric mean AWD increased from 192 to 298 m with mesoglycan, and from 192 to 238 m with placebo (p <0.001). Pain-free walking distance showed a non-significant increase with mesoglycan (p = 0.057). Changes in quality of life scores were in favour of mesoglycan. The rate of ischaemic events was 1/120 on mesoglycan and 6/122 on placebo (p = 0.053). The rate of non-ischaemic adverse events leading to treatment discontinuation was 7/120 and 4/122, respectively. CONCLUSION: Treatment with mesoglycan improves the walking capacity of patients with intermittent claudication, and might confer additional antithrombotic protection over that of aspirin.

Aged↗
PubMed2000

Prevention of pulmonary thromboembolism by NCX 4016, a nitric oxide-releasing aspirin.

We studied the antithrombotic activity of 2-acetoxybenzoate 2-[1-nitroxy-methyl]-phenyl ester (NCX 4016), a novel nitric oxide (NO)-releasing aspirin derivative, in vivo in different animal models of platelet-dependent and independent pulmonary thromboembolism and compared it with that of aspirin. NCX 4016 protected mice from death induced by the intravenous (i.v.) injection of collagen plus epinephrine, of 9,11-dideoxy-11alpha, 9alpha-epoxymethano-prostaglandin F(2alpha) (U46619) and of thrombin while aspirin was only active against collagen plus epinephrine. The drop in platelet count and number of lung emboli were reduced by NCX 4016 more effectively than aspirin. NCX 4016 protected mice also from mechanical pulmonary embolism (i.v. injection of hardened rat red blood cells) while aspirin was ineffective. In rabbits, NCX 4016 significantly reduced the accumulation of [111In]oxine-labeled platelets in the pulmonary vasculature induced by collagen and by thrombin while aspirin produced reductions which were significant only versus collagen. In conclusion, NCX 4016 exerts a more pronounced antithrombotic activity than aspirin in vivo in two different animal species, largely due to a deeper inhibitory effect on platelets. NCX 4016 may represent a better antithrombotic agent than aspirin.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2000

Involvement of platelets in experimental mouse trypanosomiasis: evidence of mouse platelet cytotoxicity against Trypanosoma equiperdum.

Platelets play an important role in the human response to parasites. Trypanosoma equiperdum, a parasite that has the horse as its natural host, is able to induce infection in mice and thus it may represent a simple model for studying the role of platelets in the development of a parasitosis. Although several aspects of the murine response to T. equiperdum infection have been clarified, the precise mechanism of killing of the parasite is still unclear. We have studied the involvement of blood platelets in experimental murine infection with T. equiperdum. Infected mice show a progressive decrease of the number of circulating platelets. The production of thromboxane A2 (TxA2) by platelets stimulated with collagen decreases progressively with the progression of T. equiperdum infection, compatible with in vivo platelet activation or with a possible antagonistic effect by trypanosomes on the production of TxA2. Finally, mouse platelets exert in vitro a direct parasitocidal activity on T. equiperdum at ratios >/=20:1. Complement fractions do not enhance platelet trypanocidal activity, whereas IgM fractions do, at least in short-term coincubation experiments. Our data show that platelets are involved in experimental murine T. equiperdum infection and confirm that platelet parasitocidal activity is a generalized phenomenon in mammals.

Analysis of Variance↗
PubMed2000

Effect of cloricromene on intermittent claudication. A randomized, double-blind, placebo-controlled trial in patients treated with aspirin: effect on claudication distance and quality of life. CRAMPS Investigator Group. Cloricromene Randomized Arteriopathy Multicenter Prospective Study.

