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G Ciabattoni

Publications and source records attributed to G Ciabattoni.

At least 19 recordsLinked to original sources
PubMed1997

Diabetes mellitus, hypercholesterolemia, and hypertension but not vascular disease per se are associated with persistent platelet activation in vivo. Evidence derived from the study of peripheral arterial disease.

BACKGROUND: Previous studies relating increased thromboxane (TX) biosynthesis to cardiovascular risk factors do not answer the question whether platelet activation is merely a consequence of more prevalent atherosclerotic lesions or reflects the influence of metabolic and hemodynamic disturbances on platelet biochemistry and function. METHODS AND RESULTS: We examined 64 patients with large-vessel peripheral arterial disease and 64 age- and sex-matched control subjects. TXA2 biosynthesis was investigated in relation to cardiovascular risk factors by repeated measurements of the urinary excretion of its major enzymatic metabolite, 11-dehydro-TXB2, by radioimmunoassay. Urinary 11-dehydro-TXB2 was significantly (P = .0001) higher in patients with peripheral arterial disease (57 +/- 26 ng/h) than in control subjects (26 +/- 7 ng/h). Seventy percent of patients had metabolite excretion > 2 SD above the normal mean. However, 11-dehydro-TXB2 excretion was enhanced only in association with cardiovascular risk factors. Multivariate analysis showed that diabetes, hypercholesterolemia, and hypertension were independently related to 11-dehydro-TXB2 excretion. During a median follow-up of 48 months, 8 patients experienced major vascular events. These patients had significantly (P = .001) higher 11-dehydro-TXB2 excretion at baseline than patients who remained event free. CONCLUSIONS: The occurrence of large-vessel peripheral arterial disease per se is not a trigger of platelet activation in vivo. Rather, the rate of TXA2 biosynthesis appears to reflect the influence of coexisting disorders such as diabetes mellitus, hypercholesterolemia, and hypertension on platelet biochemistry and function. Enhanced TXA2 biosynthesis may represent a common link between such diverse risk factors and the thrombotic complications of peripheral arterial disease.

Adult↗
PubMed1997

Platelet activation and lipid peroxidation in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Both platelet activation and lipid peroxidation are potential sources of vasoactive eicosanoids that can be produced via the cyclooxygenase pathway, ie, thromboxane (TX) A2, or by free radical-catalyzed peroxidation of arachidonic acid, ie, isoprostanes. We investigated the biosynthesis of TXA2 and F2-isoprostanes, as reflected by the urinary excretion of 11-dehydro-TXB2 and 8-epi-prostaglandin (PG) F2 alpha respectively, in 62 consecutive patients (30 men, 32 women; mean age, 67 +/- 14 years) with acute ischemic stroke. METHODS: At least two consecutive 6-hour urine samples were obtained during the first 72 hours after onset of symptoms. Urinary eicosanoids were measured by previously described radioimmunoassays. RESULTS: Repeated periods of enhanced thromboxane biosynthesis were found in 52% of patients. Urinary 11-dehydro-TXB2 averaged 221 +/- 207 (mean +/- SD; n = 197; range, 13 to 967) pmol/mmol creatinine in 30 patients treated with cyclooxygenase inhibitors (mostly aspirin) at the time of study versus 392 +/- 392 (n = 186; range, 26 to 2533) in 32 untreated patients (P < .001). The corresponding values for 8-epi-PGF2 alpha excretion were 74 +/- 42 (range, 14 to 206) and 83 +/- 65 (range, 24 to 570) pmol/mmol creatinine (P > .05). The correlation between the two metabolites was moderate in both untreated patients (r = .41, P < .001) and patients with cyclooxygenase inhibitors (r = .31, P < .001). In a multiple regression analysis, increased thromboxane production was independently associated with severity of stroke on admission, atrial fibrillation, and treatment with cyclooxygenase-inhibiting drugs. CONCLUSIONS: We conclude that during the first few days after an acute ischemic stroke (1) platelet activation occurs repeatedly in a cyclooxygenase-dependent fashion; (2) platelet activation is not associated with concurrent changes in isoprostane biosynthesis; (3) platelet activation is independently associated with stroke severity and atrial fibrillation; and (4) isoprostane biosynthesis is largely independent of platelet cyclooxygenase activity.

