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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Among endothelial secretogogues prostacyclin (PGI2), nitric oxide (NO) and tissue plasminogen activator (t-PA) play a crucial role in maintaining thromboresistance, tone and structure of the vascular wall. Most receptor agonists, such as B2 kinin receptor agonists, or shear force produce a coupled release of all three secretogogues, and therefore interactions between them are to be expected. Essentially, PGI2 is a platelet suppressant, NO a vasodilator and t-PA a fibrinolytic agent. These and other properties of endothelial secretogogues supplement each other in protecting the cardiovascular system from injuries. It is not surprising that disturbances of the secretory function of endothelial cells are associated with atherosclerosis, diabetes, thrombosis or hypertension. Traditionally, PGI2, NO, t-PA or their substitutes are used individually for the treatment of peripheral arterial disease, angina pectoris or acute myocardial infarction. In light of recent findings, their joint administration can be advocated. For instance, NO donors will potentiate platelet-suppressant action of PGI2 analogues, whereas exogenous PGI2 or TXA2 synthase inhibitors (i.e. following increase in endogenous PGI2) will abolish a paradox of prothrombotic action of t-PA or streptokinase. The replacement therapy with PGI2, NO or t-PA should match as closely as possible the physiologically coupled release of these secretogogues.
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PMID:Interactions between endothelial secretogogues. 754 32

Increased platelet aggregability has been shown in hypercholesterolemia, and stirring-induced spontaneous aggregation in whole blood is increased in insulin-dependent diabetes mellitus (DM). We have determined spontaneous aggregation in citrated (10 mM) whole blood, from 27 primary dyslipidemic patients (DYS; 14F, 13M), 16 male non-insulin-dependent DM (NIDDM) patients, and 17 normolipidemic controls (N; 6F, 11M), using platelet counting to quantify aggregation. Spontaneous aggregation was significantly higher, both in the female DYS group (median 30% [interquartile range 25,50], P < 0.005) and the NIDDM group (33% [25,41], P < 0.005), than in the N group (17% [12,27]), but did not differ significantly in the male DYS group (23% [10,33]). Similar results were obtained in the presence of indomethacin (25 mumol/l) to prevent artefactual thromboxane (TX) A2 formation, indicating that increased spontaneous aggregation was TXA2-independent. Interestingly, increased spontaneous aggregation appeared to be independent of serum cholesterol and triglyceride concentrations, as well as age and sex per se. We conclude that spontaneous platelet aggregation was increased both in female primary dyslipidemic patients and NIDDM patients, but not in male DYS patients. The clinical significance of increased spontaneous platelet aggregability is that it may favour shear-induced aggregation which may occur at critical arterial stenoses in vivo leading to thrombus formation.
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PMID:Spontaneous platelet aggregation in whole blood is increased in non-insulin-dependent diabetes mellitus and in female but not male patients with primary dyslipidemia. 777 62

The effects of hypoxia on prostanoid production were studied in atria from normal, acute diabetic and insulin-treated diabetic rats. Diabetes was induced by intravenous administration of 65 mg/kg of streptozotocin, the rats were killed 5 days later. Hypoxia was performed by incubation of the atria during 60 min in nitrogen-equilibrated glucose free Krebs' solution followed by 15 min of reoxygenation. The prostanoids 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) and thromboxane B2 (TXB2), stable metabolites of prostacyclin and TXA2, respectively, as well as PGF2, were measured by reversed phase HPLC-UV. In control atria, the production of 6-keto PGF1 alpha was equivalent to that of PGE2, whereas TXB2 was released in a much smaller amount. In diabetic atria, 6-keto PGF1 alpha production was reduced by 65%, whereas TXB2 release was increased by 158% compared to the controls. When the normal atria were exposed to 60 min of hypoxia, the release of 6-keto PGF1 alpha increased by 142% compared to basal values and remained elevated after 15 min of reoxygenation whereas in diabetic and insulin-treated diabetic tissues the 6-keto PGF1 alpha production was not modified by the hypoxia-reoxygenation period. The release of TXB2 was increased after 60 min hypoxia in normal as well as in diabetic and insulin-treated diabetic tissues and remained elevated during the reoxygenation. The PGE2 output increased only after the onset of the reoxygenation in the three groups studied.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prostanoid production in hypoxic rat isolated atria: influence of acute diabetes. 784 89

