thromboxane-a2 and Diabetic-Retinopathy

Arachidonic acid (AA) metabolites are key mediators involved in the pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases. One of these bioactive metabolites of particular importance is thromboxane A(2) (TXA(2)). It is produced by the action of thromboxane synthase on the prostaglandin endoperoxide H(2) (PGH(2)) which results from the enzymatic transformation of AA by the cyclooxygenases. It is a potent inducer of platelet aggregation, vasoconstriction and bronchoconstriction, and has been involved in a series of major pathophysiological conditions. Therefore, TXA(2) receptor antagonists, thromboxane synthase inhibitors and drugs combining both properties have been developed by different laboratories since the early 1980s. Several compounds have been launched on the market and others are under clinical evaluation. In the first part of this review, we will describe the physiological properties of TXA(2), thromboxane synthase and thromboxane receptors. The second part is dedicated to a description of each class of thromboxane modulators with the advantages and disadvantages they offer. In the third part, we aim to describe recent studies performed with the most interesting thromboxane modulators in major pathologies: myocardial infarction and thrombosis, atherosclerosis, diabetes, pulmonary embolism, septic shock, preeclampsia, and asthma. Each pathology will be systematically reviewed. Finally, in the last part we will highlight the latest perspectives in drug design of thromboxane modulators and in their future therapeutic applications such as cancer, metastasis and angiogenesis.

Topics: Animals; Atherosclerosis; Blood Platelets; Diabetic Retinopathy; Drug Design; Enzyme Inhibitors; Humans; Myocardial Infarction; Neoplasms; Neovascularization, Pathologic; Platelet Aggregation; Prostaglandins; Receptors, Thromboxane A2, Prostaglandin H2; Structure-Activity Relationship; Sulfonamides; Thromboxane A2; Thromboxane-A Synthase

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

Patients with type 1 diabetes, aged 18 to 42 years, were compared to those aged 11 to 22 years. Activities of endothelial vasoactive factors and endothelial and leukocyte adhesion molecules were studied at different stages of development diabetes complications: nephropathy and retinopathy. The findings reveal role of the vasoactive factors in microangiopathy course.

Topics: Adolescent; Adult; Biomarkers; Child; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Retinopathy; E-Selectin; Endothelin-1; Endothelium, Vascular; Epoprostenol; Humans; Intercellular Adhesion Molecule-1; Microcirculation; Nitric Oxide; Thromboxane A2

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

Although several investigators have attempted to measure the plasma levels of prostacyclin (PGI2) and thromboxane A2 (TXA2) in diabetes and normal subjects, their results have been controversial. In this study, we measured plasma PGI2 and TXA2 levels in diabetic patients and normal subjects. The plasma PGI2 and TXA2 were determined by RIA as 6-keto-PGF1 alpha and TXB2, respectively. The plasma levels of 6-keto-PGF1 alpha were significantly reduced in diabetics with microangiopathy (52.5 +/- 18.9 pg/ml, mean +/- SE, p less than 0.05) compared with those of normal subjects. Diabetics as a whole also showed lower levels of 6-keto-PGF1 alpha than normal subjects (57.8 +/- 26.1 vs. 70.2 +/- 20.7 pg/ml), though this was not significant statistically. The plasma 6-keto-PGF1 alpha levels did not significantly correlate with either age of the patients or duration of diabetes in diabetics. Interestingly, however, hemoglobin A1c significantly correlated inversely with 6-keto-PGF1 alpha levels in diabetics without microangiopathy (r = -0.60, p less than 0.05). The plasma levels of TXB2 in diabetics were significantly higher than those of normal subjects (155.2 +/- 69.5 vs. 108.0 +/- 30.0 pg/ml, p less than 0.05). These data suggest that an imbalance of circulating PGI2 and TXA2 may contribute to the development of diabetic microangiopathy.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Blood Glucose; Diabetes Mellitus; Diabetic Retinopathy; Epoprostenol; Glycated Hemoglobin; Humans; Middle Aged; Thromboxane A2; Thromboxane B2

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

Prostacyclin (PGI2) is the most potent endogenous inhibitor of platelet aggregation yet discovered. Thromboxane (TXA2) promotes aggregation and degranulation of platelets. It is hypothesized that an homeostasis exists between these pathways that is protective against vascular damage and is disturbed in several diseases such as diabetes. Circulating levels of PGI2-TXA2 in 35 patients with adult onset diabetes and 15 controls have been assayed. Twenty patients had background retinopathy, and 15 had proliferative retinopathy. Circulating levels of PGI were found to be elevated in 9/15 patients with proliferative diabetic retinopathy, 2/20 diabetic patients with background or no retinopathy, and 0/15 controls. PGI levels may correlate, therefore, with the severity of the retinopathy.

Topics: Diabetic Retinopathy; Epoprostenol; Humans; Male; Middle Aged; Prostaglandins; Thromboxane A2; Thromboxanes