Acute Disease↗
PubMed1996

Tachykinin NK2 receptor antagonists decrease eicosanoid release in lung anaphylaxis.

Two tachykinin NK2 receptor antagonists, MEN 10.627 c(Met-Asp-Trp-Phe-Dap-Leu) and MEN 10.376 [(Tyr5,Trp6,8,9,Lys10]neurokinin A-(4-10), were used to investigate the role of tachykinins in in vitro guinea-pig lung anaphylaxis. Both antagonists dose-dependently decreased bronchoconstriction and the release of thromboxane and prostaglandin E2 induced by antigen challenge in perfused sensitized lungs, but neither had any effect on the basal release of either eicosanoid. The findings indicated that tachykinins released by sensory nerve fibers may contribute to anaphylactic reactions by increasing arachidonic acid metabolite release.

Anaphylaxis↗
PubMed1996

Defective aggregation in cirrhosis is independent of in vivo platelet activation.

BACKGROUND/AIMS: Platelet function abnormalities contribute to the hemostatic defect in patients with cirrhosis. In this study we evaluated the occurrence of in vivo platelet activation as a possible mechanism of defective platelet aggregation in patients with cirrhosis. METHODS: Nine patients with severe (Child B-C) cirrhosis and defective platelet aggregation were studied in comparison with age- and sex-matched healthy controls. The presence of activated platelets in the bloodstream was evaluated by fluorescence-activated flow cytometry using antibodies directed against activation-dependent platelet proteins and by measuring plasma levels of beta-thromboglobulin and platelet factor 4. Urinary levels of 11-dehydro-TXB2 and of 2,3-dinor-TXB2 were assayed by radioimmunoassay following chromatographic separation. RESULTS: In unstimulated platelets, the expression of both GMP 140 and GP 53 was not significantly different in patients with cirrhosis and in controls. After stimulation with ADP and epinephrine, expression of activation-dependent antigens was lower in platelets from patients (GMP 140: 0.64 +/- 0.09 vs 0.73 +/- 0.04, p = 0.02; GP 53: 0.41 +/- 0.13 vs 0.54 +/- 0.14). Plasma levels of beta-thromboglobulin and platelet factor 4, as indexes of in vivo platelet activation, were also comparable in the two groups of subjects. Urinary levels of 11-dehydro-TXB2 and of 2,3-dinor-TXB2, the major systemic metabolites of TXA2, were significantly higher in patients with cirrhosis (1807 +/- 518 vs 341 +/- 121 ng/pg creatinine and 693 +/- 512 vs 205 (93 ng/pg creatinine, respectively, p < 0.001). However, increased excretion of TXB2 metabolites was also observed in three patients with chronic autoimmune thrombocytopenia. CONCLUSIONS: These data indicate that circulating platelets are not activated in cirrhosis, and that defective aggregation is most likely dependent on the alteration of the transmembrane signaling pathways. The increased urinary excretion of systemic TXA2 metabolites may be related to increased intrasplenic platelet destruction.

Aged↗
PubMed1996

Induction of prostaglandin endoperoxide synthase-2 in human monocytes associated with cyclo-oxygenase-dependent F2-isoprostane formation.

