thromboxane-a2 and Diabetes-Mellitus--Type-2

Type 2 diabetes mellitus (T2DM) is a major cardiovascular risk factor. Persistent platelet activation plays a key role in atherothrombosis in T2DM. However, current antiplatelet treatments appear less effective in T2DM patients vs nondiabetics at similar risk. A large body of evidence supports the contention that oxidative stress, which characterizes DM, may be responsible, at least in part, for less-than-expected response to aspirin, with multiple mechanisms acting at several levels. This review discusses the pathophysiological mechanisms related to oxidative stress and contributing to suboptimal aspirin action or responsiveness. These include: (1) mechanisms counteracting the antiplatelet effect of aspirin, such as reduced platelet sensitivity to the antiaggregating effects of NO, due to high-glucose-mediated oxidative stress; (2) mechanisms interfering with COX acetylation especially at the platelet level, e.g., lipid hydroperoxide-dependent impaired acetylating effects of aspirin; (3) mechanisms favoring platelet priming (lipid hydroperoxides) or activation (F2-isoprostanes, acting as partial agonists of thromboxane receptor), or aldose-reductase pathway-mediated oxidative stress, leading to enhanced platelet thromboxane A2 generation or thromboxane receptor activation; (4) mechanisms favoring platelet recruitment, such as aspirin-induced platelet isoprostane formation; (5) modulation of megakaryocyte generation and thrombopoiesis by oxidative HO-1 inhibition; and (6) aspirin-iron interactions, eventually resulting in impaired pharmacological activity of aspirin, lipoperoxide burden, and enhanced generation of hydroxyl radicals capable of promoting protein kinase C activation and platelet aggregation. Acknowledgment of oxidative stress as a major contributor, not only of vascular complications, but also of suboptimal response to antiplatelet agents in T2DM, may open the way to designing and testing novel antithrombotic strategies, specifically targeting oxidative stress-mediated mechanisms of less-than-expected response to aspirin.

Topics: Aldehyde Reductase; Aspirin; Blood Platelets; Diabetes Mellitus, Type 2; F2-Isoprostanes; Glucose; Glycosylation; Humans; Lipid Peroxides; Nitric Oxide; Oxidative Stress; Peroxynitrous Acid; Platelet Activation; Platelet Aggregation Inhibitors; Thrombosis; Thromboxane A2

Type 2 diabetes mellitus is characterised by persistent thromboxane (TX)-dependent platelet activation, regardless of disease duration. Low-dose aspirin, that induces a permanent inactivation of platelet cyclooxygenase (COX)-1, thus inhibiting TXA2 biosynthesis, should be theoretically considered the drug of choice. The most up-to-date meta-analysis of aspirin prophylaxis in this setting, which includes three trials conducted in patients with diabetes and six other trials in which such patients represent a subgroup within a broader population, reported that aspirin is associated with a non-significant decrease in the risk of vascular events, although the limited amount of available data precludes a precise estimate of the effect size. An increasing body of evidence supports the concept that less-than-expected response to aspirin may underlie mechanisms related to residual platelet hyper-reactivity despite anti-platelet treatment, at least in a fraction of patients. Among the proposed mechanisms, the variable turnover rate of the drug target (platelet COX-1) appears to represent the most convincing determinant of the inter-individual variability in aspirin response. This review intends to develop the idea that the understanding of the determinants of less-than-adequate response to aspirin in certain individuals, although not changing the paradigm of the indication to low-dose aspirin prescription in primary prevention, may help identifying, in terms of easily detectable clinical or biochemical characteristics, individuals who would attain inadequate protection from aspirin, and for whom different strategies should be challenged.

Topics: Animals; Aspirin; Biomarkers, Pharmacological; Blood Platelets; Cardiovascular Diseases; Cyclooxygenase 1; Diabetes Mellitus, Type 2; Humans; Platelet Activation; Precision Medicine; Risk Assessment; Thromboxane A2

This review describes the current status of antiplatelet therapy in prevention of cardiovascular events of an atherothrombotic nature. The efficacy of aspirin clearly outweighs bleeding risk in secondary prevention, with the relevant exception of patients with peripheral arterial disease (PAD). In trials of primary prevention, aspirin has a limited advantage, which is challenged by the risk of major bleeding. A typical example is primary prevention in type 2 diabetes mellitus, in which a number of trials and a recent meta-analysis have confirmed these limitations. In various settings, clopidogrel has been shown to be marginally more effective than aspirin. Despite a non-negligible bleeding risk, the combination of aspirin-clopidogrel has provided satisfactory results in conditions at high thrombotic risk but rather disappointing results in the long-term treatment of chronic stable cardiovascular disease. The combination of aspirin-dipyridamole was shown to be superior to aspirin alone and equivalent to clopidogrel alone for secondary prevention in cerebrovascular patients. Limitations in the efficacy of antiplatelet agents are partly inherent in their mechanism of action and should not be considered simply as 'treatment failures'. Among other factors, individual variability of response to antiplatelet drugs also plays a meaningful role. Variability of response and 'resistance' may result from drug interactions, baseline and residual platelet hyperactivity, increased platelet turnover, pharmacogenetic factors and others. Poor biological response to aspirin and/or clopidogrel is also frequent in clinical settings such as diabetes, obesity and acute coronary syndromes. The correlation between biological resistance and impaired clinical efficacy of aspirin, and especially clopidogrel, is currently accepted, although with limitations due to the different methods used to assess platelet response. Indeed, the concept of individual 'tailoring' of antiplatelet regimens on the basis of previous laboratory or 'point of care' platelet function tests has been validated in a number of recent trials. The search for and validation of new antiplatelet agents with already known, or totally new, mechanisms of action have also been undertaken with increasing eagerness. Among new adenosine diphosphate receptor antagonists, prasugrel is already registered, and ticagrelor and cangrelor are being developed. New mechanisms being explored are blockade of thrombin-induced platelet

Topics: Atherosclerosis; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Platelet Aggregation Inhibitors; Thrombosis; Thromboxane A2; Treatment Outcome

