dinoprost and Diabetic-Angiopathies

Topics: Biomarkers; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Neuropathies; Dinoprost; Electron Transport; Endothelial Cells; Glycation End Products, Advanced; Humans; Hyperglycemia; Mitochondria; NADPH Oxidases; Oxidative Stress; Polymers; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Superoxides

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

Little is known about the vascular contractile responsiveness to, and signaling pathways for, extracellular nucleotides in the chronic stage of type 2 diabetes or whether the ANG II type 1 receptor blocker losartan might alter such responses. We hypothesized that nucleotide-induced arterial contractions are augmented in diabetic Goto-Kakizaki (GK) rats and that treatment with losartan would normalize the contractions. Here, we investigated the vasoconstrictor effects of ATP/UTP in superior mesenteric arteries isolated from GK rats (37-42 wk old) that had or had not received 2 wk of losartan (25 mg·kg(-1)·day(-1)). In arteries from GK rats (vs. those from Wistar rats), 1) ATP- and UTP-induced contractions, which were blocked by the nonselective P2 antagonist suramin, were enhanced, and these enhancements were suppressed by endothelial denudation, by cyclooxygenase (COX) inhibitors, or by a cytosolic phospholipase A(2) (cPLA(2)) inhibitor; 2) both nucleotides induced increased release of PGE(2) and PGF(2α); 3) nucleotide-stimulated cPLA(2) phosphorylations were increased; 4) COX-1 and COX-2 expressions were increased; and 5) neither P2Y2 nor P2Y6 receptor expression differed, but P2Y4 receptor expression was decreased. Mesenteric arteries from GK rats treated with losartan exhibited (vs. untreated GK) 1) reduced nucleotide-induced contractions, 2) suppressed UTP-induced release of PGE(2) and PGF(2α), 3) suppressed UTP-stimulated cPLA(2) phosphorylation, 4) normalized expressions of COX-2 and P2Y4 receptors, and 5) reduced superoxide generation. Our data suggest that the diabetes-related enhancement of ATP-mediated vasoconstriction was due to P2Y receptor-mediated activation of the cPLA(2)/COX pathway and, moreover, that losartan normalizes such contractions by a suppressing action within this pathway.

Topics: Adenosine Triphosphate; Angiotensin II Type 1 Receptor Blockers; Animals; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dinoprost; Dinoprostone; Disease Models, Animal; Group IV Phospholipases A2; Losartan; Male; Membrane Proteins; Mesenteric Artery, Superior; Phosphorylation; Purinergic P2 Receptor Antagonists; Rats; Rats, Wistar; Receptors, Purinergic P2; Receptors, Purinergic P2Y2; Signal Transduction; Superoxides; Uridine Triphosphate; Vasoconstriction

Poor control of blood glucose in diabetes is known to promote vascular dysfunction and hypertension. Diabetes was recently shown to be linked to an increased prevalence of pulmonary hypertension. The aim of this study was to determine how the pharmacological reactivity of intrapulmonary arteries is altered in a rat model of diabetes.. Diabetes was induced in rats by the beta-cell toxin, streptozotocin (STZ, 60 mg/kg), and isolated conduit and resistance intrapulmonary arteries studied 3-4 months later. Isometric tension responses to the vasoconstrictors phenylephrine, serotonin and PGF2alpha, and the vasodilators carbachol and glyceryl trinitrate, were compared in STZ-treated rats and age-matched controls.. STZ-induced diabetes significantly blunted the maximum response of conduit, but not resistance pulmonary arteries to phenylephrine and serotonin, without a change in pEC50. Agonist responses were differentially reduced, with serotonin (46% smaller) affected more than phenylephrine (32% smaller) and responses to PGF2alpha unaltered. Vasoconstriction caused by K+-induced depolarisation remained normal in diabetic rats. Endothelium-dependent dilation to carbachol and endothelium-independent dilation to glyceryl trinitrate were also unaffected.. The small resistance pulmonary arteries are relatively resistant to STZ-induced diabetes. The impaired constrictor responsiveness of conduit vessels was agonist dependent, suggesting possible loss of receptor expression or function. The observed effects cannot account for pulmonary hypertension in diabetes, rather the impaired reactivity to vasoconstrictors would counteract the development of pulmonary hypertensive disease.

