thromboxane-a2 and Diabetic-Angiopathies

Platelet poor plasma thromboxane and prostacyclin levels and the quantity of metabolic control, altogether with vascular complications were evaluated in 55 children diabetes mellitus. The control group consisted of 33 healthy children of the similar age. Thromboxane levels remained unchanged in diabetics, while prostacyclin proved to be significantly decreased, which resulted in greater thromboxane/prostacyclin ratio. No meaningful differences were found according to the presence or absence of vascular complications in this group of diabetics. A positive correlation could have been detected between glycosylated haemoglobin and thromboxane levels, while a negative one between glycosylated haemoglobin and prostacyclin levels. The alterations of prostaglandin metabolism may be regarded as a consequence of diabetic metabolic changes, rather than of vascular complications. Disturbed prostaglandin metabolism in diabetic children might have a role in the pathogenesis of vascular complications.

Topics: Blood Glucose; Child; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Epoprostenol; Glycated Hemoglobin; Humans; Prostaglandins F; Thromboxane A2

The overall assessment of eicosanoids in ischemia and shock is complex. Certain prostaglandins, notably PGI2, actually improved survival in shock and ischemic states; however, some, including TxA2, act as mediators, significantly contributing to the pathophysiology of vasospasm and ischemia. This makes the intelligent use of eicosanoid-related drugs very difficult. Broad-based inhibitors (for example, cyclo-oxygenase inhibitors) are not likely to exert significant protective effects because they inhibit beneficial as well as detrimental eicosanoids. More appropriately, the therapy of ischemic disorders should be designed to employ specific agents (for example, TxSI and TxRA) rather than broad-based agents. Preliminary studies already suggest the success of such an approach. Future investigations will focus on the application of potent synthetic modulators or analogues of specific eicosanoids in an attempt to prevent the deleterious effects of eicosanoid mediators of ischemic disorders and to potentiate and prolong the beneficial actions of therapeutic eicosanoids.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Blood Circulation; Coronary Disease; Coronary Vasospasm; Death, Sudden; Diabetic Angiopathies; Eicosanoic Acids; Epoprostenol; Hemodynamics; Humans; Phospholipases A; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Receptors, Cell Surface; Thromboxane A2

Although many data regarding the biosynthesis of thromboxane A2 and prostacyclin in diabetes mellitus have recently appeared in the literature, it is not clear whether an imbalance between the generation of the two prostaglandins might be connected to the vascular complications of diabetes. In the present review we have tried to emphasize the most significant aspects of these studies and we have focused on alterations of platelet prostacyclin receptors and on the effects of circulating immune complexes on platelets of diabetics. It is likely that studies on the release of platelet derived growth factor as well as more precise definitions of its action on vessel wall cells leading to a massive release of prostacyclin, will permit us to ascertain whether an alteration in prostaglandin ratio is linked to the genesis of the vascular complications in diabetics.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antigen-Antibody Complex; Blood Platelets; Blood Vessels; Cyclic AMP; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Endothelium; Epoprostenol; Humans; Models, Biological; Platelet Aggregation; Platelet-Derived Growth Factor; Receptors, Cell Surface; Receptors, Epoprostenol; Receptors, Platelet-Derived Growth Factor; Receptors, Prostaglandin; Thromboxane A2; Thromboxane B2

Tests of platelet behaviour in vitro, particularly aggregation and retention and in vivo tests such as measurement of platelet survival and plasma levels of beta-thromboglobulin are frequently abnormal in diabetic patients, particularly in those with vascular disease. The concept has therefore arisen that platelet hyper-reactivity is one factor responsible for diabetic microangiopathy. Whereas there is experimental and histological evidence for the mediation of platelets in the pathogenesis of atherosclerosis, direct evidence of platelet involvement in microangiopathy is scanty. Similar alterations in platelet behaviour have been observed in a variety of other conditions with vessel wall damage in common and evidence is presented which suggests that these platelet abnormalities may be secondary to vessel wall injury. In diabetic subjects, some changes in platelet behaviour are reversed by improved glycaemic control. Evidence that platelets are involved in the pathogenesis of diabetic microangiopathy therefore remains circumstantial, though current trials of anti-platelet agents may enable a more precise evaluation of their role.