The percentage of diabetic patients who do not benefit from the protective effect of aspirin is larger than in other populations at cardiovascular risk.. We compared the ability of aspirin to suppress TxA2 and platelet activation in vivo, in type-2 diabetics vs. high-risk non-diabetic patients.. Urinary 11-dehydro-TXB2, plasma sCD40 L, and sP-selectin were measured, together with indices of low-grade inflammation, glycemic control, and lipid profile, in 82 patients with type-2 diabetes and 39 without diabetes, treated with low doses of aspirin.. Urinary 11-dehydro-TxB2, plasma sCD40L and sP-selectin were significantly higher in diabetics than in controls: [38.9 (27.8-63.3) vs. 28.5 (22.5-43.9) ng mmol(-1) of creatinine, P = 0.02], [1.06 (0.42-3.06) vs. 0.35 (0.22-0.95) ng mL(-1); P = 0.0001], [37.0 (16.8-85.6) vs. 20.0 (11.2-35.6) ng mL(-1), P = 0.0001], respectively. The proportion of individuals with diabetes increased across quartiles of 11-dehydro-TxB2, sCD40L, and sP-selectin, with the highest quartiles of 11-dehydro-TxB2, sCD40L and sP-selectin, including 66%, 93.3%, and 93.3% of individuals with diabetes. Markers of platelet activation positively correlated with indices of glycemic control but not with markers of low-grade inflammation.. Platelet dysfunction associated with insufficient glycemic control, may mediate persistent platelet activation under aspirin treatment.

Topics: Aspirin; Biomarkers; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Glycemic Index; Humans; Inflammation; Platelet Activation; Thromboxane A2

The goals of this study were to characterize the platelet contribution to soluble CD40 ligand (sCD40L), to correlate its formation with the extent of oxidative stress and platelet activation, and to investigate the effects of improved metabolic control and low-dose aspirin on these processes.. Inflammation, oxidative stress, and platelet activation are involved in the pathogenesis of type 2 diabetes (T2DM) and its complications. The CD40-CD40L interactions result in inflammatory and pro-thrombotic responses.. Urinary 8-iso-prostaglandin (PG)F2alpha and 11-dehydro-thromboxane (TX)B2, in vivo markers of oxidative stress and platelet activation, respectively, plasma CD40L, and C-reactive protein (CRP) were measured in 114 T2DM patients and 114 control patients. A randomized, parallel group, 17-day study of aspirin (30, 100, or 325 mg/day) was performed in 18 T2DM patients. A similar study was performed in six healthy volunteers (aspirin, 100 mg/day). Twenty poorly controlled T2DM patients were studied before and after improved metabolic control.. Compared with control patients, diabetic patients showed significantly higher levels of 8-iso-PGF2alpha, 11-dehydro-TXB2, sCD40L, and CRP. On multiple regression analysis, 11-dehydro-TXB2 and 8-iso-PGF2alpha excretion rates predicted sCD40L levels. Soluble CD40L linearly correlated with 11-dehydro-TXB2 (rho = 0.67, p < 0.0001), and both were reduced after one week of aspirin (p < 0.0026), with slow recovery over 10 days after aspirin withdrawal. Improved metabolic control was associated with a reduction in sCD40L, 8-iso-PGF2alpha, and 11-dehydro-TXB2.. This study provides several lines of evidence for the dependence of sCD40L release on TXA(2)-dependent platelet activation in T2DM and provides novel mechanistic insight into the amplification loops of persistent platelet activation in this setting.

Topics: Aged; Aspirin; CD40 Ligand; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Dinoprost; Female; Humans; Lipid Peroxidation; Male; Middle Aged; Oxidative Stress; Platelet Activation; Platelet Aggregation Inhibitors; Radioimmunoassay; Thromboxane A2; Thromboxane B2

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.. 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.. 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.

Topics: Adult; Aged; Aspirin; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Multivariate Analysis; Platelet Activation; Prospective Studies; Reproducibility of Results; Risk Factors; Smoking; Thromboxane A2; Thromboxane B2; Vascular Diseases

Chronic hyperglycemia contributes to vascular complications in diabetes. Resveratrol exerts anti-diabetic and anti-platelet action. This study aimed to evaluate the effects of resveratrol on metabolism and the function of blood platelets under static and in in vitro flow conditions in patients with type 2 diabetes. Blood obtained from 8 healthy volunteers and 10 patients with type 2 diabetes was incubated with resveratrol and perfused over collagen-coated capillaries. Isolated blood platelets were incubated with resveratrol and activated by collagen to assess platelet function, metabolism, ATP release, TXA

Topics: Blood Platelets; Cardiovascular Diseases; Collagen; Diabetes Mellitus, Type 2; Humans; Platelet Aggregation; Resveratrol; Thrombosis; Thromboxane A2

We studied the relationship between 3-phosphoinositide-dependent protein kinase 1 (PDK1) and contractions induced by serotonin, phenylephrine, and thromboxane A

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 3-Phosphoinositide-Dependent Protein Kinases; Animals; Carotid Arteries; Chronic Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Indazoles; Male; Nitric Oxide; Nitric Oxide Synthase; Phenylephrine; Pyrimidines; Rats; Rats, Wistar; Serotonin; Signal Transduction; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents

Dipeptidyl peptidase-4 (DPP4) is a key protein in glucose homeostasis and a pharmacological target in type 2 diabetes mellitus. This study explored whether the novel adipokine soluble DPP4 (sDPP4) can cause endothelial dysfunction, an early marker of impaired vascular reactivity.. Reactivity was studied in mesenteric arteries from 3-month-old female mice, using a small vessel myograph. Thromboxane A2 (TXA2) release was explored in cultured human coronary artery endothelial cells by enzyme immunoassay.. Neither the contractility to noradrenaline nor the endothelium-independent relaxations induced by sodium nitroprusside were modified by sDPP4. However, sDPP4 impaired in a concentration-dependent manner the endothelium-dependent relaxation elicited by acetylcholine. The DPP4 inhibitors K579 and linagliptin prevented the defective relaxation induced by sDPP4, as did the protease-activated receptor 2 (PAR2) inhibitor GB83. Downstream of PAR2, the cyclooxygenase (COX) inhibitor indomethacin, the COX2 inhibitor celecoxib or the thromboxane receptors blocker SQ29548 prevented the deleterious effects of sDPP4. Accordingly, sDPP4 triggered the release of TXA2 by endothelial cells, whereas TXA2 release was prevented by inhibiting DPP4, PAR2 or COX.. In summary, these findings reveal sDPP4 as a direct mediator of endothelial dysfunction, acting through PAR2 activation and the release of vasoconstrictor prostanoids. By interfering with these actions, DPP4 inhibitors might help preserving endothelial function in the context of cardiometabolic diseases.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Female; Mesenteric Arteries; Mice; Mice, Inbred C57BL; Receptor, PAR-2; Thromboxane A2

1-[4-[2-(4-Bromobenzene-sulfonamino)ethyl]phenylsulfonyl]-3-(trans-4-methylcy-clohexyl)urea(I(4), CAS865483-06-3); a totally synthetic new sulfonylurea compound, combining the hypoglycemic active structure of Glimepiride (CAS 93479-97-1) and anti-TXA(2) receptor (TP) active structure of BM-531(CAS 284464-46-6), was designed and synthesized. Its effects on TXA(2) synthesis and TP have not been reported yet.. To study the inhibitory effects of I(4) and its mechanisms of action on TXA(2) and TP.. Platelet aggregation studies were performed on human platelet, rat whole blood platelet and rabbit platelet, platelets aggregation was induced by TP agonist U-46619(stable analog of TXA(2), CAS 56985-40-1). Plasma TXB(2) and 6-keto-prostaglandin F(1α) (6-keto-PGF(1α)) were used as markers to determine the effect of I(4) on thromboxane synthesis. Fluo-3-AM was used to measure the cytosolic Ca(2+) concentrations ([Ca(2+)](i)) in rabbit platelet. Aorta rings with and without endothelium were prepared and aorta contraction was induced by U-46619. A model of type 2 diabetes mellitus was established by intraperitoneal injection of low dose of streptozocin to rats fed a high-calorie diet. Both normal rats and type 2 diabetic rats were used to assay the inhibitory effect of I(4) on platelet aggregation induced by U-46619.. I(4) exhibited a higher inhibitory potency than Glimepiride on U-46619 induced platelet aggregation in vitro and in vivo. I(4) increased the ratio of plasma PGI(2)/TXA(2) and decreased [Ca(2+)](i) release from platelet internal stores. In addition, I(4) presented a vasorelaxant activity on isolated rat aorta contraction induced by U-46619.Oral administration of I(4) (1~10mg/kg) markedly and dose-dependently inhibited platelet aggregation in both normal rats and type 2 diabetic rats.. I(4) significantly inhibited platelet aggregation induced by U-46619 in vitro and in vivo, and rat aorta contraction. It probably acts by partly blocking TXA(2) action, decreasing the platelet intracellular Ca(2+), and increasing the PGI(2)/TXA(2) ratio.

Topics: Animals; Aorta; Blood Platelets; Calcium; Diabetes Mellitus, Type 2; Humans; Male; Muscle Contraction; Muscle, Smooth, Vascular; Platelet Aggregation; Platelet Aggregation Inhibitors; Rabbits; Rats; Rats, Sprague-Dawley; Sulfonylurea Compounds; Thromboxane A2

Angiotensin II has a key role in the control of resistance artery tone and local blood flow. Angiotensin II possesses 2 main receptors. Although angiotensin II type 1 receptor is well known and is involved in the vasoconstrictor and growth properties of angiotensin II, the role of the angiotensin II type 2 receptor (AT2R) remains much less understood. Although AT2R stimulation induces vasodilatation in normotensive rats, it induces vasoconstriction in pathological conditions involving oxidative stress and cyclooxygenase 2 expression. Thus, we studied the influence of cyclooxygenase 2 on AT2R-dependent tone in diabetes mellitus. Mesenteric resistance arteries were isolated from Zucker diabetic fatty (ZDF) and lean Zucker rats and studied using in vitro using wire myography. In ZDF rats, AT2R-induced dilation was lower than in lean rats (11% versus 21% dilation). Dilation in ZDF rats returned to the control (lean rats) level after acute superoxide reduction (Tempol and apocynin), cyclooxygenase 2 inhibition (NS398), or thromboxane A(2) synthesis inhibition (furegrelate). Cyclooxygenase 2 expression and superoxide production were significantly increased in ZDF rat arteries compared with arteries of lean rats. After chronic treatment with Tempol, AT2R-dependent dilation was equivalent in ZDF and lean rats. Chronic treatment of ZDF rats with NS398 also restored AT2R-dependent dilation to the control (lean rats) level. Plasma thromboxane B(2) (thromboxane A(2) metabolite), initially high in ZDF rats, was decreased by chronic Tempol and by chronic NS398 to the level found in lean Zucker rats. Thus, in type 2 diabetic rats, superoxide and thromboxane A(2) reduced AT2R-induced dilation. These findings are important to take into consideration when choosing vasoactive drugs for diabetic patients.

