Sulfido-peptide leukotrienes in coronary heart disease - relationship with disease instability and myocardial ischaemia.

BACKGROUND: Urinary excretion of leukotriene (LT) E(4) is an index of LTC(4) biosynthesis and platelet-neutrophil interactions, which may occur in coronary heart disease and contribute to myocardial ischaemia. Enhanced LTC(4) biosynthesis may be a consequence of myocardial ischaemia or be linked to its pathogenetic substrate. METHODS AND RESULTS: Overnight urine collections were obtained from 17 patients with chronic stable angina, three patients with Prinzmetal's angina, 16 patients with non ST-elevation acute coronary syndromes (NSTE-ACS) and six patients with acute ST-elevation myocardial infarction (STEMI). LTE(4) excretion was measured by enzyme immunoassay after HPLC separation. Compared with healthy controls (51.1 +/- 21.3 pg mg(-1) creatinine, mean +/- SD, n = 11) and with non-coronary cardiac controls (36.6 +/- 9.8 pg mg(-1) creatinine, n = 9), LTE(4) excretion was unchanged in stable angina (40.5 +/- 25.8 pg mg(-1) creatinine), but significantly (P < 0.01) increased in NSTE-ACS (122.7 +/- 137.2 pg mg(-1) creatinine) and STEMI (213.4 +/- 172.4 pg mg(-1) creatinine). In these patients, LTE(4) excretion rapidly dropped after day 1, consistent with effective coronary reperfusion. In patients with NSTE-ACS, the increase in LTE(4) excretion was entirely restricted to patients with recent (< 48 h) spontaneous anginal episodes. Myocardial ischaemia elicited by a positive exercise stress test was not accompanied by any detectable increase in LTE(4) excretion, while a significant (P < 0.01) increase was detected after a single-vessel percutaneous coronary interventions (PCI) procedure (n = 10), as compared with diagnostic angiography (n = 9). CONCLUSIONS: In coronary heart disease, increased LTC(4) biosynthesis is restricted to ACS and not linked to myocardial ischaemia per se, but likely to the occurrence of plaque disruption.

Soluble E-selectin in essential hypertension: a correlate of vascular structural changes.

BACKGROUND: Increased expression of the endothelial leukocyte adhesion molecule E-selectin is implicated in vascular disease and may accompany the development of hypertension. We evaluated plasma soluble (s) E-selectin to assess its relationship with endothelium-dependent and endothelium-independent vasodilation in patients with hypertension. METHODS: Thirty-one previously untreated and uncomplicated essential hypertensive patients were compared with 16 normotensive controls for changes in forearm blood flow (by strain-gauge plethysmography) in response to brachial artery infusion of the endothelium-dependent vasodilator acetylcholine, and of the endothelium-independent vasodilator sodium nitroprusside. As an index of structural changes, minimal forearm vascular resistances were calculated as the ratio between maximal vasodilation after 13 min of ischemia and mean blood pressure. RESULTS: Responses to acetylcholine were significantly lower and minimal forearm vascular resistances higher in hypertensives versus controls, whereas responses to nitroprusside were comparable. Baseline sE-selectin concentrations were (mean +/- SEM) 37.4 +/- 1.8 ng/mL in hypertensives and 27.8 +/- 0.7 ng/mL in normotensives (P < .001). In essential hypertensive patients, a significant (P < .01) correlation with the response to nitroprusside (r = -0.47) was found, but not with the response to acetylcholine or minimal forearm vascular resistances. sE-selectin was also positively correlated with age and LDL cholesterol. At multivariate analysis, sE-selectin remained significantly correlated with nitroprusside responses and LDL cholesterol. CONCLUSIONS: In patients with essential hypertension, plasma levels of sE-selectin are higher than in normotensive controls and mostly related to structural vascular changes.

111In platelet scintigraphy for the noninvasive detection of carotid plaque thrombosis.