Topics: Animals; Calcium Signaling; Carbachol; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Dinoprost; Endothelium, Vascular; Hypertension, Pulmonary; Male; Membrane Potentials; Muscle, Smooth, Vascular; Nitroglycerin; Phenylephrine; Potassium; Pulmonary Artery; Pulmonary Circulation; Rats; Rats, Wistar; Serotonin; Streptozocin; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents

Endothelial dysfunction often precedes Type 2 diabetes-associated cardiovascular complications. One important cause of endothelial dysfunction is oxidative stress, which can lead to reduced nitric oxide (NO) bioavailability. In this study, we examined the effects of ramipril (an angiotensin-converting enzyme inhibitor, ACEI) on reactive oxygen species (ROS) production and endothelium-dependent vasodilation using a Type 2 diabetic (db/db) murine model. Plasma concentration of 8-isoprostane ([8-isoP]) was measured and used as an indication of the amount of ROS production. Six weeks of ramipril (10 mg/kg/day) treatment significantly reduced [8-isoP] and improved acetylcholine(ACh)-induced vasodilation in db/db mice without altering responses in wild-type (WT) mice. Responsiveness of smooth muscle cells to NO, assessed by sodium nitroprusside-induced vasodilation, was not different between db/db and WT mice regardless of ramipril or vehicle treatment. Our results suggest that ramipril specifically improved endothelium-dependent vasodilation in Type 2 diabetic mice, possibly by reducing ROS levels.

Topics: Acetylcholine; Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dinoprost; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Male; Mice; Mice, Inbred Strains; Muscle, Smooth, Vascular; Nitric Oxide; Nitroprusside; Oxidative Stress; Ramipril; Reactive Oxygen Species; Time Factors; Vasodilation; Vasodilator Agents

Advanced glycation end products (AGEs) contribute to diabetic vascular complications by engaging the AGE receptor (RAGE). A soluble RAGE form (sRAGE) acts as a decoy domain receptor, thus decreasing AGE cellular binding. A cross-sectional comparison of sRAGE, asymmetric dimethylarginine (ADMA) plasma levels (index of endothelial dysfunction), and urinary 8-iso-prostaglandin (PG)F(2alpha) (marker of oxidative stress) was performed between 86 diabetic patients and 43 controls. Plasma sRAGE levels were significantly lower and ADMA levels were significantly higher in diabetic patients as compared to controls (P<0.0001). HbA1c and urinary 8-iso-PGF(2alpha) were correlated inversely with sRAGE and directly with ADMA. On multivariate analysis HbA1c was independently related to sRAGE levels in diabetic patients. Twenty-four of 86 patients with newly diagnosed diabetes and 12 patients in poor metabolic control were reevaluated after treatment with a hypoglycemic agent or insulin, respectively. Improvement in metabolic control by oral agents or insulin resulted in a significant increase in sRAGE and decrease in ADMA levels (P<0.0001). Thus, poor glycemic control reduces sRAGE levels, in association with enhanced oxidative stress and endothelial dysfunction in diabetes. These abnormalities are susceptible to modulation by improvement in metabolic control.