Topics: Analysis of Variance; Animals; Blotting, Western; Cyclic N-Oxides; Cyclooxygenase 2; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Male; Mesenteric Arteries; Microscopy, Confocal; Probability; Random Allocation; Rats; Rats, Zucker; Reactive Oxygen Species; Receptor, Angiotensin, Type 2; Spin Labels; Thromboxane A2; Vascular Resistance; Vasodilation

Although aspirin treatment is useful in reducing ischaemic events in diabetic patients, recent studies suggest that it is less effective when compared with non-diabetics (ND). We sought to evaluate COX-1 sensitivity and thromboxane A(2) (TxA(2)) production in type 1 (T1DM) and type 2 diabetic (T2DM) patients under chronic aspirin treatment, and also evaluate the association between thromboxane A(2) (TxA(2)) production and markers of inflammation and metabolic control, such as high-sensitivity C-reactive protein, fasting blood glucose, and haemoglobin A1c (HbA1c).. Agonist-induced platelet aggregation (PA) and TxB(2), a stable metabolite of TxA(2), production, serum TxB(2), and platelet COX-1 and COX-2 expression were studied in T2DM patients, T1DM patients, and high-risk ND subjects, all receiving a low dose of aspirin. TxB(2) formation was studied in platelets treated in vitro with aspirin alone or with a COX-2 inhibitor (NS-398). PA, collagen-induced TxB(2) production, and serum TxB(2) were higher in T1DM and T2DM patients than in ND subjects. TxB(2) production was reduced in diabetic patients by in vitro treatment with aspirin. COX-2 was expressed in all diabetic patients but only in 46% of ND patients. In diabetic patients significant correlations were observed between TxB(2) production and both fasting plasma glucose and HbA1c.. COX-1 sensitivity and TxB(2) production is similarly reduced in both T1DM and T2DM patients under chronic aspirin treatment. The association between TxB(2) production and either fasting plasma glucose and HbA1c levels suggests that in diabetic patients hyperglycaemia is a determinant of the reduced platelet sensitivity to aspirin.

Topics: Adult; Aged; Aspirin; Blood Platelets; C-Reactive Protein; Case-Control Studies; Cyclooxygenase 1; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Resistance; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Statistics, Nonparametric; Thromboxane A2

Type-2 diabetes is characterized by endotheliopathy, which increases target organ damage and mortality. There is excessive endothelin-1 and TXA(2) production, and abnormal vascular reactivity to endothelin-1, manifested as a paradoxical hypotensive action in Zucker diabetic, but not lean rats. We examined the hypothesis that there is an alteration in the ET-A/ET-B receptor subtype sensitivity, and/or the interaction or cross-talk between ET-1 and TXA(2) in type-2 diabetes, using Zucker diabetic rats and their lean littermates.. Hemodynamic studies were performed in lean and Zucker fatty diabetic rats of both sexes. Laser doppler flowmetry was used to measure renal cortical (RCF) and medullary blood flow (MBF) responses. Dose response curves for mean arterial blood pressure (MAP), MBF and RCF in response to ET-1, U46619, acetylcholine, and L-NAME (25mg/kg) were constructed after pre-treatment of the rats with either BQ610 1mg/kg i.v. or BQ788 0.5mg/kg i.v. The effects of BQ610 and BQ788 on whole blood impedance aggregation were also assessed.. BQ788, but not BQ610 abolished both the paradoxical hypotensive action of ET-1 in Zucker diabetic rats (n=7 each, P<0.001 ANOVA) as well as the dose-dependent rise in MBF (P<0.001 ANOVA). BQ788, but not BQ610 abolished the difference in response to ET-1 between lean and diabetic Zucker rats. U46619 caused a hypotensive action in male Zucker rats which was abolished by L-NAME 25mg/kg or indomethacin 10mg/kg i.v. The U46619 interaction with BQ788 on both MAP and MBF was significantly (P<0.03 ANOVA) different between lean and diabetic Zucker rats. BQ788, but not BQ610 attenuated both the MAP and MBF responses to acetylcholine or L-NAME P<0.02 ANOVA). However, BQ610 dose-dependently attenuated the slope of platelet aggregation in both lean and Zucker diabetic rats (P<0.02 ANOVA).. ET-B receptor antagonism abolished the abnormal vascular reactivity and MBF responses to ET-1, and also normalized the vasoactive responses to the level seen in healthy lean Zucker rats. ET-1 receptor blockade influences the responses to TXA(2) receptor activation. In the systemic and renal circulation, this interaction appears to be mostly ET-B receptor mediated, whilst in platelets, ET-A receptor role may be predominant. The interaction or cross-talk between ET-1 and TXA(2) is altered in the type-2 diabetic state. Collectively, these pathophysiological changes may contribute to the vicious circle of diabetic endotheliopathy.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Antihypertensive Agents; Blood Flow Velocity; Blood Pressure; Diabetes Mellitus, Type 2; Drug Interactions; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Hypertension; Kidney Cortex; Kidney Medulla; Male; NG-Nitroarginine Methyl Ester; Oligopeptides; Piperidines; Platelet Aggregation; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptor Cross-Talk; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Thromboxane A2

To study the change of vascular tension factors (VTF), including vascular contractile factors as endothelin-1 (ET-1), thromboxane A2 (TXA2) and vascular dilatory factors as nitric oxide (NO), prostacyclin (PGI2), in different stage of peripheral diabetic arterial occlusion (PDAO), and to preliminarily explore the clinical significance of these changes.. VTF in 40 diabetic patients, 15 of 2nd stage and 25 of 3rd stage, were observed by measuring level of ET-1, NO, TXB2 and 6-keto-PGF1alpha in blood plasma with RIA assay.. (1) ET-1 and TXB2 levels in all patients were higher than those in control (P < 0.05 and P < 0.01), those in patients of 3rd stage was higher than those of 2nd stage, showing significant difference (P < 0.05). (2) NO and 6-keto-PGF1alpha levels in all patients was lower than those in control, but showed no significant difference between patients of various stages (P > 0.05).. There are changes of VTF in patients with PDAO, manifesting as increase of vascular contractive factors and decrease of vascular dilative factor. The changes are diffrent in various stages, the vascular contractive and thrombotic factors in patients of 3rd stage are higher than those in patients of 2nd stage, but the injury on vascular dilative factors in the two stages showed insignificant difference.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelin-1; Epoprostenol; Female; Humans; Lower Extremity; Male; Middle Aged; Nitric Oxide; Thromboxane A2; Thromboxane B2; Vasomotor System