Thromboxane A2 (TXA2) has been implicated in the pathogenesis of progressive glomerulosclerosis and stimulates the synthesis of matrix protein by mesangial cells (MCs). This study examined the role of transforming growth factor beta (TGF-beta) in the mediation of the action of the stable TXA2/prostaglandin (PG) endoperoxide analog U-46619 to stimulate fibronectin (Fn) synthesis in cultured rat MC. Exogenous TGF-beta increased Fn synthesis by MC in a concentration- and time-dependent fashion, as reflected by incorporation of [35S]methionine into immunoprecipitable Fn. Submaximal concentrations of TGF-beta (1-2.5 pmol/l) increased Fn synthesis two- to threefold, a response comparable in magnitude to that observed with a maximal stimulatory concentration (1 mumol/l) of U-46619. Anti-TGF-beta antibody, but not isotypic IgG, blocked the increases in Fn synthesis induced by both U-46619 and exogenous TGF-beta. Endogenous TGF-beta bioactivity in MC culture media, assessed by the mink lung epithelial cell system, was significantly increased by 1 mumol/l U-46619 (1.7 +/- 0.3 pmol/l) compared with that of control media (0.6 +/- 0.1 pmol/l, P < 0.05). Total (active plus latent) TGF-beta bioactivity, assayed after heat activation of latent TGF-beta, was also significantly higher in media of MCs cultured with U-46619 (45 +/- 4 pmol/l) compared with control (24 +/- 4 pmol/l). Thus, U-46619 increased endogenous TGF-beta bioactivity to a level sufficient to account for the enhancement of Fn synthesis observed with U-46619, as reflected by the Fn synthetic response to exogenous TGF-beta.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Mar
PMID:Role for transforming growth factor beta in thromboxane-induced increases in mesangial cell fibronectin synthesis. 788 21

We examined acute and chronic effects of thromboxane (TX) A2 inhibition on the renal hemodynamics at early and late stage of untreated streptozotocin (STZ)-induced diabetic rats. Two weeks and 28 weeks after the induction of diabetes, renal blood flow (RBF) under anesthesia was measured with an electromagnetic flowmeter before and after TXA2 inhibition. In two-week-old diabetic rats, a specific TXA2 synthetase inhibitor, OKY-046, or a specific TXA2 receptor antagonist, Sulotroban, increased renal vascular resistance (RVR) and ameliorated the hyperperfusion. The renal vasoconstrictive effect of OKY-046 was blunted by an angiotensin converting enzyme (ACE) inhibitor, MK422, or an angiotensin II receptor antagonist, Saralasin. On the contrary, OKY-046 ameliorated the renal hypoperfusion by decreasing RVR in 28-week-old diabetic rats. Chronic oral administration of OKY-046 ameliorated not only the renal hyperperfusion but increased urinary albumin excretion (UAE) at two weeks, but also the renal hypoperfusion, filtration fraction and UAE at 24 weeks. It is suggested that TXA2 might, at least in part, play important roles in the hyperperfusion by modulating activity of the renin-angiotensin system at an early stage of untreated diabetic rats and in the hypoperfusion at the late stage of untreated diabetic rats, and that TXA2 is also involved in the increase of UAE. These results support roles for TXA2 in the progression of renal injury in STZ-induced diabetic rats.
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PMID:Acute and chronic effects of thromboxane A2 inhibition on the renal hemodynamics in streptozotocin-induced diabetic rats. 819 81

Thromboxane A2 (TXA2) and prostaglandin H2 (PGH2) are potent vasoactive and proaggregatory agents whose synthesis has been shown to be elevated in diabetes mellitus. In the present study the effects of streptozotocin (STZ)-induced uncontrolled diabetes (Severe) and insulin-treated STZ diabetes (Moderate) on TXA2/PGH2 receptor density and affinity in platelets, glomerular membranes and aortic membranes were determined using [125I]-BOP, a TXA2/PGH2 receptor agonist. The affinity and density of platelet TXA2/PGH2 receptors in Control, Moderate and Severe groups and glomerular membranes were not significantly different. However, daily insulin therapy caused significant changes in both TXA2/PGH2 receptor affinity and density of aortic membranes: Kd (nM) = 0.67 +/- 0.09, (n = 5), for Control; 0.27 +/- 0.05*, (n = 6), Moderate; and 0.74 +/- 0.16, (n = 5), Severe; Bmax (fmoles/mg protein) = 38.6 +/- 3.1, Control; 20.2 +/- 4.2*, Moderate; and 37.1 +/- 4.1, Severe: (*p < 0.05 compared to Control and Severe). Contractile responses of aortic segments to the TXA2/PGH2 receptor agonist U46619 were determined. Untreated diabetes mellitus (Severe) was associated with a decreased responsiveness of aortic segments without affecting maximum contractile responses (EC50 = 24.6 +/- 5.9* nM, (n = 10); *p < 0.05) compared to Control rats (EC50 = 11.8 +/- 1.6 nM, (n = 13)). Insulin therapy reversed the decrease seen in the Severe group to a value not different from Control (EC50 = 11.4 +/- 1.2* nM, (n = 10); *p < 0.05 compared to Severe). These results suggest that insulin therapy in the diabetic state significantly influences aortic TXA2/PGH2 receptors, as well as vascular responsiveness to TXA2/PGH2 mimetics.
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PMID:Thromboxane A2/prostaglandin H2 receptors in streptozotocin-induced diabetes: effects of insulin therapy in the rat. 832 12

