15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Diabetes-Mellitus--Type-1

There is clinical and experimental evidence for altered adenosine signalling in the fetoplacental circulation in pregnancies complicated by diabetes, leading to adenosine accumulation in the placenta. However, the consequence for fetoplacental vasocontractility is unclear. This study examined contractility to adenosine of chorionic vessels from type 1 diabetes mellitus, gestational diabetes mellitus and normal pregnancies.. Chorionic arteries and veins were isolated from human placenta from normal, gestational diabetes mellitus and type 1 diabetes mellitus pregnancies. Isometric tension recording measured responses to adenosine and the thromboxane A. Adenosine elicited contractions in chorionic arteries and veins which were impaired in both gestational diabetes mellitus and type 1 diabetes mellitus. Contractions to potassium chloride were unchanged. Adenosine A. These data are consistent with the concept of aberrant adenosine signalling in diabetes; they show for the first time that this involves impaired adenosine contractility of the fetoplacental vasculature.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine; Arteries; Case-Control Studies; Chorion; Diabetes Mellitus, Type 1; Diabetes, Gestational; Female; Humans; Pregnancy; Pregnancy in Diabetics; Receptor, Adenosine A2A; Receptor, Adenosine A2B; Receptor, Adenosine A3; Signal Transduction; Term Birth; Vasoconstriction; Vasoconstrictor Agents; Veins

Oxidative stress may increase production of superoxide and nitric oxide, leading to formation of prooxidant peroxynitrite to cause vascular dysfunction. Having found nitrotyrosine residues, a marker of peroxynitrite action, in placental vessels of preeclamptic and diabetic pregnancies, we determined whether vasoreactivity is altered in these placentas and treatment with peroxynitrite produces vascular dysfunction. The responses of diabetic, preeclamptic, and normal placentas to increasing concentrations of the vasoconstrictors U-46619 (10(-9)-10(-7) M) and ANG II (10(-9)-10(-7) M) and the vasodilators glyceryl trinitrate (10(-9)-10(-7) M) and prostacyclin (PGI(2); 10(-8)-10(-6) M) were compared as were responses to these agents in normal placentas before and after treatment with 3.16 x 10(-4) M peroxynitrite for 30 min. Responses to both vasoconstrictors and vasodilators were significantly attenuated in diabetic and preeclamptic placentas compared with controls. Similarly, responses to U-46619, nitroglycerin, and PGI(2), but not ANG II, were significantly attenuated following peroxynitrite treatment. The presence of nitrotyrosine residues confirmed peroxynitrite interaction with placental vessels. Overall, our data suggest that peroxynitrite formation is capable of attenuating vascular responses in the human placenta.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adult; Angiotensin II; Antihypertensive Agents; Diabetes Mellitus, Type 1; Epoprostenol; Female; Fetus; Humans; In Vitro Techniques; Muscle, Smooth, Vascular; Nitrates; Nitric Oxide; Nitroglycerin; Oxidative Stress; Placenta; Pre-Eclampsia; Pregnancy; Reactive Oxygen Species; Tyrosine; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents

Platelet aggregation to collagen in 12 Type 1 (insulin-dependent) diabetic patients with background retinopathy and 12 Type 1 diabetic patients with proliferative retinopathy was compared with an age- and sex-matched control group. An analogue of prostaglandin H2, 11,9 epoxymethano-prostaglandin H2, which directly stimulates thromboxane receptors, and EP 092, which is a competitive thromboxane A2 receptor antagonist, were used to investigate changes at platelet thromboxane receptor level in these groups. The concentration of collagen (EC50) required to give 50% of maximum aggregation did not differ between the two diabetic groups and the control group. However, platelets from the proliferative retinopathy group were significantly more sensitive to the thromboxane mimetic (11,9 epoxymethano-prostaglandin H2) (p less than 0.005) than the background retinopathy and control groups. This change may be a factor in the development of proliferative retinopathy.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adult; Blood Platelets; Collagen; Cyclic AMP; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Drug Resistance; Female; Humans; In Vitro Techniques; Male; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Prostaglandins, Synthetic; Receptors, Prostaglandin; Receptors, Thromboxane

Previous studies suggested a role for prostaglandins or thromboxane A2, or both in the exposure of fibrinogen receptors on normal platelets in response to several aggregating agents. Platelets from diabetics are known to be more sensitive to aggregating agents and to produce more prostaglandins and thromboxane than platelets from normal subjects. We compared fibrinogen binding to platelets from diabetic subjects with binding to platelets from normal subjects and determined whether aspirin (which inhibits the formation of prostaglandins and thromboxane) would inhibit the binding of fibrinogen to platelets from diabetic subjects and whether this correlated with its effects on platelet aggregation. We found the following: Aspirin suppressed thromboxane formation and rendered the platelets less sensitive to the induction of aggregation by adenosine diphosphate (ADP) or collagen. The amount of U-46619 [( 15s]-hydroxy-11-alpha, 9-alpha [epoxy-methano]-prosta[5Z,13E]-dienoic acid, a stable analog of prostaglandin endoperoxide/thromboxane A2) necessary to induce aggregation, was similar in normal and diabetic subjects and was unchanged after ingestion of aspirin. Binding of 125I-fibrinogen following stimulation of platelets by ADP or collagen was greater in diabetic (because more binding sites were exposed) than in normal subjects. However, following stimulation by U-46619, binding was similar in diabetic and normal subjects. Aspirin caused a reduction in the exposure of binding sites on both platelets from diabetic and normal subjects, so that (in this respect) platelets from diabetic subjects became more like those from normal subjects. Effects of the monoclonal antibody B59.2, which is specific for the platelet glycoprotein IIb-IIIa complex (the presumed receptor for fibrinogen on the platelet surface) were also studied. The amount of this antibody that bound to platelets was the same for normal and diabetic subjects both before and after aspirin and with or without stimulation by ADP or collagen. In addition, B59.2 inhibited aggregation and fibrinogen binding in both platelets from diabetic and normal subjects. The combined data suggest that the glycoprotein IIb-IIIa complex of platelets from diabetic subjects is similar to that of platelets from normal subjects and that the increased fibrinogen binding and aggregation of platelets from diabetic subjects in response to ADP or collagen is mediated by increased formation of prostaglandin endoperoxide or thrombo

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Diphosphate; Adenosine Triphosphate; Adolescent; Adult; Antibodies, Monoclonal; Binding Sites, Antibody; Binding, Competitive; Blood Platelets; Collagen; Diabetes Mellitus, Type 1; Female; Fibrinogen; Humans; In Vitro Techniques; Male; Platelet Aggregation; Platelet Membrane Glycoproteins; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Receptors, Cell Surface; Thromboxane B2