Topics: Arginine; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dinoprost; Enzyme-Linked Immunosorbent Assay; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Oxidative Stress; Receptor for Advanced Glycation End Products; Receptors, Immunologic

Hyperglycemia has been linked to increased oxidative stress, a resultant endothelial cell dysfunction, and, ultimately, apoptosis. Heme oxygenases (HO-1/HO-2) and the products of their activity, biliverdin/bilirubin and carbon monoxide (CO), play a physiological role in the vascular system. The effects of heme-mediated HO-1 induction, CO, and biliverdin on urinary 8-epi-isoprostane PGF(2alpha) and endothelial cell sloughing were examined in an animal model of streptozotocin (STZ)-induced diabetes. Hyperglycemia itself did not affect HO-1 and HO-2 protein levels, but caused a net decrease in HO activity. Weekly heme administration induced HO-1 protein, as demonstrated by immunohistochemistry and Western blot analyses. Administration of biliverdin or the CO donor, CORM-3, decreased urinary 8-epi-isoprostane PGF(2alpha), P < 0.5 compared to diabetes. Hyperglycemia increased endothelial cell sloughing; 8.2 +/- 0.8 cells/ml blood in control rats vs. 48 +/- 4.8 cells/ml blood in diabetic rats (P < 0.05). Heme administration significantly increased endothelial cell sloughing in diabetic rats (98 +/- 8.1 cells/ml blood, P < 0.0007) whereas biliverdin modestly decreased endothelial cell sloughing (26 +/- 3.5 cells/ml blood, P < 0.003). Administration of CORM-3 to diabetic rats resulted in a significant decrease in endothelial cell sloughing to 21.3 +/- 2.3 (P < 0.001). Administration of SnMP to CORM-3 diabetic rats only partially reversed the protective effects of CORM-3 on endothelial cell sloughing from 21.3 +/- 2.3 to 29 +/- 2.1 cells/ml, thus confirming a direct protective of CO, in addition to the ability of CORM-3 to induce HO-1 protein. These results demonstrate that exogenously administered CO or bilirubin can prevent endothelial cell sloughing in diabetic rats, likely via a decrease in oxidative stress, and thus represents a novel approach to prophylactic vascular protection in diabetes.

Topics: Animals; Biliverdine; Carbon Monoxide; Cell Aggregation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Dinoprost; Endothelial Cells; Endothelium, Vascular; Heme; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Organometallic Compounds; Protective Agents; Rats

The extent of involvement of cyclooxygenase (COX)-mediated inflammation in type 1 diabetes is unknown, and the association between the COX- and cytokine-mediated inflammatory responses in type 1 diabetes is not fully understood.. Plasma high-sensitivity C-reactive protein (CRP), 24-h urinary and plasma 15-keto-dihydro-prostaglandin F(2alpha) (a metabolite of prostaglandin F(2alpha) [PGF(2alpha)] and an indicator of COX-mediated inflammation), serum amyloid protein A (SAA), and interleukin (IL)-6 (indicators of inflammation) were measured in 38 subjects with type 1 diabetes and 41 healthy age- and sex-matched control subjects.. The inflammatory indicators (urinary 15-keto-dihydro-PGF(2alpha), P < 0.01; IL-6, P < 0.04) were increased in men with diabetes. CRP and SAA did not show any significant difference between the diabetic and the control subjects. Urinary levels of 15-keto-dihydro-PGF(2alpha) correlated with the degree of glycemic control, HbA(1c) (r = 0.42, P < 0.0005). No correlation was found between the duration of diabetes and the inflammatory biomarkers or metabolic measurements.. These results suggest that an early low-grade inflammatory process reflected by elevated levels of PGF(2alpha) and IL-6 is involved in type 1 diabetes. Thus, both COX- and cytokine-mediated inflammatory pathways are significantly related to type 1 diabetes.