The main aim of medical treatment for intermittent claudication (IC) is the reduction of mortality and morbidity from ischemic cardiovascular disease. However, symptomatic treatment with the aim of improving exercise performance and the overall quality of life may also be an important target of the clinical management of patients with intermittent claudication. Cloricromene, a drug with antithrombotic and anti-ischemic activities, has previously shown some promising results in patients with claudication. We have carried out a clinical trial to assess the effect of cloricromene on the claudication distance and on the quality of life of patients with IC chronically treated with aspirin. A total of 159 patients with IC, Stage II (Fontaine), were enrolled in a double-blind, randomized, prospective, multicenter study comparing cloricromene (100 mg orally b.i.d.) or an identical placebo for 6 months. All patients received 160 mg/day aspirin. The primary end-point was the improvement of initial claudication distance (ICD) at 6 months as measured by a standardized treadmill test. The secondary end-points were the absolute claudication distance (ACD) at 6 months, the percentage of patients defined as responders to treatment (improvement of ICD of at least 40%), changes in the ischemic window (IW), quality of life as assessed by the SF-36 questionnaire, and the occurrence of major cardiovascular events. The ICD increased in both treatment groups, with a non-significant difference at 6 months in favor of cloricromene of +12.3 m. The ACD, percentage of responders to treatment and ischemic window also improved in both groups with a slight, non-significant trend in favor of cloricromene. Pretreatment quality of life scores showed only a slight worsening compared with an age-matched, healthy population and did not change upon treatment. A post hoc subgroup analysis showed a significant benefit from cloricromene in patients with an ICD at enrollment higher than the median of the patient population. In conclusion, treatment with cloricromene for 6 months does not significantly improve claudication in patients with Stage II Fontaine peripheral arteriopathy chronically treated with aspirin. An improvement of 40-60 m in the ICD on a standardized treadmill test does not translate into a self-perceived improvement in the quality of life as assessed by the SF-36 questionnaire.

Adult↗
PubMed2000

Detrimental effects of high-dose dexamethasone in severe, refractory, HIV-related thrombocytopenia.

OBJECTIVE: To report a case of HIV-related thrombocytopenia in which high-dose dexamethasone was ineffective and immunologically detrimental. CASE SUMMARY: A 39-year-old white man with persistent, severe, HIV-1-related thrombocytopenia was admitted for epistaxis, bleeding gums, petechiae, and bruising. Previous unsuccessful attempts to reverse the thrombocytopenia included zidovudine, prednisone, vincristine, interferon alfa, and intravenous immune globulins. Based on previous anecdotal reports of the effectiveness of high-dose dexamethasone in refractory, HIV-related thrombocytopenia, we instituted treatment with intravenous dexamethasone 40 mg/d for four sequential days every 28 days. After three cycles of therapy, the platelet count remained < 15 x 10(9)/L; however, the CD4+ lymphocyte count decreased progressively from 1447 x 10(6)/L at baseline to 560 x 10(6)/L three months after the third cycle. Due to persistent, severe thrombocytopenia and bleeding, the patient underwent splenectomy, resulting in normalization of the platelet count. DISCUSSION: High-dose dexamethasone has been proposed as treatment for patients with immune thrombocytopenia as an alternative to chronic oral corticosteroids and claimed to be associated with better effectiveness and fewer adverse effects. The results of this treatment in our patient show that this regimen may not only be ineffective, but may also be immunologically detrimental in HIV-infected patients. Although the deterioration of the immunologic status of our patient cannot be fully attributed to high-dose dexamethasone based on the Naranjo scale, the previous long-lasting stability of CD4+ cells and the temporal relationship of a decrease in the CD4+ cell count coinciding with administration of high-dose dexamethasone suggest a causative role of the treatment. CONCLUSIONS: A possible cause-effect relationship between the treatment and the decrease in the CD4+ cell count suggests that the use of high-dose dexamethasone may not be justified in patients with severe, HIV-related thrombocytopenia.

Adult↗
PubMed2000

Platelets release their lysosomal content in vivo in humans upon activation.

Platelets contain, besides alpha- and delta-granules, lysosomes which store glycohydrolases able to degrade glycoproteins, glycolipids and glycosaminoglycans. While several studies have shown that alpha- and delta-granule secretion takes place "in vivo" in humans upon platelet activation, no data are available on the "in vivo" release of lysosomes. We have studied the release of platelet lysosomal contents "in vivo" in healthy volunteers at a localized site of platelet activation by measuring markers of lysosomal secretion in the blood oozing from a skin wound inflicted for the measurement of the bleeding-time. The levels of beta-N-acetylhexosaminidase (Hex) were 13.1 +/- 0.85 mU/ml in bleeding-time blood and 10.2 +/- 0.66 mU/ml in plasma (p <0.001). Hex in serum was 16.4 +/- 0.72 mU/ml. The levels of beta-galactosidase were also higher in bleeding-time blood than in plasma (0.85 +/- 0.07 mU/ml vs 0.4 +/- 0.05 mU/ml, p <0.001). In bleeding-time blood collected at one minute intervals, Hex rose progressively consistent with ongoing platelet activation and flow-cytometry showed a progressive increase of the expression of LIMP and LAMP-2, two lysosomal associated proteins. In conclusion, our data demonstrate that platelet lysosomal glycohydrolases are released "in vivo" in humans upon platelet activation.