1. The isoprostane 8-epi-prostaglandin (PG)F2 alpha is produced by free radical-catalyzed peroxidation of arachidonic acid. It may also be formed as a minor product of the cyclo-oxygenase activity of platelet PGH synthase (PGHS)-1. We investigated 8-epi-PGF2 alpha production associated with induction of the human monocyte PGHS-2 and its pharmacological modulation. 2. Heparinized whole blood samples were drawn from healthy volunteers, 48 h following oral dosing with aspirin 300 mg to suppress platelet cyclo-oxygenase activity. One ml aliquots were incubated with lipopolysaccharide (LPS: 0.1-50 micrograms ml-1) for 0-24 h at 37 degrees C. PGE2 and 8-epi-PGF2 alpha were measured in separated plasma by radioimmunoassay and enzyme immunoassay techniques. 3. Levels of both eicosanoids were undetectable (i.e. < 60 pg ml-1) at time 0. LPS induced the formation of PGE2 and 8-epi-PGF2 alpha in a time- and concentration-dependent fashion, coincident with the induction of PGHS-2 detected by Western blot analysis of monocyte lysates. After 24 h at 10 micrograms ml-1 LPS, immunoreactive PGE2 and 8-epi-PGF2 alpha averaged 10,480 +/- 4,643 and 295 +/- 140 pg ml-1 (mean +/- s.d., n = 6), respectively. 4. Dexamethasone and 5-methanesulphonamido-6-(2,4-difluorothiophenyl)-1-indano ne (L-745,337), a selective inhibitor of the cyclo-oxygenase activity of PGHS-2, reduced PGE2 and 8-epi-PGF2 alpha production in response to LPS. 5. Isolated monocytes produced PGE2 and 8-epi-PGE2 alpha in response to LPS (10 micrograms ml-1) in a time-dependent fashion. Monocyte PGE2 and 8-epi-PGF2 alpha production was largely prevented by dexamethasone (2 microM) and cycloheximide (10 micrograms ml-1) in association with suppression of PGHS-2 but not of PGHS-1 expression. 6. We conclude that the induction of PGHS-2 in human monocytes is associated with cyclo-oxygenase-dependent generation of the vasoconstrictor and platelet-agonist 8-epi-PGF2 alpha.

Adult↗
PubMed1995

Immunological characterization of urinary 8-epi-prostaglandin F2 alpha excretion in man.

F2-isoprostanes are prostaglandin (PG) F2-like compounds that are formed in vivo directly by free radical-catalyzed lipid peroxidation. One of the compounds that can be produced in abundance by such mechanism is 8-epi-PGF2 alpha, a potent vasoconstrictor. We have developed an enzyme immunoassay and a radioimmunoassay for measuring urinary concentrations of 8-epi-PGF2 alpha by raising antibodies against this compound. The antisera presented high titers (> 1/300,000) and provided highly sensitive assays (IC50, 8 and 24 pg/ml, for EIA and RIA, respectively); cross-reactivity with other PG was negligible. The interassay reproducibility of EIA was assessed by measuring the same urine stored frozen in aliquots after solid phase extraction and thin-layer chromatography (17%, n = 13). Measurements of urinary 8-epi-PGF2 alpha by immunoassays were validated using different antisera and by comparison with gas chromatography/mass spectrometry. Healthy volunteers excreted 25 +/- 12 ng of 8-epi-PGF2 alpha/mmol creatinine (n = 19), with no circadian variation over three consecutive 8-hr collection periods (n = 10); preliminary results showed that excretion increased as a function of age. Urinary excretion of 8-epi-PGF2 alpha was unchanged by treatment with two nonsteroidal antiinflammatory drugs, Ibuprofen at 1.2 g/day for 4 days (n = 4) or aspirin as a single administration of 1 g (n = 6). In contrast, the urinary excretion of 11-dehydro-thromboxane B2, a platelet cyclooxygenase-derived metabolite was reduced by more than 80% after aspirin administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Increased thromboxane biosynthesis in essential thrombocythemia.

In order to investigate the in vivo thromboxane (TX) biosynthesis in essential thrombocythemia (ET), we measured the urinary excretion of the major enzymatic metabolites of TXB2, 11-dehydro-TXB2 and 2,3-dinor-TXB2 in 40 ET patients as well as in 26 gender- and age-matched controls. Urinary 11-dehydro-TXB2 was significantly higher (p < 0.001) in thrombocythemic patients (4,063 +/- 3,408 pg/mg creatinine; mean +/- SD) than in controls (504 +/- 267 pg/mg creatinine), with 34 patients (85%) having 11-dehydro-TXB2 > 2 SD above the control mean. Patients with platelet number < 1,000 x 10 (9)/1 (n = 25) had significantly higher (p < 0.05) 11-dehydro-TXB2 excretion than patients with higher platelet count (4,765 +/- 3,870 pg/mg creatinine, n = 25, versus 2,279 +/- 1,874 pg/mg creatinine, n = 15). Average excretion values of patients aging > 55 was significantly higher than in the younger group (4,784 +/- 3,948 pg/mg creatinine, n = 24, versus 2,405 +/- 1,885 pg/mg creatinine, n = 16, p < 0.05). Low-dose aspirin (50 mg/d for 7 days) largely suppressed 11-dehydro-TXB2 excretion in 7 thrombocythemic patients, thus suggesting that platelets were the main source of enhanced TXA2 biosynthesis. The platelet count-corrected 11-dehydro-TXB2 excretion was positively correlated with age (r = 0.325, n = 40, p < 0.05) and inversely correlated with platelet count (r = -0.381, n = 40, p < 0.05). In addition 11 out of 13 (85%) patients having increased count-corrected 11-dehydro-TXB2 excretion, belonged to the subgroup with age > 55 and platelet count < 1,000 x 10(9)/1. We conclude that in essential thrombocythemia: 1) enhanced 11-dehydro-TXB2 excretion largely reflects platelet activation in vivo; 2) age as well as platelet count appear to influence the determinants of platelet activation in this setting, and can help in assessing the thrombotic risk and therapeutic strategy in individual patients.