BACKGROUND AND PURPOSE: Thrombosis on atherosclerotic lesions in the large extracranial arteries is the main cause of embolization in the distal cerebral circulation and thus is involved in the pathogenesis of ischemic stroke. The assessment of biological characteristics of lesions that are predictive of thrombotic complications might help in stratification of the risk for stroke but is currently imperfect. METHODS: We compared the performance of (111)In-platelet scintigraphy with blood pool subtraction, ultrasound-based tissue texture analyses, and transcranial Doppler techniques in their ability to predict the occurrence of superficial thrombosis or the presence of a lipid pool in carotid artery plaque specimens removed at the time of carotid endarterectomy in 22 patients with unilateral carotid artery stenosis of >70%. RESULTS: Positivity at (111)In-platelet scintigraphy was present in 8 patients and correctly identified the presence of thrombosis superimposed on a complicated plaque. Neither tissue texture analysis nor emboli detection by transcranial Doppler, performed in 12 patients, significantly identified plaque thrombosis. None of the techniques used were able to detect the presence of a significant lipid pool inside the plaque. CONCLUSIONS: Indium-platelet scintigraphy is an accurate noninvasive diagnostic tool to detect thrombotic complications in carotid plaques. Prospective studies should assess its ultimate value in risk stratification, possibly to guide the decision of whether to perform endarterectomy in selected patient categories.

Platelet-vessel wall interactions with third-generation oral contraceptives: no evidence of detrimental effects.

Because of the association of oral contraceptives (OC) and cigarette smoking with an increased thrombotic risk, we evaluated thromboxane (TX) and prostacyclin urinary (u) metabolites, as in vivo indices of platelet-vessel wall interactions, in women assigned to third generation OC. Twenty-eight women (15 smokers) underwent a 6-month trial of 30 microg ethinylestradiol plus 0.150 mg desogestrel. Cotinine plasma levels were elevated only in persons classified as smokers and serum TXB2 determination confirmed the absence of cyclooxygenase inhibition throughout the study. u-TXB2 and 11-dehydro-TXB2 were higher in smokers than in non-smokers. OC decreased u-11-dehydro-TXB2 both in smokers (from (pg/micromol creatinine) 35.1+/-6.9 to 15.8+/-2.8; P<0.025) and non-smokers (from 31.7+/-9.8 to 20.6+/-4.8, P = N.S.). u-6-keto-prostaglandin(PG)F1alpha excretion, also higher in smokers compared to non-smokers, was also reduced after OC in smokers (from (pg/micromol creatinine) 24.3+/-5.2 to 14.8+/-2.3; P<0.05). Smokers also had a trend to higher u-2,3-dinor-6-keto-PGF1alpha, marginally reduced by OC. Thus, the OC regimen used here improves - if anything - platelet vessel wall interactions as assessed by prostanoid production in vivo. The prothrombotic tendency associated with the use of OC in smokers does not appear to be mediated by changes in platelet-vessel wall interactions.

Anti-D treatment for chronic immune thrombocytopenic purpura: clinical and laboratory aspects.

We used low-dose anti-D immunoglobulins for home treatment of Rh+ adult patients with chronic immune thrombocytopenic purpura (ITP). After informed consent, 15 unselected outpatients (ten males and five females, aged 22 to 72), affected by chronic ITP with negative HIV test, were given intramuscular injection of 900-1500 micrograms of anti-Rh0 (D) IgG over 3 days every month for 2 or 3 consecutive months. Platelet count (mean +/- SD) significantly increased from basal value of 17,000 +/- 9,000/microL to 72,000 +/- 55,000/microL at the end of treatment. Eight patients achieved a rise in platelet count above 50,000/microL (five above 100,000/microL) and two of them maintained the increase longer than 6 months without further anti-D administration. Three patients responsive to the first cycle responded to further treatment with substantially identical results. Seven patients had no response. Four of them had not responded to previous glucocorticoid and intravenous IgG therapy. Direct antiglobulin test became strongly positive in all patients and mean serum haptoglobin decreased from a basal value of 118 +/- 59 to 61 +/- 43 mg/dL; nevertheless no clinically overt hemolysis was observed in any patient, there was no rise of serum indirect bilirubin and hemoglobin level was unchanged (mean +/- SD basal level 13.6 +/- 2.2 g/dL; after anti-D 13.9 +/- 1.2 g/dL). No hematoma developed at the injection site, and no other side effects occurred. Our results show that anti-D therapy is effective in the majority of patients well tolerated, and feasible as home treatment: thus it can be recommended as a cheap and safe alternative treatment in ITP Rh+ patients.