Topics: Adenosine Diphosphate; Animals; Arteriosclerosis; beta-Thromboglobulin; Blood Glucose; Blood Platelets; Blood Vessels; Cell Survival; Diabetes Mellitus; Diabetic Angiopathies; Endothelium; Epoprostenol; Humans; Platelet Adhesiveness; Platelet Aggregation; Platelet Factor 4; Platelet Function Tests; Thromboxane A2

Alteration in prostanoid and TXA2 production are involved in the development of diabetic microangiopathy underlying DR. Diabetic microangiopathy is characterized by abnormalities in platelet function and increased susceptibility to thrombus formation. The synthesis of excessive amounts of PGs and TXA2 by platelets obtained from diabetic patients is underlying alteration in platelet responsiveness seen in diabetes mellitus. An associated reduction in PGI2 by endothelial blood vessels results in further disruption of the homeostatic mechanism regulating the aggregatory process. However, PGI2 behaviour in different tissues, and in blood vessels of varied calibre is yet unclear. PGI2 synthesis is restored to normal on reduction of blood glucose levels. Restoration of the synthesis of both prostanoids and PGI2 to normal, might be achieved by using drugs that inhibit prostanoid and TXA2 formation as well as by controlling glucose blood levels. Affecting the imbalance of prostanoid and TXA2 seen in diabetes might be of clinical implication in prevention and treatment of DR.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Diabetic Retinopathy; Dinoprostone; Epoprostenol; Homeostasis; Humans; Prostaglandins; Prostaglandins E; Rats; Rats, Inbred Strains; Retina; Thromboxane A2; Thromboxanes

This report describes, at least in part, the role of prostaglandin and cyclic nucleotide metabolism in the etiology of the vascular disease associated with diabetes mellitus. Alterations in this metabolism seem associated with induction of platelet aggregation leads to microthromboses leads to microangiopathy sequences that are subtle but inexorable over a long period of time. Prostaglandins are generally elevated in blood from patients having frank signs of diabetic retinopathy when compared with nondiabetic subjects. Prostaglandin concentration remained elevated in diabetic retinopathy patients receiving indomethacin. We formed, therefore, the working hypothesis--yet to be fully tested either in patients or animal models with and without indomethacin treatment--that the increased prostacyclin (synthesized by endothelial microsomes) and cyclic-AMP production, both of which favor prevention of platelet aggregation, accompany the increased concentration of one or more of the prostaglandin E and F compounds. Concurrently, there may be an accompanying reduction of thromboxane A2 (synthesized by platelet microsomes) and cyclic-GMP (both of which favor platelet aggregation) production in the diabetic patients. The elevated prostaglandin in the diabetic patients not receiving indomethacin could possibly be directed toward slowing but not preventing the progression of the complex disease process in diabetes.

Topics: Alprostadil; Aspirin; Blood Platelets; Calcimycin; Collagen; Cyclic AMP; Cyclic GMP; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Dinoprost; Dinoprostone; Humans; Indomethacin; Models, Biological; Platelet Aggregation; Prostaglandins; Prostaglandins E; Prostaglandins F; Thromboxane A2

Patients with diabetes are at excessive risk of mortality and cardiovascular morbidity. Previous studies suggest that aspirin may be less effective in diabetic patients. In this multi-centre, randomized, double blind trial picotamide, a dual inhibitor of thromboxane A2 synthase and receptor, was compared with aspirin for the prevention of mortality and major cardiovascular events in diabetics with peripheral arterial disease (PAD).. A total of 1209 adults aged 40-75 years with type 2 diabetes and PAD were randomized to receive picotamide (600 mg bid) or aspirin (320 mg od) for 24 months. The cumulative incidence of the 2 years overall mortality was significantly lower amongst patients who received picotamide (3.0%) than in those who received aspirin (5.5%) with a relative risk ratio for picotamide versus aspirin of 0.55 (95% CI: 0.31-0.98%). Events were reported in 43 patients (7.1%) on picotamide and 53 (8.7%) on aspirin. The combined endpoint of mortality and morbidity had a slightly lower incidence in the picotamide group but this difference did not reach statistical significance.. Picotamide is significantly more effective than aspirin in reducing overall mortality in type 2 diabetic patients with associated PAD.

Topics: Adult; Aged; Aspirin; Diabetic Angiopathies; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Peripheral Vascular Diseases; Phthalic Acids; Platelet Aggregation Inhibitors; Risk Factors; Survival Analysis; Thromboxane A2

Although vascular dysfunction is a key event in the development of diabetic complications, and abnormal toll-like receptor 4 (TLR4) may contribute to the pathophysiology of vascular diseases, the direct relationships between TLR4 and vascular function in diabetic arteries are still poorly understood. Thus, to investigate whether pharmacological blockade of TLR4 affects vascular function in the superior mesenteric artery (SMA) of streptozotocin (STZ)-induced diabetic rats, the SMA was isolated from male Wistar rat injected once with STZ (65 mg/kg, 27-34 weeks) which was treated with TAK-242 (10