Adult↗
PubMed1994

Evidence that interleukin-1 beta and tumor necrosis factor inhibit gastric fundus motility via the 5-lipoxygenase pathway.

In this study, we compared the effects of interleukin-1 beta and tumor necrosis factor (TNF) on in vitro rat gastric fundus motility. Interleukin-1 beta produced rapid, concentration-dependent relaxation of rat gastric fundus strips, similar to that seen with TNF, with a maximal effect at 30 U/ml and an estimated EC50 at 0.9 U/ml. The relaxant effects of interleukin-1 beta and TNF were not influenced by the inhibition of cyclooxygenase or nitric oxide-synthase activities. Interleukin-1 beta- and TNF-induced gastric relaxations were concentration dependently inhibited by BW 755c, which inhibits both cyclooxygenase and lipoxygenase, BW A4, which selectively inhibits the 5-lipoxygenase pathway, and SC 41930, a selective leukotriene B4 receptor antagonist, providing pharmacological evidence that leukotriene B4 is involved in the relaxant effects of both cytokines. The interleukin-1 beta- and TNF-induced activation of 5-lipoxygenase pathway did not appear to be triggered by phospholipase A2. An alternative pathway could involve the following steps: (i) activation of phospholipase C and the formation of diacylglycerol; (ii) diacylglycerol-induced activation of protein kinase C; (iii) formation of free arachidonic acid from diacylglycerol by diacylglycerol-lipase. This mechanism is suggested by the finding that leukotriene B4 is able to mimic cytokine-induced strip relaxation only in the presence of phorbol 12-myristate 13-acetate, which selectively activates protein kinase C.

Animals↗
PubMed1994

Peptide histidine isoleucine-like immunoreactivity release from the rat gastric fundus.

1. Longitudinal muscle strips from the rat gastric fundus were subjected to in vitro electrical field stimulation (EFS) under non-adrenergic non-cholinergic (NANC) conditions to study the release of peptide histidine isoleucine-like immunoreactivity (PHI-LI) and the correlation between PHI-LI release and NANC relaxation. 2. Different radioimmunoassay (RIA) systems employing C-terminal- and N-terminal-specific anti-PHI sera were used to determine the relative contributions of PHI and its C-terminally extended forms, peptide histidine glycine (PHI-Gly) and peptide histidine valine [PHV(1-42)], to the PHI-LI released by the rat gastric fundus. 3. In the presence of atropine (1 microM) and guanethidine (5 microM), EFS (120 mA, 1 ms, 0.25-32.0 Hz, trains of 2 min) induced frequency-dependent relaxations of 5-hydroxytryptamine (3 microM) pre-contracted strips. 4. EFS at frequencies of 8-32 Hz evoked significant increases in PHI-LI outflow. The increases in PHI-LI outflow evoked by 16-Hz EFS were abolished by tetrodotoxin (3 microM) and by a calcium-free medium, indicating an active release process from intramural nerves. 5. The EFS-induced release of PHI-LI measured with the N-terminal-specific antiserum was significantly greater than that detected with the C-terminal-specific antisera. 6. Sephadex G-25 gel permeation chromatographic analysis was performed on the PHI-LI release in response to 32-Hz EFS. A C-terminal-specific antiserum revealed one peak co-eluting with the rat PHI standard. When PHI-LI was measured with the N-terminal-specific antiserum, two peaks were found that co-eluted with the rat PHV(1-42) and rat PHI-Gly/PHI standards, respectively. 7. The present data suggest that the extended forms of PHI are the primary components of the PHI-LI released by NANC inhibitory neurones in the rat gastric fundus and support a NANC inhibitory neurotransmitter role for PHI and its extended forms in this tissue.