We used rats (the Otsuka Long-Evans Tokushima Fatty strain) as a model of type 2 diabetes to find whether thromboxane (TX) A2 is involved in diabetic nephropathy, and if so, to identify where it is synthesized. We measured urinary excretion of TXB2 and 2,3-dinor-TXB2 in rats up to 60 weeks of age as markers of renal and platelet synthesis of TXA2, respectively. Some diabetic rats were given daily oral doses of OKY-046 (100 mg/kg), a TXA2 synthase inhibitor, starting when they were 10 weeks of age. Healthy Long-Evans Tokushima Otsuka rats served as the controls. Urinary excretion of protein was greater in diabetic rats at 26 weeks than in controls, and the difference increased with age. Urinary excretion of TXB2 by diabetic rats was about 150% that of controls at 14 weeks, and remained at that level. In diabetic rats, urinary excretion of 2,3-dinor-TXB2 increased with age in parallel to increases in proteinuria, but in controls, excretion of these metabolites did not change with age. In diabetic rats, OKY-046 prevented the increase in urinary excretion of both metabolites, and decreased the proteinuria. Histologic examination at 60 weeks showed intraglomerular thrombi in diabetic rats but not in controls. OKY-046 reduced intraglomerular thrombi formation and the score for glomerulosclerosis. When platelet aggregation began, more TXA2 than before was released from the thrombi that formed, and the TXA2 contributed to the progress of nephropathy in this rat model of type 2 diabetes.

Topics: 6-Ketoprostaglandin F1 alpha; Aging; Animals; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Enzyme Inhibitors; Glomerular Mesangium; Male; Methacrylates; Prostaglandins; Proteinuria; Rats; Rats, Inbred OLETF; Thrombosis; Thromboxane A2; Thromboxane-A Synthase

Type 2 diabetes is characterized by increased plasma triglyceride levels and a fourfold increase in ischemic heart disease, but the mechanism is unclear. CD36 is a receptor/transporter that binds fatty acids of lipoproteins. CD36 deficiency has been linked with insulin resistance. There is strong evidence of in vivo interaction between platelets and atherogenic lipoproteins suggesting that atherogenic triglyceride-rich lipoproteins, such as VLDL, that are increased in diabetic dyslipidemia are important in this process. This study demonstrates that VLDL binds to the platelet receptor CD36, enhances platelet thromboxane A2 production, and causes increased collagen-mediated platelet aggregation. VLDL enhanced collagen-induced platelet aggregation by 1) shortening the time taken for aggregation to begin (lag time) to 70% of control (P = 0.001); 2) increasing maximum aggregation to 170% of control (P = 0.008); and 3) increasing thromboxane production to 3,318% of control (P = 0.004), where control represents platelets stimulated with collagen (100%). A monoclonal antibody against CD36 attenuated VLDL-enhanced collagen-induced platelet aggregation by 1) inhibiting binding of VLDL to platelets by 75% (P = 0.041); 2) lengthening lag time to 190% (P < 0.001); and 3) decreasing thromboxane production to 8% of control (P < 0.001). In support of this finding, platelets from Cd36-deficient rats showed no increase in aggregation, thromboxane production, and VLDL binding in contrast to platelets from rats expressing CD36. These data suggest that platelet Cd36 has a key role in VLDL-induced collagen-mediated platelet aggregation, possibly contributing to atherothrombosis associated with increased VLDL levels.

Topics: Antigens, CD; CD36 Antigens; Collagen; Diabetes Mellitus, Type 2; Humans; In Vitro Techniques; Lipoproteins, VLDL; Platelet Activation; Platelet Aggregation; Reference Values; Thromboxane A2; Triglycerides

Having developed a non-insulin-dependent diabetes mellitus (NIDDM) syndrome model in the rabbit using Wirsung duct ligation, it appeared interesting to use it to study the relationship between glycemia and the plasma levels of TXA(2)and PGI(2), and of some other biochemical parameters such as cholesterol, triglycerides, alkaline phosphatase and transaminases. A comparative study was carried out in the sham-operated rabbits (controls, C) and those having their pancreatic duct ligatured (NIDDM, D) at 15, 30, 40, 50 and 60 days post-ligation. On the 40th days, whereas in the controls, glycemia was 1.17 +/- 0.04 g.l(-1), it reached a maximum of 4.62 +/- 0.76 g.l(-1)(25.40 mM) in the NIDDMs. No significant modification was observed either in cholesterolemia or in triglyceridemia in either group. The GOT and GPT were highly increased, from 11.50 +/- 4.00 IU. l(-1)and 27.00 +/- 1.50 IU.l(-1)(C) to 37.50 +/- 5.64 IU.l(-1)(P<0. 001) and 58.50 +/- 7.50 IU.l(-1)(D) (P<0.001) in the NIDDM group, suggesting that hyperglycemia occurred simultaneously with the degeneration of the pancreatic tissue. In parallel, in D rabbits, the plasma levels of TXB(2)and 6 keto PGF(1alpha)were augmented to 68.22 +/- 6.20 pg.ml(-1)versus 22.49 +/- 5.74 pg.ml(-1)(C) (P<0.001), and 127.11 +/- 14.39 pg.ml(-1)versus 48.65 +/- 4.51 pg.ml(-1)(C) (P<0. 001) respectively. Statistical studies showed a significant correlation (P<0.05 and <0.02) between glycemia and the biosynthesis of eicosanoids under study. Moreover, 25 mM was found to be the threshold level of glucose excess essential to increase the TXA(2)and PGI(2)biosynthesis significantly. This supports the results obtained by other authors studying the action of glucose on phospholipase activity and consequent eicosanoid production.

Topics: 6-Ketoprostaglandin F1 alpha; Alkaline Phosphatase; Animals; Blood Glucose; Blood Proteins; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Epoprostenol; Hyperglycemia; Ligation; Pancreatic Ducts; Platelet Aggregation Inhibitors; Rabbits; Thromboxane A2; Thromboxane B2; Time Factors; Transaminases

Effects of troglitazone, an antidiabetic thiazolidinedione that enhances insulin sensitivity, on thromboxane (TX) production were assessed in human erythroleukemia (HEL) cells and human platelets. Measurement of TX was performed by using the gas chromatography/selected ion monitoring (GC/SIM) method. We found that troglitazone reduced the TX production from HEL cells and human platelets. Furthermore, troglitazone also reduced arachidonic acid (AA)-induced TX production from HEL cell and thrombin-induced TX release from platelets. In addition, we compared the effect of troglitazone with that of alpha-tocopherol and BRL 49653. Other thiazolidinedione compound BRL 49653 had effects similar to troglitazone, but alpha-tocopherol had no effect on TX production. Our findings suggest that the thiazolidinedione group had an antithrombotic effect and was beneficial in preventing vascular complications often observed in diabetes mellitus.