Structural requirements for inhibition of cytokine-induced endothelial activation by unsaturated fatty acids.

Dietary long-chain fatty acids (FA) may influence pathological processes involving endothelial activation, including inflammation and atherosclerosis. We have previously shown that the n-3 FA docosahexaenoate (DHA) inhibits endothelial activation in the range of nutritionally achievable plasma concentrations. The present study assessed structural determinants for this effect. Saturated, monounsaturated, and n-6 and n-3 polyunsaturated FA were incubated with cultured endothelial cells for 24-72 h alone, and then in the presence of interleukin-1, tumor necrosis factor, or bacterial lipopolysaccharide for an additional 24 h before assessing the expression of the vascular cell adhesion molecule-1 (VCAM-1) or other products of endothelial activation. No FA tested per se elicited endothelial activation. While saturated FA did not inhibit cytokine-induced expression of adhesion molecules, a progressively increasing inhibitory activity was observed, for the same chain length, with an increase in double bonds. Comparison of FA with the same length and number of unsaturation and only differing for the double bond position or for the cis/trans configuration indicated no difference in inhibitory potency, indicating no effect of the double bond position or configuration. As judged by Northern analysis, these latter FA also inhibited VCAM-1 messenger RNA steady state levels to the same extent, indicating a pre-translational site of action attributable to the single double bond. Thus the double bond is the minimum necessary and sufficient requirement for FA inhibition of endothelial activation. These properties are likely relevant to the anti-atherogenic and anti-inflammatory properties ascribed to n-3 FA, which are able to accommodate the highest number of double bonds in a fatty acid of given chain length.

A prostacyclin-sparing effect of indobufen vs. aspirin.

Indobufen ((+/-)-2-[p-(1-oxo-2-insoindolinyl)-phenyl]-butyric acid, indo) is a drug inhibiting platelet function by a reversible block of the arachidonic acid metabolism at the level of cyclooxygenase. Since tolerability profile of such drugs is mostly linked to extra-platelet cyclooxygenase inhibition, we prospectively evaluated the extent of platelet and extra-platelet cyclooxygenase inhibition by in vivo administration of indo in comparison with ASA. We assessed the effects of the two drugs on the ex vivo generation of TXB2 and 6-keto-PGF1 alpha in whole blood, as indices of the production of TXA2 and PGI2 (prostacyclin), respectively, either after spontaneous clotting at 37 degrees C for 1 h (Study 1) or after the addition of 2 micrograms/ml collagen (Study 2). Generation of 6-keto-PGF1 alpha in whole blood is a mixed index of platelet and extra-platelet cyclooxygenase activity, deriving from both platelet and white blood cell arachidonic acid metabolization. Fifteen patients with ischemic heart disease and baseline serum TXB2 levels > 300 ng/ml were allocated to receiving one single administration of either indobufen 200 mg (n = 6) or aspirin 500 mg (n = 9). Whole blood prostanoid generation was assessed at 0, 1, 2, 4, 6, 8, 12 and 24 h after drug administration (Study I). Ten healthy male volunteers were allocated to a double-blind, randomized crossover comparison of indo 200 mg b.i.d. vs. ASA 300 mg/d for 7 days (Study 2). Prostanoid generation and whole blood platelet aggregation were performed before and at the end of each study period (Day 0 and Day 7). At each time-point after single dose administration (Study 1), indobufen caused less % inhibition of whole blood 6-keto-PGF1 alpha than of TXB2. At 2 h, TXB2 was reduced to a similar extent after ASA (98 +/- 4%) and indo (97 +/- 6%) (p = N.S.), while inhibition of 6-keto-PGF1 alpha was clearly different ( > 98% after ASA, 81 +/- 2.5% after indo, p < 0.01). After one week of ASA or indo (Study 2) the maximum extent of whole blood platelet aggregation was similarly inhibited (from 17.2 +/- 1.4 ohms to 3.6 +/- 1.3 ohms with ASA; from 18.3 +/- 1.0 ohms to 1.6 +/- 0.7 ohms with indo (p ASA vs. indo = N.S.). Despite equal inhibition of whole blood TX production after collagen (from 49.0 +/- 4.3 ng/ml to 1.1 +/- 0.6 ng/ml with ASA, from 49.8 +/- 1.3 ng/ml to 1.4 +/- 0.6 ng/ml with indo), again, however, 6-keto-PGF1 alpha production was less affected by indo than by ASA (from 409 +/- 30 pg/ml to 37 +/- 13 pg/ml with ASA, inhibition = 91%; from 396 +/- 35 to 318 +/- 40 with indo, inhibition = 20%). These differential effects of indo and ASA might lead to a better platelet selectivity, tolerability and benefit/risk profile of indo vs. ASA, which are worthy of further assessment.