Animals↗
PubMed1994

Evidence for episodic platelet activation in acute ischemic stroke.

BACKGROUND AND PURPOSE: Enhanced thromboxane biosynthesis has previously been reported in patients with acute ischemic stroke. In this study we examined the time course of thromboxane biosynthesis after the onset of symptoms in 13 patients with acute cerebral infarction. METHODS: We obtained five to eight consecutive 6-hour urine samples from each of these 13 patients within the first 48 hours after onset of symptoms to study the dynamics of platelet activation in this setting. The urinary excretion of the major enzymatic metabolite of thromboxane B2, 11-dehydro-thromboxane B2, was measured by a previously validated radioimmunoassay. The excretion rate was compared with that of 20 control patients with nonvascular neurological diseases. RESULTS: Eleven patients (85%) had at least one value exceeding 2 SD of the control mean (251 pmol/mmol creatinine). The proportion of samples with an elevated 11-dehydro-thromboxane B2 level was markedly similar in each of the eight 6-hour collection periods (mean, 52 +/- 8%; range, 40% to 67%). In 4 patients (31%) the excretion rate was elevated in all measurements obtained. In the 11 patients with enhanced thromboxane biosynthesis, no uniform pattern of changes over time in metabolite excretion emerged, with 3 patients having peak values at 0 to 12 hours, 3 at 12 to 24 hours, 3 at 24 to 36 hours, and 2 at 36 to 48 hours. The level and dynamics of 11-dehydro-thromboxane B2 excretion were related neither to the neurological symptoms nor to the type or site of the cerebral ischemia. CONCLUSIONS: We conclude that episodes of platelet activation occur repeatedly during the first 48 hours after the onset of symptoms of an acute ischemic stroke. Given its apparent dynamic nature, this ongoing process may be amenable to pharmacologic modulation.

Adult↗
PubMed1994

Effects of unfractionated and low molecular weight heparins on platelet thromboxane biosynthesis "in vivo".

Several "in vitro" and "in vivo" studies indicate that heparin administration may affect platelet function. In this study we investigated the effects of prophylactic heparin on thromboxane (Tx)A2 biosynthesis "in vivo", as assessed by the urinary excretion of major enzymatic metabolites 11-dehydro-TxB2 and 2,3-dinor-TxB2. Twenty-four patients who were candidates for cholecystectomy because of uncomplicated lithiasis were randomly assigned to receive placebo, unfractionated heparin, low molecular weight heparin or unfractionated heparin plus 100 mg aspirin. Measurements of daily excretion of Tx metabolites were performed before and during the treatment. In the groups assigned to placebo and to low molecular weight heparin there was no statistically significant modification of Tx metabolite excretion while patients receiving unfractionated heparin had a significant increase of both metabolites (11-dehydro-TxB2: 3844 +/- 1388 vs 2092 +/- 777, p < 0.05; 2,3-dinor-TxB2: 2737 +/- 808 vs 1535 +/- 771 pg/mg creatinine, p < 0.05). In patients randomized to receive low-dose aspirin plus unfractionated heparin the excretion of the two metabolites was largely suppressed thus suggesting that platelets are the primary source of enhanced thromboxane biosynthesis associated with heparin administration. These data indicate that unfractionated heparin causes platelet activation "in vivo" and suggest that the use of low molecular weight heparin may avoid this complication.

Adult↗
PubMed1993

Aspirin, but not heparin, suppresses the transient increase in thromboxane biosynthesis associated with cardiac catheterization or coronary angioplasty.