Topics: Arachidonic Acid; Blood Platelets; Chromans; Diabetes Mellitus, Type 2; Fibrinolytic Agents; Gas Chromatography-Mass Spectrometry; Humans; Leukemia, Erythroblastic, Acute; Rosiglitazone; Thiazoles; Thiazolidinediones; Thromboxane A2; Troglitazone; Tumor Cells, Cultured; Vitamin E

The purpose of this study was to investigate prostanoid synthesis in different segments of the umbilicoplacental vascular tree and its relationship to impaired maternal glucose tolerance. Segments from the umbilical artery and vein, allantochorionic artery branches, and the cotyledon artery from 21 women with diabetes or impaired glucose tolerance and 10 healthy women were studied. Production of prostacyclin (PGI2) and thromboxane (TxA2) metabolites was determined. The Mann-Whitney U test, Wilcoxon signed-ranks matched-pairs test, Kruskal-Wallis test, analysis of variance, and simple linear regression analysis were used. A two-tailed P value of < 0.05 was considered statistically significant. From the umbilical artery distal to the cotyledon artery, the PGI2 synthesis decreased and the TxA2 synthesis increased gradually towards the periphery in normal pregnancy. The PGI2/TxA2 ratio was more than 200 times higher in the umbilical artery than in the cotyledon artery. The TxA2 production tended in general to be higher in the diabetic group than in the control group, resulting in significantly lower PGI2/TxA2 ratios in some vessels. The prostanoid production was not significantly correlated to maternal HbA1c or cord C-peptide concentrations. The balance between vascular prostacyclin and thromboxane synthesis in the umbilicoplacental arterial tree changed gradually towards the periphery: the more peripheral, the lower the prostacyclin and the higher the thromboxane production. The physiological role of this phenomenon is unknown, but may be of importance for the equilibration of vascular tone between arteries of different calibers. The altered prostanoid balance found in diabetic pregnancy was not directly attributable to the degree of maternal glycemic control, but may reflect increased free radical activity and peroxide production in diabetes.

Topics: 6-Ketoprostaglandin F1 alpha; Cohort Studies; Culture Techniques; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Placenta; Pregnancy; Pregnancy Trimester, Third; Reference Values; Thromboxane A2; Umbilical Arteries

Thromboxane B2, a stable metabolite of thromboxane A2, was studied in type 2 diabetic patients to evaluate the role played by prostaglandins in the onset of vascular complications.. The study was carried out in 30 subjects, 20 of whom were diabetics and 10 controls. Thromboxane B2 was assayed using the "Biotrak Thromboxane B2" kit.. In the first group of control subjects, the mean value of TXB2 was 6.39 +/- 0.89 pg/ml; in the second group, including diabetic patients without vascular complications, TXB2 levels were 8.89 +/- 1.51; in the third, consisting of diabetic patients with microangiopathy, the mean level was 46.28 +/- 6.82; in the fourth, including patients with micro- and macroangiopathy, the mean level was 98.78 +/- 17.15; the fifth group, with a mean value of 41.00 +/- 9.86, included diabetic patients with cerebral vasculopathy. Thromboxane B2 was correlated with glycemia but the results were not statistically significant (r = 0.28; p < 0.05). The correlation with the years since onset of diabetes was positive and statistically significant (r = 0.49; p < 0.05).. In conclusion, the authors emphasise that TXB2 is present in the circulation in diabetes in steadily increasing quantities over time since the onset of diabetes, leading to chronic vasoconstriction which in turn leads to a deterioration of vascular lesions in the districts where hypoglycemia has already caused the activation of neurotransmitter hormones with consequent slowing down of the blood flow and progressive tissue hypoxia.

Topics: Age of Onset; Blood Glucose; Cerebrovascular Disorders; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Middle Aged; Prostaglandins; Thromboxane A2; Thromboxane B2; Vasoconstriction

Severe uterine and placental disturbances have been described in diabetes pathology. The relative severity of these changes appears to correlate with high glucose levels in the plasma and incubating environment. In order to characterize changes in eicosanoid production we compared uterine and placental arachidonic acid conversion from control and non-insulin-dependent diabetes mellitus (NIDDM) rats on day 21 of pregnancy, into different prostanoids, namely PGE2, PGF22alpha, TXB2 (indicating the production of TXA2) and 6-keto-PGF1 (indicating the generation of PGI2). PGE2, PGF2alpha and TXB2 production was higher and 6-keto-PGF1alpha was similar in diabetic compared to control uteri. PLA2 activity was found diminished in the NIDDM uteri in comparison to control. A role for PLA2 diminution as a protective mechanism to avoid prostaglandin overproduction in uterine tissue from NIDDM rats is discussed. Placental tissues showed an increment in TXB2 generation and a decrease in 6-keto PGF1alpha level in diabetic rats when compared to control animals. Moreover, when control uterine tissue was incubated in the presence of elevated glucose concentrations (22 mM), similar generation of 6-keto PGF1alpha and elevated production of PGE2, PGF2alpha and TXB2 were found when compared to those incubated with glucose 11 mM. Placental TXB2 production was higher and 6-keto PGF1alpha was lower when control tissues were incubated in the presence of high glucose concentrations. However, high glucose was unable to modify uterine or placental prostanoid production in diabetic rats. We conclude that elevated glucose levels induced an abnormal prostanoid profile in control uteri and placenta, similar to those observed in non-insulin-dependent diabetic tissues.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acids; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dinoprost; Dinoprostone; Eicosanoids; Female; Maternal-Fetal Exchange; Placenta; Pregnancy; Pregnancy in Diabetics; Pregnancy, Animal; Prostaglandins A; Rats; Rats, Wistar; Thromboxane A2; Thromboxane B2; Uterus