Omega-3 fatty acid supplementation and lipoprotein(a) concentrations in patients with chronic glomerular diseases.

Renal disease patients often exhibit alterations in the lipid profile which may become an important risk of accelerated atherosclerosis and contribute to disease progression. Among such alterations, increased levels of lipoprotein(a) [Lp(a)] are common and may be related, in part, to the degree of proteinuria. Omega-3 polyunsaturated fatty acids (omega-3 FA) have been reported to decrease Lp(a) concentrations in nonrenal subjects. In addition, they have recently been shown to reduce proteinuria in patients with chronic glomerular disease. We therefore tested the hypothesis that omega-3 FA treatment in patients with chronic glomerular disease may reduce Lp(a) concentrations. Eight patients (2 with membranous glomerulonephritis, 6 with focal glomerular sclerosis) were submitted to a total of 13 six-week courses of treatment with omega-3 FA, at a dose of 3 g/day with a triglyceride preparation (n = 4) and of 7.7 g/day with an ethyl-ester preparation (n = 9). Both treatments significantly increased the proportions of omega-3 to omega-6 FA in total serum lipids, documenting compliance to treatment. Both treatments were also effective in decreasing serum thromboxane (from mean 490 +/- (SEM) 70 to 325 +/- 49 ng/ml, p < 0.05, in the high-dose group) and prolonging the bleeding time (from 5.8 +/- 0.4 to 7.7 +/- 0.5 min, p < 0.05, in the high-dose group), thus documenting the biological efficacy of treatment. However, despite a significant reduction in serum triglyceride levels (from 137 +/- 20 to 104 +/- 19 mg/dl in the high-dose group), Lp(a) concentrations did not change (292 +/- 120 U/l before, 315 +/- 130 U/l after the high-dose therapy). Treatment-related changes in proteinuria (from 2.9 +/- 0.5 to 2.1 +/- 0.7 g/24 h) were not related at all to changes in Lp(a) levels. We conclude that omega-3 FA do not decrease Lp(a) concentrations in renal patients with chronic glomerular diseases and that Lp(a) levels are unlikely to be related to the degree of proteinuria within the short-term modifications induced by omega-3 FA.

Antiplatelet activity of cis-resveratrol.

The anti-aggregating effect of cis-resveratrol (cis-3,4,5- trihydroxystilbene) has been evaluated in vitro in different concentrations on platelet-rich plasma from health volunteers. Cis-resveratrol at the concentration of 1 x 10(-5) and 1 x 10(-6) M was able to decrease collagen-induced platelet aggregation by 43.5 +/-11.4% and 26.8 +/- 14.6%, while trans-resveratrol at the same concentration showed a slightly lower activity. In view of the behaviour of these two isomers in biological fluids, the evaluation of resveratrol activity in animals and humans take into account the total amount of the two isomers.

Platelet radiolabelling with 111 Indium for in vivo studies: a methodological reappraisal.