Topics: Adult; Albuminuria; C-Reactive Protein; Cytokines; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Dinoprost; Female; Humans; Hypertension; Inflammation; Lipids; Male; Reference Values; Regression Analysis

Diabetic patients manifest an increased incidence of heart failure (HF) after myocardial infarction (MI), which presages an increase in morbidity and mortality. Although oxidative stress has been implicated in diabetic complications, oxidative stress status associated with comorbid conditions that frequently accompany diabetes remains unknown. Therefore, we examined antioxidants and oxidative stress in the surviving myocardium in relation to ventricular function during diabetic HF following MI. MI was produced in diabetic and nondiabetic rats by ligation of the left coronary artery. At 4 weeks post-MI, LV systolic pressure (LVSP), rate of pressure rise (+dP/dt), and rate of pressure decay (-dP/dt) were depressed to a significantly greater extent in diabetic compared to nondiabetic MI animals. Higher levels of myocardial 8-isoprostane (8-iso PGF(2alpha)), oxidized glutathione (GSSG), as well as greater upregulation of superoxide dismutase (SOD) and catalase (CAT) protein expression paralleled by increases in enzymatic activity was observed in the diabetic MI animals, indicating higher oxidative stress. These data demonstrate a greater derangement of oxidative stress in the surviving tissues of diabetic post-MI rat hearts concomitant with an increased functional severity of HF, and suggest that chronic antioxidant therapy may be useful for the prophylaxis of subsequent HF after MI associated with diabetes.

Topics: Animals; Antioxidants; Cardiac Output, Low; Catalase; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Dinoprost; Glutathione Disulfide; Male; Myocardial Infarction; Myocardium; Oxidative Stress; Proteins; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

Diabetes mellitus (DM) is a well-established risk factor of cardiovascular diseases. We investigated the mechanism of the progression of arteriosclerosis in DM, focusing on the role of oxidative stress and insulin resistance in vivo. Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an experimental model of type 2 DM, were assigned to 3 groups, based on supplementation with vitamin E (VE) or troglitazone (TR), a VE-derived agent which improves insulin-resistance. At 36 weeks, plasma and aortic tissue 8-iso-PGF2alpha contents, a vascular proliferating eicosanoid produced in vivo by oxidative stress, were measured by EIA. TGF-beta1 and TGF-beta1 receptor II were immunohistochemically analyzed. Histopathologically, medial area and the nuclear number of smooth muscle cells of the aorta were measured. The tissue 8-iso-PGF2alpha content (pg/g tissue) was significantly decreased by either VE or TR in the aorta (untreated-OLETF, 15,332+/-3,254 vs. TR-treated-OLETF, 7,092+/-1,992 or VE-treated-OLETF, 5,394+/-836, both p<0.01), but that in plasma decreased by only VE. VE and TR improved the increased the level of the actual medial area and the number of smooth muscle cells. The expression of TGF-beta1 was reduced, but TGF-beta1 receptor II was not. 8-iso-PGF2alpha may play an important role in the progression of arteriosclerosis. Antioxidant treatment may promise significant clinical benefits in the early diabetic stage.

Topics: Animals; Aorta; Arteriosclerosis; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dinoprost; Disease Progression; Eicosanoids; F2-Isoprostanes; Lipids; Male; Oxidative Stress; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta; Transforming Growth Factor beta1

Adult offspring of severely diabetic pregnant rats are insulin resistant and display cardiovascular dysfunction. When pregnant they develop mild hyperglycaemia. Diets high in saturated fat have been implicated in the development of cardiovascular disease and vascular dysfunction. In the present study we have determined vascular function in small mesenteric arteries from offspring of normal (OC) and diabetic (OD) rats fed standard chow and offspring of diabetic rats fed a diet high in saturated fats (OD-HF) from weaning to adulthood, and throughout their subsequent pregnancies. OD rats displayed an increased sensitivity to noradrenaline (P < 0.05) and impaired sensitivity to the endothelium-dependent vasodilator, acetylcholine. The component of acetylcholine-induced relaxation attributable to endothelium-derived hyperpolarizing factor was reduced in OD-HF rats. Pregnant OD rats also demonstrated impaired maximum relaxation to acetylcholine (pregnant OD rats v. pregnant OC rats P < 0.05). In pregnant OD-HF rats noradrenaline sensitivity was enhanced and endothelium-dependent relaxation further reduced (pregnant OD-HF rats v. pregnant OC rats P < 0.001). The isoprostane, 8-epi-prostaglandin F2alpha, a marker of oxidative stress, was increased in pregnant OD rats (pregnant OD rats v. pregnant OC rats P