Eicosanoid production by intrauterine tissues from control and neonatal-streptozotocin induced diabetic rats during late pregnancy was evaluated. In diabetic placenta the release of 6-keto-PGF1alpha was found diminished when compared to controls. In addition, LTB4 generation was increased in diabetic placenta. No alterations in the production of TXA2, PGE2, PGE1 and PGF2alpha was found when diabetic and control placenta were compared. In amnion tissue a decreased generation of 6-keto-PGF1alpha was observed in the diabetic group, but no alteration in any other eicosanoid evaluated was found. Oxytocin (5 mU/ml, in vitro), which increases prostaglandin synthesis in rabbit and human amnion tissues, did not modify eicosanoid generation in control rat amnion. In contrast, in diabetic amnion the presence of oxytocin further decreased the release of 6-keto-PGF1alpha and diminished PGE1 generation. The present results suggest that this mildly diabetic state induces alterations in eicosanoid production in intrauterine tissues, abnormalities probably enhanced during parturition, when endogenous concentrations of oxytocin are elevated.

Topics: 6-Ketoprostaglandin F1 alpha; Alprostadil; Amnion; Animals; Culture Media; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dinoprost; Dinoprostone; Eicosanoids; Female; Humans; In Vitro Techniques; Oxytocin; Placenta; Pregnancy; Pregnancy in Diabetics; Rabbits; Rats; Rats, Wistar; Thromboxane A2

To evaluate the secretion of vasoactive factors in vascular endothelium of patients with non-insulin-dependent diabetes mellitus (NIDDM) the authors examined 31 NIDDM patients. Of them, 18 had no signs of renal involvement, 13 patients showed apparent diabetic nephropathy (DN). In the former patients the blood contained much greater content of vasodilating factor prostacyclin than of vasoconstricting factor endothelin-1 (ET-1) and thromboxan A2 (TxA2). In diabetic nephropathy the balance of vasoactive factors shifted to predominance of vasoconstrictors ET-1 and TxA2. Such rearrangement of vasoactive factors to higher quantities of vasoconstrictors in diabetes mellitus may initiate or promote progression of diabetic nephropathy with resultant spasm of afferent glomerular vessels, reduced glomerular filtration and renal blood flow rates, arterial hypertension, increased thrombogenesis. Thus, elevated levels of ET-1 and TxA2 in diabetics and their rise with progression of diabetic nephropathy are likely to act as pathogenetic factors underlying onset and progression of nephroangiopathy.

Topics: Albuminuria; Chronic Disease; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Endothelin-1; Endothelium, Vascular; Epoprostenol; Female; Humans; Male; Middle Aged; Thromboxane A2

We studied the effect of a thromboxane A2 (TXA2) dual blocker KDI-792 on skin blood flow as well as on the peripheral nerve function of nine diabetics with neuropathy. After administration of KDI-792, there was no change in urinary TXB2; however, urinary 6-keto-prostaglandin (PG) F1 alpha increased significantly. Nerve conduction velocity (NCV) and vibration perception threshold (VT) in the four extremities improved significantly, as did deep skin temperature and skin blood flow. The degree of improvement in sensory NCV in the lower extremities correlated significantly with that of deep skin temperature in the toes and the degree of improvement of VT in the lower extremities correlated well with that of deep skin temperature in the soles and of skin blood flow in the toes. Based on these findings, treatment of diabetic neuropathy with a TXA2 dual blocker appears to increase PGI2 production, improving blood flow, and resulting in improvement of nerve functions.

Topics: 6-Ketoprostaglandin F1 alpha; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Enzyme Inhibitors; Extremities; Female; Humans; Male; Middle Aged; Neural Conduction; Perception; Pyridines; Pyrrolidines; Skin; Skin Temperature; Thromboxane A2; Thromboxane B2; Toes; Vibration

We studied serum thromboxane (TXB2), the prostacyclin metabolite, 6-keto-PGF1 (6KPGF1) glucose, insulin, and lipid/lipoprotein profiles in 27 patients with non-insulin-dependent diabetes mellitus (NIDDM) who were switched from therapy with glibenclamide (GLB) (with [GLBH] or without phenformin) to gliclazide for 3 months. We found that therapy with gliclazide was followed by a decrease in serum TXB2 (281.8 +/- 128.3 to 149.1 +/- 77.0 mg/L, P less than .001) and an increase in serum 6KPGF1 (60.5 +/- 19.1 to 96.0 +/- 40.3 mg/L, P less than .001). This was accompanied by a decrease in total and low-density lipoprotein (LDL) cholesterol and an increase in high-density lipoprotein (HDL) cholesterol, within the HDL3 cholesterol fraction. These changes were seen despite the fact that neither fasting plasma glucose nor insulin changed with therapy. These findings suggest that gliclazide may have beneficial actions on cardiovascular risk factors in these NIDDM patients.

Topics: Diabetes Mellitus, Type 2; Epoprostenol; Gliclazide; Humans; Lipids; Thromboxane A2

Topics: Arachidonic Acid; Arachidonic Acids; Blood Platelets; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Platelet Activation; Thromboxane A2

The present study was designed to determine urinary excretion of kallikrein(KAL)-kinin as well as prostaglandin (PG) E2, TXB2 and 2,3-dinor-TXB2, a major urinary metabolite of TXA2 synthesized in platelets, by specific RIAs in patients with diabetes mellitus (DM). KAL or kinin excretion in 26 type II DM did not differ from control values obtained in 18 age-matched healthy subjects (C), although DM with HbA1 greater than 11% excreted less KAL. Urinary PGE2 excretion (7.6 +/- 2.8 ng/mg creatinine, mean +/- SE) was significantly lower in DM compared to C (17.5 +/- 3.9, p less than 0.05), while DM excreted more TXB2 (0.57 +/- 0.09, p less than 0.01) and 2,3-dinor-TXB2 (0.56 +/- 0.12, N.S.) than C (0.19 +/- 0.02 or 0.33 +/- 0.01). DM with or without mild proteinuria demonstrated lower PGE2, but higher TXB2 and 2,3-dinor-TXB2 excretion. A positive correlation of TXB2/2,3-dinor-TXB2 with proteinuria was observed in this group. However, in DM with massive proteinuria over 500 micrograms/mg creatinine, TXB2 and 2,3-dinor-TXB2 excretion decreased to levels almost identical to C. As a whole, a ratio of TXB2 to PGE2 or 2,3-dinor-TXB2 in DM was significantly higher than in C. The results suggest that a relative preponderance of TXB2 to 2,3-dinor-TXB2 may indicate an augmented renal, in addition to platelet, TXA2 synthesis. An excessive vasoconstrictive and proaggregatory TXA2 renal synthesis, concomitant with a decrease in vasodilatory and antiaggregatory PGE2, may have profound effects on renal functions such as protein excretion in DM.