Two ligands widely used for 111In labeling of human platelets, oxine and tropolone, were compared as to the degree of their influence on platelet function. The labelling efficiency was assessed as a function of experimental variables. A good preservation of platelet function as evaluated by ex vivo aggregation was obtained with both techniques. The extent of tracer detached from platelets was evaluated in vitro and in vivo: in normal subjects 111In was virtually all bound to platelets. A significant reduction in radiolabelling efficiency and a decreased percentage of 111In bound to platelets in vivo was observed in patients with platelet counts < 150,000/mL.

Effects of systemic glucocorticosteroids on peripheral neutrophil functions in asthmatic subjects: an ex vivo study.

In 21 asthmatic subjects, several functions of isolated peripheral neutrophils (chemokinesis and chemotaxis toward 10% E. coli; superoxide anion generation after PMA; leukotriene B(4) (LTB(4)) release from whole blood and isolated neutrophtls, before and after different stimuli) were evaluated during an acute exacerbation of asthma, and after 14 - 54 days of treatment with systemic glucocorticosteroids (GCS). During acute exacerbation, superoxide anion generation was higher in asthmatics than in eleven normal subjects (39.2 +/- 14.1 vs. 25.2 +/- 7.3 nmol, p < 0.05); there was a significant correlation between FEV(1) (% of predicted) and neutrophil chemotaxis (r = -0.52, p = 0.04). After treatment, there was no significant change in all neutrophil functions, except for a decrease in neutrophil chemotaxis in subjects who showed an FEV(1) increase > 20% after GCS treatment (from 131 +/- 18 to 117 +/- 21 mum, p = 0.005). Chemokinesis sicantly decreased in all subjects, and the changes significantly correlated with an arbitrary score of the total administered dose of GCS (r = 0.57, p < 0.05). These data suggest that neutrophil activation plays a minor role in asthma, and that treatment with GCS is not able to modify most functions of peripheral neutrophils in asthmatic subjects; chemotaxis seems to be related only to the severity of the asthma and it could reflect the improvement of the disease.

Antiplatelet activity of synthetic and natural resveratrol in red wine.

The antiaggregating effect of the phytoalexin resveratrol (3,4,5-trihydroxystilbene), alone or associated with red wine, and polyphenol have been evaluated in vitro at different concentrations on platelet-rich plasma from healthy volunteers. Resveratrol at the concentration of 3.56 micrograms/l was able to lower platelet aggregation by 50.3% +/- 1.83. Red wine containing 1.2 mg/l of natural trans-resveratrol and 3.6 milligrams of polyphenols diluted 1000-fold (final resveratrol concentration: 1.2 micrograms/l) inhibited platelet aggregation by 41.9% +/- 2.11. By adding resveratrol to the wine up to a concentration of 1.2 micrograms/l, inhibition was raised to 78.5% +/- 4.70. These results suggest that the antiaggregating activity of resveratrol is related to its concentration in wine.

Macrophage-specific eicosanoid synthesis inhibition and lipocortin-1 induction by glucocorticoids.

It has been suggested that the induction of lipocortin-1, a phospholipase A2-inhibitory protein, may mediate the anti-inflammatory action of glucocorticoids. We assessed the production of prostaglandin E2, thromboxane B2, and leukotriene B4 and the expression of lipocortin-1 in different populations of blood leukocytes and in alveolar macrophages (obtained by bronchoalveolar lavage) from patients with inflammatory lung diseases (bronchial asthma, n = 21; interstitial lung disease, n = 6) undergoing glucocorticoid treatment at clinically effective doses. No inhibition of eicosanoid production was observed in either whole blood or single populations of blood leukocytes (granulocytes and monocytes) stimulated with ionophore A-23187, N-formyl-L-methionyl-L-leucyl-L-phenylalanine, or zymosan. Conversely, eicosanoid production from alveolar macrophages (assessed in 9 cases) was significantly inhibited by glucocorticoids. After ionophore stimulation, eicosanoid production was as follows (in ng/ml): prostaglandin E2, 0.19 +/- 0.06 and 0.06 +/- 0.01; thromboxane B2, 2.9 +/- 0.9 and 0.5 +/- 0.1; leukotriene B4, 6.6 +/- 1.1 and 3.6 +/- 1.0, before and after treatment, respectively (P < 0.05 for all differences). Lipocortin-1 expression, determined by Western blot and enzyme immunoassay, was significantly (P < 0.05) stimulated in alveolar macrophages, but not in blood leukocytes, by glucocorticoid treatment. These results indicate that alveolar macrophages, at variance from blood leukocytes, are the most likely cell target for glucocorticoid-induced eicosanoid inhibition and lipocortin expression. We suggest that cell responsiveness to glucocorticoids is acquired during differentiation from monocyte to tissue macrophage.