OBJECTIVES: We sought to study the dose dependence of in vivo suppression by aspirin of enhanced thromboxane biosynthesis in the setting of coronary angioplasty and to evaluate the effects of heparin and aspirin during cardiac catheterization. BACKGROUND: Percutaneous transluminal coronary angioplasty induces a controlled injury of the intima of the diseased arterial segment, with rapid deposition of platelets at the site of dilation. Thus, it provides a clinical model of intracoronary platelet activation. METHODS: The urinary excretion of a major enzymatic metabolite of thromboxane A2, 11-dehydro-thromboxane B2, was measured in 57 patients with stable coronary artery disease undergoing cardiac catheterization (n = 28) or elective single-vessel percutaneous transluminal coronary angioplasty (n = 29). Three consecutive urine collections were obtained from all patients before during and after either procedure. Patients undergoing catheterization were treated with the following regimens: a) no aspirin for > or = 10 days and no heparin (n = 12); b) no aspirin for > or = 10 days but heparin, 10,000 IU, at the time of catheterization (n = 5); c) aspirin, 300 mg/day, for at least 5 days (n = 11). Patients undergoing coronary angioplasty were randomly assigned to short-term treatment with aspirin given as a) 75 mg/day for > or = 5 days before angioplasty (n = 11); b) 300 mg/day for > or = 3 days before angioplasty (n = 9); or c) 300 mg/day for > or = 3 days before angioplasty followed by 1,000 mg during angioplasty (n = 9). RESULTS: In patients undergoing catheterization, urinary 11-dehydro-thromboxane B2 excretion (pg/mg creatinine) increased from 563 +/- 481 (mean +/- SD) to 1,684 +/- 1,332 in the absence and from 620 +/- 191 to 1,588 +/- 597 in the presence of heparin. No increase was observed in the group receiving aspirin (from 240 +/- 141 to 215 +/- 115). In patients undergoing coronary angioplasty treated with aspirin, 75 mg/day, urinary 11-dehydro-thromboxane B2 averaged 180 +/- 112, 223 +/- 178 and 294 +/- 260, respectively, before, during and after the procedure. At 300 mg/day, the corresponding values were 185 +/- 48, 217 +/- 70 and 197 +/- 93. In patients also receiving aspirin, 1,000 mg, during angioplasty, 11-dehydro-thromboxane B2 averaged 151 +/- 66, 138 +/- 43 and 133 +/- 77, respectively. CONCLUSIONS: Enhanced thromboxane biosynthesis associated with cardiac catheterization or coronary angioplasty can be largely suppressed by low dose aspirin. This finding is consistent with the view that this alteration reflects platelet activation.

Aged↗
PubMed1993

Effects of vasoactive intestinal polypeptide on antigen-induced bronchoconstriction and thromboxane release in guinea-pig lung.