Topics: Adult; Aged; Blood Pressure; Diabetes Mellitus, Type 2; Dinoprostone; Eicosanoids; Esterases; Female; Humans; Kallikreins; Kidney; Kinins; Male; Middle Aged; Thromboxane A2; Thromboxane B2

It has been suggested that platelet hyperreactivity in patients with diabetes mellitus is associated with increased platelet production of thromboxane. We therefore compared the excretion of a thromboxane metabolite and platelet function in 50 patients with Type II diabetes mellitus who had normal renal function and clinical evidence of macrovascular disease and in 32 healthy controls. The mean (+/- SD) excretion rate of urinary 11-dehydro-thromboxane B2 was significantly higher in the patients than in the controls (5.94 +/- 3.68 vs. 1.50 +/- 0.79 nmol per day; P less than 0.001), irrespective of the type of macrovascular complication. Tight metabolic control achieved with insulin therapy reduced the levels of 11-dehydro-thromboxane B2 by approximately 50 percent. The fractional conversion of exogenous thromboxane B2 (infused at a rate of 4.5, 45.3, or 226.4 fmol per kilogram of body weight per second) to urinary 11-dehydro-thromboxane B2 was assessed in four patients, in whom it averaged 5.4 +/- 0.1 percent; this value did not differ from that measured in healthy subjects. Aspirin in low doses (50 mg per day for seven days) reduced urinary excretion of the metabolite by approximately 80 percent in four patients. The fact that thromboxane biosynthesis recovered over the following 10 days was consistent with a platelet origin of the urinary metabolite.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Aspirin; Blood Platelets; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Platelet Aggregation; Thromboxane A2; Thromboxane B2; Thromboxanes

Topics: Arachidonate Lipoxygenases; Blood Platelets; Calcium; Diabetes Mellitus, Type 2; Humans; In Vitro Techniques; Middle Aged; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Thromboxane A2

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Platelets; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Reference Values; Thromboxane A2; Thromboxane B2

The time-dependent relationship between the levels of the reduced form of glutathione (GSH) and thromboxane A2 (TXA2) synthesis, as measured by the accumulation of TXB2, in platelets from human diabetic and control subjects was investigated during aggregation. In platelets from control subjects, the GSH level decreased to 21% of the initial level within 30 sec in response to arachidonic acid (1.65 mM) and rapidly recovered to 91% by 1 min. In platelets from diabetic subjects, the GSH level decreased to 3% of the initial level within 30 sec and recovered to only 41% by 1 min. During collagen (20 ug/ml) aggregation, platelets from control subjects had a 15 sec lag phase which was followed by a decrease in the GSH level to 21% of the initial level within 1 min and a recovery to 74% by 2 min. Platelets from diabetic subjects in response to collagen showed no lag phase and decreased to 10% of the initial level within 1 min which was followed by a recovery to 34% by 2 min. In all aggregations, the initial GSH level was significantly (p less than .001) lower in platelets from diabetic subjects and remained significantly (p less than .01) lower than GSH in platelets from control subjects throughout the aggregation. The amount of TXB2 formed by platelets from control subjects reached a maximum in response to arachidonic acid and collagen by 1 min and 2 min, respectively, whereas, the TXB2 continued to increase up to 4 min when platelets from diabetic subjects were aggregated. These data indicate that TXA2 synthesis occurs during the decrease in GSH and ceases when the GSH level recovers. The continued synthesis of TXA2 by platelets from diabetic subjects coincides with the gradual recovery of the GSH level.

Topics: Arachidonic Acids; Blood Platelets; Collagen; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glutathione; Humans; Male; Middle Aged; Platelet Aggregation; Thromboxane A2; Time Factors

Arachidonic acid uptake activity was measured in platelets obtained from 27 Type 2 diabetic patients and 18 age-matched control subjects. In both groups after 1 h incubation almost all the incorporated 14C-arachidonic acid was located in the phospholipids of the platelets. Arachidonic acid was predominantly incorporated into phosphatidylcholine. The radioactivity incorporated into platelets increased linearly with incubation time, up to 90 min. The linear increase was observed at arachidonic acid concentrations of 0.1-1.0 micrograms/ml in both groups. The rate of incorporation of radioactivity in diabetic platelets was about 1.4 times higher than that in control platelets at all arachidonic acid concentrations studied. The arachidonic acid uptake activity of diabetic platelets (577 +/- 26 ng/60 min per 10(9) platelets) was significantly higher than that in control platelets (410 +/- 26 ng/60 min per 10(9) platelets). No significant correlations were found between the arachidonic acid uptake activity and fasting plasma glucose, total cholesterol or triglyceride levels. The arachidonic acid uptake activity of platelets was significantly higher in diabetic patients with proliferative retinopathy than in those with little or no background retinopathy. In addition, there were no significant differences between control and diabetic subjects in the uptake activity of platelets for linoleic acid and oleic acid. These data may explain the elevated arachidonic acid content in diabetic platelet phospholipids and enhancement of thromboxane synthesis in diabetes.

Topics: Aged; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Fatty Acids, Nonesterified; Female; Humans; Male; Middle Aged; Phospholipids; Platelet Aggregation; Thromboxane A2