n-3 fatty acids reduce proteinuria in patients with chronic glomerular disease.

Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) has been shown to reduce proteinuria in experimental models of renal diseases, but their potential role in the treatment of human renal disease is unknown. We administered n-3 PUFA in the form of triglycerides [with eicosapentaenoic (EPA)+docosahexaenoic (DHA) = 3 g/day into 4 patients] and of ethyl esters (EPA+DHA = 7.7 g/day) into 10 patients (one patient twice) with chronic glomerular disease (membranous glomerulonephritis and focal glomerular sclerosis), all diagnosed histologically. Serum albumin was > 2.4 g/dl and serum creatinine < 2.5 mg/dl in all patients. Treatment was given for periods of six weeks, followed by a prolonged follow-up for 27 weeks in 10 cases. Dietary supplementation with n-3 PUFA caused the expected reduction in platelet generation of thromboxane B2 (mean +/- SEM, from 490 +/- 70 ng/ml at baseline, to 342 +/- 147 ng/ml at 6 weeks, P < 0.05) of serum triglycerides (from 236 +/- 60 to 170 +/- 43, P < 0.01), and a prolongation of the bleeding time (from 5.8 +/- 0.4 min to 7.7 +/- 0.4 min, P < 0.01) in patients treated with ethyl esters. A modest but significant reduction in serum total cholesterol was noticed (from 275 +/- 27 to 252 +/- 24 mg/dl).(ABSTRACT TRUNCATED AT 250 WORDS)

[The use of picotamide in nephropathy with mesangial IgA deposits. The effect on thromboxane generation]. / L'impiego della picotamide nella nefropatia a depositi mesangiali di IgA. Effetto sulla generazione del trombossano.

IgA nephropathy (Berger's disease) is one of the commonest forms of glomerular disease, not rarely progressing to renal failure. Hemostatic system activation may play a role in the development of glomerular injury. In a series of 12 adult patients affected with IgA nephropathy we have observed increased plasma levels of D-dimer, a stable end-product of cross-linked fibrin degradation that is considered a reliable index of blood clotting activation, as well as "in vitro" raised generation of thromboxane, the main platelet product of arachidonic acid metabolism that seems to play an important role in glomerulosclerosis. Picotamide, a novel antiplatelet drug acting as thromboxane synthase inhibitor as well as thromboxane receptor antagonist, administered for 8-12 weeks, was effective in reducing thromboxane generation. We conclude that picotamide may be useful in the management of glomerular nephropathy.

The d-enantiomer form of indobufen totally accounts for the anti-cyclooxygenase and antiplatelet activity ex vivo and for the increase in bleeding time by indobufen in man.

Indobufen is an antiplatelet drug able to inhibit thromboxane production and cyclooxygenase-dependent platelet aggregation by a reversible inhibition of cyclooxygenase. Indobufen exists in two enantiomeric forms, of which only d-indobufen is active in vitro in inhibiting cyclooxygenase. In order to verify that also inhibition of platelet function is totally accounted for by d-indobufen, ten patients with proven coronary artery disease (8 male, 2 female, age, mean +/- S.D., 58.7 +/- 7.5 years) were given, in random sequence, both 100 mg d-indobufen and 200 mg dl-indobufen as single administrations in a double-blind crossover design study with a washout period between treatments of 72 h. In all patients thromboxane (TX) B2 generation after spontaneous clotting (at 0, 1, 2, 4, 6, 8, 12, 24 h), drug plasma levels (at the same times), platelet aggregation in response to ADP, adrenaline, arachidonic acid, collagen, PAF, and bleeding time (at 0, 2, 12 h) were evaluated after each treatment. Both treatments determined peak inhibition of TXB2 production at 2 h from administration, with no statistical difference between the two treatments (97 +/- 3% for both treatments). At 12 h inhibition was 87 +/- 6% for d-indobufen and 88 +/- 6% for dl-indobufen (p = NS). Inhibition of TXB2 production correlated significantly with plasma levels of the drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Benefit/risk profile of combined antiplatelet therapy with ticlopidine and aspirin.