Topics: Animals; Blood Glucose; Body Composition; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Dietary Fats; Dinoprost; Female; Insulin; Mesenteric Arteries; Pregnancy; Rats; Rats, Wistar; Vasoconstriction; Vasodilation

Pathological, muscular arteries (common and superficial femoral [FC, FS], anterior and posterior tibial [TA, TP] arteries) of patients suffering from arteriosclerosis obliterans (ASO), thromboangiitis obliterans (TAO), and diabetes mellitus (DIA), removed during amputation of the lower limb were studied as isolated organs. The vessels were cut into transverse rings and contractile force was measured isometrically. The total number of used rings was 828. The following agonists were applied: KCl (80 mM), serotonin (5-HT) (10 microM), prostaglandin F2 alpha (PGF2 alpha) (0.1 mM) or phenylephrine (PE) (10 microM). It was established that applying KCl, 5-HT or PGF2 alpha, the majority of arterial rings display a contraction, but most of the preparations (66%) give no response against PE. The measure of contraction depends on the diagnosis (TAO greater than ASO greater than DIA), on the age of patient and also the anatomical location of the artery in the case of TAO (TP greater than greater than TA), on the associated hypertension in the case of ASO (normotensive greater than hypertensive) and finally on the time elapsed between the operation and usage of preparation if the agonist is KCl. As a conclusion, despite the terminal clinical stage the majority of studied human arteries retained at least a part of their functional integrity.

Topics: Adult; Aged; Arteries; Arteriosclerosis Obliterans; Diabetic Angiopathies; Dinoprost; Female; Femoral Artery; Humans; Hypertension; In Vitro Techniques; Male; Middle Aged; Muscle Contraction; Muscle, Smooth, Vascular; Phenylephrine; Potassium Chloride; Reference Values; Serotonin; Thromboangiitis Obliterans

Contractile responses to prostaglandin F2 alpha, serotonin, noradrenaline, and potassium were examined in isolated intramyocardial arteries of Wistar rats 8 weeks after the induction of diabetes mellitus by administration of streptozotocin (STZ). The concentration-response curves obtained were compared with those noted in vessels both from age- and from weight-matched control rats. Light and electron microscopy did not reveal any major change in coronary artery wall thickness or morphology. There was no difference in the pattern of vasomotor responses between the two control groups. Contractile responses to prostaglandin F2 alpha, and potassium were significantly reduced, while contractile responses to serotonin and noradrenaline were unaltered in coronary arteries from diabetic rats. The vasomotor responses to noradrenaline and potassium showed a biphasic pattern in control vessels, i.e. contraction noted at high agonist concentrations was preceded by slight, but reproducible relaxation at lower concentrations. In diabetic vessels these relaxant responses were absent. The contraction produced by noradrenaline was markedly enhanced by the presence of propranolol in both diabetic and control vessels. Dilator responses to verapamil, diltiazem, nifedipine, papaverine and magnesium were studied in serotonin-precontracted coronary arteries; the concentration-response curves obtained by verapamil and diltiazem were shifted to the right in diabetic vessels. It appears justified to use vessels from age-matched rats as controls when vasomotor reactivity in coronary arteries from STZ-diabetic rats is investigated. The reduction in contractile responses to prostaglandin F2 alpha and potassium, and the reduction or lack of relaxant responses to noradrenaline, potassium, verapamil and diltiazem, in diabetic coronary arteries, indicate a selective modification of the coronary circulation by the diabetic disease.

Topics: Animals; Arteries; Body Weight; Coronary Vessels; Diabetic Angiopathies; Dinoprost; Male; Muscle Contraction; Muscle, Smooth, Vascular; Norepinephrine; Potassium; Rats; Rats, Inbred Strains; Serotonin; Vasodilator Agents