Topics: Acetylcholine; Animals; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Endothelium-Dependent Relaxing Factors; Male; Mesenteric Artery, Superior; Rats; Rats, Wistar; Streptozocin; Sulfonamides; Thromboxane A2; Toll-Like Receptor 4; Vasodilation

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

Cardiovascular disease is the major cause of morbidity and mortality in diabetic patients, which in turn is also associated with low levels of serum testosterone. The working hypothesis was that diabetes might modify the mechanisms involved in the vascular actions of testosterone in isolated rabbit carotid arteries. Testosterone (10(-8)-3x10(-4)M) induced a concentration-dependent relaxation of precontracted carotid arteries, which was higher in diabetic than in control rabbits. In control rabbits neither endothelium removal nor the nitric oxide synthase (NOS) inhibitor N(G)-nitro-l-arginine (l-NOArg, 10(-5)M) modified the relaxant action of testosterone, and the cyclooxygenase (COX) inhibitor indomethacin (10(-5)M) enhanced this relaxation. In contrast, in diabetic rabbits endothelium removal, l-NOArg (10(-5)M) or indomethacin (10(-5)M) inhibited the testosterone induced relaxation. In arteries from diabetic rabbits, eNOS, iNOS and COX-2 expression and testosterone induced release of prostacyclin resulted enhanced in comparison with arteries from control rabbits. Testosterone (10(-4)M) strongly inhibited CaCl(2) (10(-5)-3x10(-2)M) concentration-related contractions of the carotid artery both in control and diabetic rabbits. These results suggest that testosterone relaxes the rabbit carotid artery by blocking the extracellular calcium entry. Diabetes enhances the vasodilator response of the rabbit carotid artery to testosterone by a mechanism that at least includes an increased modulatory activity of the endothelial nitric oxide and an augmented release of COX-2 vasodilator, prostacyclin rather than the absence of COX-1 vasoconstrictor, thromboxane A(2). The hypotestosteronemia observed in diabetic rabbits could be a consequence of the increased expression of iNOS and could contribute to the hyperreactivity of the rabbit carotid artery to testosterone.

Topics: Animals; Apamin; Blood Glucose; Blotting, Western; Calcium; Carotid Arteries; Carotid Artery Diseases; Charybdotoxin; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Dose-Response Relationship, Drug; Endothelium, Vascular; Epoprostenol; Immunoenzyme Techniques; Indomethacin; Male; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitroarginine; Potassium; Potassium Channel Blockers; Rabbits; Testosterone; Thromboxane A2; Vasodilation

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

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

Thromboxane A(2) (TXA(2)) synthesis and expression of procoagulant activity (PCA) were investigated in mononuclear cells and monocytes prepared from a control and a Type 2 diabetic group. Monocytes from the diabetic group produced 2.10+/-0.81 ng of TXB(2)/5 x 10(5) monocytes compared to 1.26+/-0.43 ng/5 x 10(5) monocytes by the control group (P<0.01, n=11) when incubated in autologous plasma containing arachidonic acid (200 microg/ml). When monocytes were incubated in buffer containing arachidonic acid (20 microg/ml), cells from the diabetic group produced 1.65+/-0.68 ng of TXB(2)/5 x 10(5) monocytes compared to 1.07+/-0.31 ng/5 x 10(5) monocytes by the control group (P<0.02, n=12). Expression of PCA was examined in mononuclear cell preparations. Basal and maximally stimulated PCA with lipopolysaccharide (4.2 microg/ml) were not different between control and diabetic groups. However, arachidonic acid induced a four-fold (P<0.001) increase in PCA in the diabetic group. This activity was characterized as tissue factor. Increased synthesis of TXA(2) and expression of PCA may potentiate thrombosis and increase fibrin deposition, events that play primary roles in the development of vascular disease.

Topics: Arachidonic Acid; Arteriosclerosis; Blood Coagulation Factors; Cells, Cultured; Culture Media, Serum-Free; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Female; Humans; Kinetics; Leukocytes, Mononuclear; Lipopolysaccharides; Male; Middle Aged; Monocytes; Thrombosis; Thromboxane A2