Ticlopidine (T) and aspirin (ASA) are two antiplatelet drugs both capable of prolonging bleeding time (BT), with a different mechanism of action. A synergism in BT prolongation has been reported and is currently considered an argument for not recommending their combination. However, a profound suppression of platelet function might be a desirable counterpart of a marked prolongation of BT, with a possible use in selected clinical situations. We therefore studied ex vivo platelet function (aggregation by ADP 0.5-1-2.5 microM; adrenaline 0.75-2.5 microM; collagen 1.5-150 micrograms/ml; arachidonic acid 1 mM; PAF 1 microM; adrenaline 0.17 microM + ADP 0.62 microM; serum thromboxane [( TX]B2 generation) and BT (Mielke) in 6 patients with stable coronary artery disease receiving such combination. Patients underwent sequential laboratory evaluations at baseline, after 7 days of T 250 mg b.i.d., before and after the intravenous administration of ASA 500 mg, respectively, and, finally, after a minimum of 7 days of sole ASA oral administration (50 mg/day). The experimental design, therefore, allowed a comparison of T and ASA effects (2nd and 4th evaluation), and an assessment of the combination effect (3rd evaluation). Platelet aggregation in response to all doses of ADP was depressed more by T than by ASA. Conversely, responses to adrenaline, and arachidonate were affected more by ASA than by T. For all other agents, differences were not significant. T + ASA combination was more effective (p less than 0.05) than either treatment alone in depressing responses to high-dose collagen (% over control, mean +/- SEM: T: 95 +/- 3; ASA: 96 +/- 5; T + ASA: 89 +/- 4).(ABSTRACT TRUNCATED AT 250 WORDS)

Vascular prostacyclin is increased in patients ingesting omega-3 polyunsaturated fatty acids before coronary artery bypass graft surgery.

Interest in the antithrombotic potential of diets enriched with fish oil-derived polyunsaturated fatty acids (omega-3 PUFAs) prompted us to examine how these fatty acids, when taken preoperatively, affect hemostasis, plasma lipid levels, and production of prostacyclin (PGI2) by vascular tissues in atherosclerotic patients undergoing coronary artery bypass graft surgery. Fifteen patients with angiographically proven coronary artery disease received 3 g/day eicosapentaenoic acid and 1.3 g/day docosahexaenoic acid as capsules of purified fish oil for 28 days before surgery. Platelet aggregation induced by low concentrations of ADP, collagen, and epinephrine decreased (p less than 0.05) and serum thromboxane B2 decreased 36% (p less than 0.01) from baseline values. Bleeding times increased 40% (p less than 0.01) from baseline. Serum triglycerides decreased 50% (p less than 0.05) without a change in total serum cholesterol. Spontaneous production of PGI2 measured as 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), its stable hydrolytic product, by saphenous vein and aortic and atrial tissues obtained at surgery was greater in tissues from patients receiving omega-3 PUFA supplements than in tissues from matched controls (13.8 +/- 2.2 versus 8.6, 21.0 +/- 3.1 versus 11.5 +/- 2.1, and 166 +/- 13 versus 102 +/- 15 ng/g, respectively, all p less than 0.05). Arachidonate-stimulated production of PGI2, as indicated by increased levels of 6-keto-PGF1 alpha, was increased. Despite changes in platelet function, bleeding time, and vascular PGI2, the perioperative blood loss was not increased in subjects receiving fish oil supplements. Thus, omega-3 PUFAs at moderate dosages may exert antithrombotic effects by increasing prostacyclin production by vessel walls as well as by direct inhibition of platelet activity.