1. Exogenous vasoactive intestinal polypeptide (VIP) infused into the pulmonary artery of isolated and ventilated lungs of guinea-pigs decreased, in a dose-dependent fashion (1.0-10.0 nmol), airway resistance and thromboxane B2 (TXB2, the stable hydrolysis product of TXA2) release in the perfusion medium. Prostacyclin (PGI2) synthesis, as reflected by the release of its stable hydrolysis product 6-oxo-PGF1 alpha, was unaffected. Pretreatment with the 5-lipoxygenase inhibitor BWA4c (3.5 x 10(-5) M) did not modify the bronchodilatory effect of VIP or its inhibitory action on TXB2 release. 2. Basal release of immunoreactive VIP from perfused lungs decreased from an initial value of 0.96 +/- 0.10 ng min-1 (mean +/- s.e.mean) in the first 2 min to an average of 0.58 +/- 0.10 ng min-1 in the following 15-20 min. 3. Antigen challenge with ovalbumin (0.1%) in sensitized lungs caused an anaphylactic reaction in 45% of tested lungs, concomitant with a 5 fold increase in both VIP and TXB2 release. Tetrodotoxin pretreatment (10(-6) M) reduced basal VIP release by > 80% and abolished the VIP increase observed during anaphylaxis, without modifying TXB2 release or the bronchoconstrictor response. 4. Indomethacin (10(-6) M) inhibited TXB2 synthesis and release by > 90%, delayed the bronchoconstrictor response and blunted the increased VIP release during lung anaphylaxis, without influencing basal VIP release. 5. The 5-lipoxygenase inhibitor BWA4c (3.5 x 10(-5) M) blunted the increase of TXB2 and VIP release from guinea-pig lung and attenuated the bronchoconstrictor response following ovalbumin challenge. 6. The administration of exogenous VIP as a continuous infusion (10-8 M) attenuated the bronchoconstriction and the release of cyclo-oxygenase metabolites following antigen challenge.7. Acetylcholine (10-6-l0-5 M) infused into the pulmonary artery induced a dose-dependent bronchoconstriction not associated with enhanced VIP or TXB2 release.8. The TXA2 mimetic U-46619 (0.1-1.0 nmol) caused dose-dependent increases in airway resistance,concomitant with an up to 10 fold increase in VIP release. VIP inhibited arachidonate-induced in vitro aggregation of washed rabbit platelets in a dose-dependent manner over a dose range 10-8 10-6 M.Despite the antiaggregatory effect of VIP, TXB2 and PGE2 synthesis was reduced only to a minor extent,and there was no redirection of arachidonate metabolism from TXA2 to PGE2, indicating that VIP does not act as a TX synthase inhibitor in vitro.9. We conclude that VIP may play a role in regulating bronchial smooth muscle reactivity in lung anaphylaxis by inhibiting the synthesis and release of TXA2, a potent vasoactive and bronchoconstrictor agent. TXA2, on the other hand, strongly enhances neuronal VIP release.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

Excretion of thromboxane metabolites in healthy women after cessation of smoking.

Cigarette smokers, but not former smokers, excrete more thromboxane A2 (TxA2) metabolites in the urine than do lifelong nonsmokers, which suggests chronic activation of their platelets. To further characterize the effect elicited by smoking on platelet function, we followed the change in urinary excretion of the 2,3-dinor (Tx-M) and 11-dehydro (dTx) metabolites of TxA2, analyzed by gas chromatography/mass spectrometry and radioimmunoassay, respectively, in eight healthy women who quit habitual smoking and compared it with the recovery of these metabolites after a single dose of acetylsalicylic acid (ASA). Tx-M and dTx before cessation of smoking were approximately 550 and 600 pg/mg creatinine, respectively. Within 3 days after quitting smoking, Tx-M and dTx had dropped to stable levels of approximately 300 and 350 pg/mg, respectively. The rates of change in excretion of Tx-M and dTx after smoking cessation were more rapid (p < 0.02 and 0.02, respectively) than those observed during the recovery of platelet function after a single dose of ASA. The excretion of 2,3-dinor-6-keto-prostaglandin F1 alpha, a metabolite of prostacyclin, was not affected by smoking cessation. We conclude that cigarette smoking elicits an increase in platelet activity in the absence of vascular injury. This increase is reversible within the life span of the platelets.

Administration, Oral↗
PubMed1993

Increased thromboxane biosynthesis in patients with acute cerebral ischemia.

BACKGROUND AND PURPOSE: Clinical and experimental studies suggest that platelets have a major role in the pathogenesis of cerebral ischemia. However, ex vivo both platelet aggregation studies and measurements of platelet-derived products in patients with cerebral ischemia have shown inconsistent results. The present study was designed to resolve this inconsistency. METHODS: We have measured the urinary excretion of a thromboxane metabolite, 11-dehydro-thromboxane B2, by a previously validated radioimmunoassay technique in 51 patients with acute cerebral ischemia who had experienced either a transient ischemic attack (14 patients) or an ischemic stroke (37 patients) and in 20 control patients with nonvascular neurological disorders. The median time between the onset of symptoms and urine sampling was 24 hours (range, from 2 hours to 8 days). RESULTS: The excretion rate of immunoreactive 11-dehydro-thromboxane B2 ranged between 39 and 478 pmol/mmol creatinine in patients with a transient ischemic attack and between 23 and 5,916 pmol/mmol creatinine in stroke patients, with 29% (p = 0.18) and 51% (p = 0.004) of the urine samples, respectively, exceeding the upper limit of the control samples (251 pmol/mmol creatinine [mean +/- 2 SD]) (p = 0.01). In stroke patients, metabolite excretion was not related to the type (cortical or "lacunar") or site of cerebral infarction. Low-dose aspirin (50 mg per day for 7 days) reduced the urinary excretion by approximately 85% in 11 consecutive stroke patients. CONCLUSIONS: We conclude that 1) episodes of enhanced thromboxane biosynthesis are detected infrequently in patients with a transient ischemic attack, 2) aspirin-suppressible episodes of increased thromboxane formation can be detected during the early phase of acute ischemic stroke, and 3) this finding may provide a rationale for testing the efficacy and safety of this drug in this setting.