The primary etiologic factor in diabetic glomerulosclerosis appears to be an overproduction of transforming growth factor-beta by mesangial cells, which in turn reflects a hyperglycemically mediated overactivation of protein kinase C (PKC) throughout the glomerulus. Membrane-active antioxidants, fish oil, and angiotensin-converting enzyme inhibitors can act to down-regulate glomerular PKC activity, via a variety of mechanisms that may include activation of diacylglycerol kinase and suppression of phosphatidate phosphohydrolase, support of endothelial nitric oxide and heparan sulfate production, inhibition of thromboxane and angiotensin synthesis/activity, and correction of glomerular hypertension. The beneficial impact of these measures on vascular endothelial function may be of more general utility in the prevention of diabetic complications such as retinopathy, neuropathy, and atherosclerosis. Adjunctive use of gamma-linolenic acid is indicated for prevention of neuropathy, and it is conceivable that bioactive chromium will have protective activity not solely attributable to improved glycemic control. Re-establishing euglycemia must clearly remain the core strategy for preventing diabetic complications, but when glycemic control remains suboptimal, practical, safe measures are at hand for decreasing risk.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antioxidants; Diabetic Angiopathies; Diabetic Nephropathies; Enzyme Activation; Fish Oils; Heparitin Sulfate; Humans; Hyperglycemia; Kidney Glomerulus; Lipid Peroxidation; Models, Biological; Nitric Oxide; Protein Kinase C; Thromboxane A2; Transforming Growth Factor beta

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

16 patients with insulin-dependent diabetes mellitus (IDDM) lasting 8-19 years had pronounced diabetic nephropathy (proteinuria stage), retinopathy (stage I, II or III), disturbed circulation in the lower limbs detected at foot dopplerography. For 3 months these patients received ibustrin (inhibitor of cyclooxigenase, blocker of tromboxane A2 synthesis and platelet aggregation) before renal function underwent positive changes: glomerular filtration rate increased in 13 patients (81%), 24-h proteinuria decreased in 12 patients (75%). Retinal vascular condition improved in 5 of 6 patients with nonproliferative retinopathy and in 2 of 5 patients with preproliferative retinopathy, in 1 and 3 patients stabilization occurred, respectively. In proliferative retinopathy improvement and stabilization were registered in 1 and 3 of 5 patients, respectively. According to feet artery dopplerography the improvement, no changes and moderate aggravation occurred in 10(62%), 3(19%) and 3(19%) of patients, respectively The conclusion is made that ibustrin effectively inhibits progression of IDDM vascular complications, especially at early angiopathy stages.

Topics: Adolescent; Adult; Blood Coagulation; Chronic Disease; Cyclooxygenase Inhibitors; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Drug Evaluation; Foot; Humans; Isoindoles; Middle Aged; Phenylbutyrates; Platelet Aggregation Inhibitors; Thromboxane A2

The present study was undertaken to clarify the altered effect of arachidonic acid on inner ear blood flow in rats with streptozotocin-induced diabetes by use of the laser-Doppler flowmeter. Drugs were administered intraarterially via the subclavian artery in a dose range that did not affect the systemic blood pressure. Both arachidonic acid and papaverine hydrochloride increased inner ear blood flow dose-dependently. Diabetic rats at 12 weeks, but not at 8 weeks, after the induction of diabetes showed a significant decrease in arachidonic acid response. However, there were no differences in papaverine response between diabetic and control rats. Pretreatment with ONO-3708, a selective thromboxane A2 antagonist, reversed the attenuated response to arachidonic acid found in diabetic rats. An increased response to thromboxane A2, which decreased inner ear blood flow, was also found in 12-week diabetic rats. In electrocochleograms, the latency in 12-week diabetic rats was significantly delayed compared with that in control rats, and this prolonged latency improved with insulin treatment. These results suggest that the responsiveness of inner ear blood flow to prostaglandins may be altered in individuals with diabetes mellitus.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Audiometry, Evoked Response; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Ear, Inner; Hearing Loss, Sensorineural; Male; Papaverine; Rats; Rats, Inbred Strains; Regional Blood Flow; Stimulation, Chemical; Thromboxane A2; Time Factors

The follow-up of children and adolescents (n-41) suffering from insulin-dependent diabetes mellitus has demonstrated that the increase of the thromboxane/prostacyclin ratio pointing to the derangement of microcirculatory regulation occurs during the decompensation phase of the disease and is a risk factor of the development of diabetic complications. The revealed disorders of arachidonic acid metabolism may be one of the causes of the tendency towards decrease of pulse arterial pressure in grave diabetes mellitus.