Bleeding Time↗
PubMed1999

Evidence that cytosolic phospholipase A2 is down-regulated by protein kinase C in intact human platelets stimulated with fluoroaluminate.

We reported that protein kinase C (PKC) inhibitors increase the release of arachidonic acid induced by fluoroaluminate (AlF4-), an unspecific G-protein activator, in intact human platelets. Now we demonstrate that this effect is independent of the extracellular Ca2+ concentration and that AlF4(-)-induced release of AA is abolished by BAPTA, an intracellular Ca2+ chelator, even in the presence of GF 109203X, a specific and potent PKC inhibitor. This compound also blocks the liberation of the secretory phospholipase A2 in the extracellular medium, indicating that this enzyme is not involved in the potentiation of arachidonic acid by PKC inhibitors. On the other hand, the latter effect is completely abolished by treatment of platelets with AACOCF3, a specific inhibitor of cytosolic phospholipase A2 (cPLA2). These observations indicate that cPLA2 is responsible for the AlF4(-)-induced release of arachidonic acid by a mechanism that is down-regulated by PKC.

Aluminum↗
PubMed1999

Assessment of occlusion of the vascular access in patients on chronic hemodialysis: comparison of physical examination with continuous-wave Doppler ultrasound. STOP Investigators. Shunt Thrombotic Occlusion Prevention with Picotamide.

BACKGROUND: Dialysis access occlusion is the most common cause of hospitalization and a frequent indirect cause of mortality in patients on chronic hemodialysis. The clinical assessment of an arteriovenous shunt is presently the most widely adopted method for the diagnosis of vascular access occlusion in hemodialysis patients, but no studies have yet investigated objectively its sensitivity and positive predictive value (PPV). Continuous-wave (CW) Doppler ultrasound is a simple, inexpensive, and noninvasive technique for the assessment of arterial blood flow. We have carried out a prospective evaluation of the PPV of CW Doppler for the diagnosis of vascular access occlusion in hemodialysis patients and compared it with clinical investigation. METHODS: Fourty-one hemodialysis patients with clinical diagnosis of occlusion of their fistula were studied, and in 23 of them the diagnosis of occlusion was objectively validated. RESULTS: CW Doppler in the patients in whom occlusion was objectively validated showed PPV of 86 and 83% under basal conditions and after fistula compression, respectively, with sensitivities of 95 and 100%, respectively. Clinical diagnosis, under the same conditions, showed a PPV of 83% and a sensitivity of 100%. CONCLUSIONS: CW Doppler and clinical examination have a similar high sensitivity for the diagnosis of occlusion of the dialysis access; thus, there is no need to use routinely Doppler CW examination, unless objective documentation is required.

Arteriovenous Shunt, Surgical↗
PubMed1999

Endogenous nitric oxide acts as a natural antithrombotic agent in vivo by inhibiting platelet aggregation in the pulmonary vasculature.

Nitric oxide (NO) is a powerful vasodilator and an inhibitor of platelet aggregation in vitro. While the ability of NO to modulate vascular tone in vivo has been proven, only a few studies have assessed its platelet inhibitory activity in vivo. We have employed two complementary animal models of pulmonary platelet thromboembolism to assess the antithrombotic activity of endogenous NO in vivo. The inhibition of nitric oxide synthase (NOS) by L-NAME significantly potentiated while the administration of the NOS substrate L-arginine significantly reduced the accumulation of 111In-labelled platelets in the pulmonary vasculature of rabbits induced by intravenous collagen plus epinephrine. L-NAME or L-arginine did not, however, modify 111In-labelled erythrocyte distribution in lungs and phenylephrine had no effect on platelet accumulation following collagen + adrenaline, suggesting that the effects of L-NAME were not due to vasoconstriction but rather to a direct modification of platelet function. In mice, L-NAME significantly reduced the dose of collagen + adrenaline required to induce thromboembolic mortality, increased the fall in circulating platelets and increased the % of pulmonary vessels occluded by platelet thrombi. The effects of L-NAME were reversed by L-arginine but not by a dose of nicardipine exerting maximal vasodilatation. Phenylephrine did not potentiate collagen + adrenaline-induced mortality. In the pulmonary vasculature in vivo, endogenous NO inhibits collagen + adrenaline-induced aggregation and enhances platelet disaggregation. This natural modulator function of NO is exerted via a direct effect on platelets and not as a result of haemodynamic changes.

Animals↗