Acute Disease↗
PubMed1993

Abnormally high thromboxane biosynthesis in homozygous homocystinuria. Evidence for platelet involvement and probucol-sensitive mechanism.

Homocystinuria due to homozygous cystathionine beta-synthase deficiency is an inborn error of metabolism characterized by a high incidence of thrombosis and premature atherosclerosis. We evaluated TXA2 biosynthesis in vivo and several in vitro tests of platelet function in 11 homocystinuric patients and 12 healthy controls. In vitro, patients' platelet aggregation was within control values as were TXB2 formation, fibrinogen binding, and ATP secretion in response to thrombin. In contrast, the urinary excretion of 11-dehydro-TXB2, a major enzymatic derivative of TXA2, was > 2 SD of controls in all patients (1,724 +/- 828 pg/mg creatinine, mean +/- SD, in patients vs. 345 +/- 136 in controls, P < 0.001). The administration to four patients of low-dose aspirin (50 mg/d for 1 wk) reduced metabolite excretion by > 80%. The recovery of 11-dehydro-TXB2 excretion over the 10 d that followed aspirin cessation occurred with a pattern consistent with the entry into the circulation of platelets with intact cyclooxygenase activity. Prolonged partial reduction in the abnormally high excretion of both 11-dehydro-TXB2 and 2,3-dinor-TXB2, was also observed in seven patients who ingested 500 mg daily for 3 wk of the antioxidant drug probucol. These results provide evidence for enhanced thromboxane biosynthesis in homocystinuria and for its partial dependence on probucol-sensitive mechanisms. Furthermore, the elevated TXA2 formation in homocystinuria is likely to reflect, at least in part, in vivo platelet activation.

Adolescent↗
PubMed1992

Increased thromboxane biosynthesis in patients with polycythemia vera: evidence for aspirin-suppressible platelet activation in vivo.

Increased thromboxane (TX) production and modified aspirin sensitivity has been detected in vitro in platelets isolated from patients with polycythemia vera. To verify the relevance of these capacity-related measurements to the actual rate of TXA2 biosynthesis in vivo and its suppression by oral aspirin, we have investigated the urinary excretion of major enzymatic metabolites of TXB2 in 17 patients with polycythemia vera and 23 gender- and age-matched controls. Urinary 11-dehydro-TXB2 and 2,3-dinor-TXB2 were measured by previously validated radioimmunoassays. In addition, urinary immunoreactive leukotriene (LT) E4 was measured to explore the 5-lipoxygenase pathway of arachidonate metabolism. Polycythemic patients had significantly (P < .001) higher excretion rates of both 11-dehydro-TXB2 (1,033 +/- 1,050 v 117 +/- 45 pmol/mmol creatinine; mean +/- SD) and 2,3-dinor-TXB2 (725 +/- 676 v 82 +/- 43 pmol/mmol creatinine) than controls. In contrast, urinary LTE4 was not significantly different. Enhanced metabolite excretion did not correlate with the platelet count or with the hematocrit value, and was not related to the current treatment or to a clinical history of thrombotic complications. Platelet TX receptor studies did not show any significant changes in the binding characteristics of two different ligands. A platelet-selective regimen of aspirin therapy (50 mg/d for 7 to 14 days) was associated with greater than 80% suppression in metabolite excretion in nine patients. These results are consistent with abnormal stimuli operating in polycythemia vera to induce a selective enhancement in the platelet biosynthesis of TXA2 without changes in receptor binding. This in vivo abnormality in platelet biochemistry can be largely suppressed by low doses of aspirin.

Adult↗