Topics: Adolescent; Blood Pressure; Blood Vessels; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Epoprostenol; Humans; Infant; Microcirculation; Risk Factors; Thromboxane A2

Topics: Arteriosclerosis; Blood Platelets; Chromatography, Affinity; Chromatography, High Pressure Liquid; Diabetes Mellitus; Diabetic Angiopathies; Humans; Lipoproteins; Radioimmunoassay; Thromboxane A2

Lipid composition of platelet membranes and thromboxane A2 (TxA2) generation by platelets were investigated in 42 diabetic patients (14 with macroangiopathic complications, 10 with microangiopathy and 18 without vascular complications) and in 42 clinically healthy subjects of similar age. All subjects were on a similar dietary regimen and the adherence to diet was checked by analysis of red blood cell lipids. Platelets from all groups of diabetic patients produced increased amounts of TxA2 than platelets from controls (at least p less than 0.01) and patients with macroangiopathy (p less than 0.01). Platelet cholesterol and total platelet phospholipids were higher in patients with macroangiopathy, while the relative percentage of the different phospholipid fractions in platelet membrane and their saturated and unsaturated fatty acids were similar in the different groups. Arachidonic acid (AA) content in phosphatidylcholine (PC) was found to be significantly higher in diabetic patients than in controls (at least p less than 0.005). Moreover patients with macroangiopathy had higher AA (p less than 0.001) and lower eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) levels in PC (p less than 0.001) than the other groups of patients and controls.

Topics: Adult; Blood Platelets; Diabetes Mellitus; Diabetic Angiopathies; Erythrocytes; Fatty Acids; Female; Humans; Male; Membrane Lipids; Thromboxane A2

Topics: Adult; Arteriosclerosis; Diabetic Angiopathies; Epoprostenol; Female; Humans; Male; Middle Aged; Thrombocytopenia; Thromboxane A2

Patients with diabetes mellitus manifest increased in vitro platelet aggregation and increased synthesis of the proaggregant and vasoconstrictor, thromboxane A2 (TXA2). We studied the effects of continuous insulin infusion treatment on platelet aggregation and arachidonic acid (AA)-stimulated platelet TXA2 synthesis (15 and 30 s post-AA, 1 mM) in 16 type I diabetic patients. Strict glycemic control was induced with the Biostator for 2 days and maintained for 12-14 days with continuous subcutaneous insulin infusion (CSII). The average premeal plasma glucose level (4/day) fell from 184 +/- 15, before treatment, to 107 +/- 6 mg/dl on the final day (P less than 0.001). After control, platelet synthesis of TXA2, measured by radioimmunoassay of its stable metabolite, immunoreactive TXB2 (iTXB2), decreased in all patients (30 s: 276 +/- 31 versus 199 +/- 28 ng iTXB2/ml/5 X 10(5) platelets; P less than 0.05). The reduction in platelet iTXB2 synthesis (15 and 30 s) was greater in poorly controlled patients (HbA1c greater than 12%; N = 8), and for all patients the decrease in iTXB2 (15 and 30 s) was correlated with the prestudy HbA1c level (15 s: r = 0.6; P less than 0.01). In contrast, platelet aggregation responses did not improve during intensive insulin treatment. The ED50 for AA (dose producing 50% maximum aggregation at 1 min) was unchanged after 2 wk of treatment and the ED50 for aggregation induced by ADP fell significantly in patients with HbA1c greater than 12% (2.8 +/- 1.3 versus 1.2 +/- 0.6 microM; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Diphosphate; Adolescent; Adult; Arachidonic Acid; Arachidonic Acids; Blood Glucose; Blood Platelets; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Female; Humans; Insulin; Insulin Infusion Systems; Lipoproteins; Male; Middle Aged; Platelet Aggregation; Thromboxane A2; Thromboxane B2

Topics: Adolescent; Adult; Aged; beta-Thromboglobulin; Blood Platelets; Diabetes Mellitus; Diabetic Angiopathies; Female; Humans; Male; Middle Aged; Platelet Aggregation; Thromboxane A2

Prostacyclin is a very unstable prostaglandin, which is continuously synthetized and released by blood vessels. It fulfills 2 main functions, namely strong inhibition of platelet aggregation and vasodilation. Thus it acts as an important defense mechanism of the vascular wall, which is directed against overwhelming platelet aggregation and against the development of atherosclerosis. Besides endogenous prostacyclin is an important antihypertensive factor. In several diseases, as diabetes mellitus, obliterative arteriopathy and haemolytic-uraemic syndrome, the reduced prostacyclin-synthesis is thought to be a key mechanism for the development of vascular lesions. On the other hand the haemorrhagic diathesis of uraemics is seen in connection with an increased vascular prostacyclin release. Synthetic prostacyclin is now under trial for therapy in peripheral obliterative arteriopathy and extracorporeal circulation, as haemodialysis and cardiopulmonary bypass.

Topics: Arteriosclerosis; Diabetic Angiopathies; Epoprostenol; Female; Hemolytic-Uremic Syndrome; Humans; Intermittent Claudication; Muscle, Smooth, Vascular; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Prostaglandins; Purpura, Thrombotic Thrombocytopenic; Thromboxane A2; Vasodilation