This study investigated the possible involvement of prostaglandin H2, an acetylcholine-induced endothelium-derived contracting factor in rat aorta, in the development of abnormality of the vasculature in diabetes. Rings of thoracic aorta were prepared from control Wistar-Kyoto and STZ-induced diabetic rats to examine the changes in isometric tension. In 10(-7) M norepinephrine-precontracted rings, acetylcholine induced relaxations, which were significantly impaired in diabetic rats. Inhibition of thromboxane A2-prostaglandin H2 receptors with ONO-3708 (10(-6) M) prevented the development of the impairment of relaxation in diabetic rats. Thromboxane A2 synthesis inhibition with OKY-046 (10(-5) M) did not affect the acetylcholine-induced relaxation in both control and diabetic rats. In aortic rings under resting tension, acetylcholine induced a contraction that was greater in diabetic than control rats, when the nitric oxide production was inhibited by NG-nitro-L-arginine methylester (10(-4) M). This acetylcholine-induced contraction was observed only in the rings with intact endothelium and was completely abolished by ONO-3708 (10(-6) M). The concentration of 6-keto-prostaglandin F1 alpha in the solution bathing diabetic rat aortic rings increased significantly after acetylcholine (10(-5) M) administration. Prostacyclin (10(-9)-10(-6) M) did not induce contractions at all. Prostacyclin is unlikely to mediate contractions because of its low contractile potency.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Sep
PMID:Role of prostaglandin H2 as an endothelium-derived contracting factor in diabetic state. 834 35

Indobufen is a reversible inhibitor of platelet prostaglandin G/H-synthase. To verify the dose dependence of the antiplatelet effect of indobufen on ex vivo and in vivo indexes of thromboxane (TX) biosynthesis and TXA2-dependent platelet function, we studied nine patients with non-insulin-dependent diabetes mellitus (NIDDM). This was a randomized, double-blind, crossover study in which each patient was treated with three different daily regimens (50 mg BID, 100 mg BID, and 200 mg BID) of indobufen for 1 week, with a 7-day washout period between treatments. Urinary 11-dehydro-TXB2 excretion averaged 58.2 +/- 21.8 ng/h at baseline. TX metabolite excretion was reduced dose dependently by indobufen: by 67% at 50 mg BID, 72% at 100 mg BID, and 81% at 200 mg BID. Platelet cyclooxygenase activity, ATP release, collagen-induced platelet aggregation, and bleeding time also were modified dose dependently by indobufen. Biochemical demonstration of suppressed platelet TXA2 in vivo was accompanied by evidence of inhibited platelet function as assessed ex vivo. Under pathophysiological conditions, such as NIDDM, which are associated with enhanced TXA2 synthesis, more than 95% suppression of platelet cyclooxygenase activity may be necessary to produce virtually maximal inhibition of platelet TXA2 biosynthesis in vivo.
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PMID:Inhibition of thromboxane biosynthesis and platelet function by indobufen in type II diabetes mellitus. 836 18

The disparate results reported in the literature on the effects of low dose aspirin in preventing pre-eclampsia might be caused by non-compliance in the more recent large trials in low-risk patients. All the earlier small trials were done on identified high-risk patients who consider themselves as patients, as do their doctors. Compliance in these patients will be very high. In fact, the only study in healthy subjects in which aspirin intake was controlled for (Hauth et al 1993) showed a marked reduction in the incidence of pre-eclampsia. However, the recent large trials have demonstrated, without any doubt, that low dose aspirin is not a miracle drug. The combined literature points at a 25% reduction in the incidence of pre-eclampsia in association with the use of aspirin (Collins, 1994). The correct indication for the use of low-dose aspirin appears to be the patient that is at very high risk of developing early-onset (less than 32 weeks gestation) pre-eclampsia. Since early-onset pre-eclampsia can begin at any time after 20 weeks gestation, it is necessary to initiate low-dose aspirin therapy early in pregnancy, preferably at 10-14 weeks gestation. The results of the recent large trials emphasize the need for a reliable, sensitive method of predicting or detecting pre-eclampsia at a very early gestational age (Dekker and Sibai, 1991). Valensise et al (1993) recently confirmed earlier studies (McParland et al, 1990) on the useful combination of uteroplacental Doppler flow velocimetry and aspirin in low-risk primigravidae. Results from current large-scale trials, such as the ECPPA, the BLASP, the WHO Jamaica and the second NICHHD studies, will be available in the near future. The results of especially the second NICHHD study on low-dose aspirin, in more than 2000 high-risk women (previous pre-eclampsia/eclampsia, chronic hypertension, class B to F diabetes or multiple gestation), will hopefully give us a more definitive picture on the potential benificial effects of low-dose aspirin in high-risk patients. The effect of aspirin on placental TXA2 deserves further studies. It might be that the optimal level to inhibit placental TXA2 and lipid peroxide production is actually higher than the minimal effective doses of aspirin that are needed to inhibit platelet TXA2 production (Walsh, 1994). Low-dose aspirin appears to be safe for the fetus and neonate. If there is an increased risk of abruptio placentae, this risk appears to be minimal. The final word on the use of low-dose aspirin has not yet been reached; however, we may be getting closer to profiling patients for whom the therapy may be efficacious and beneficial to both mother and fetus. Further studies are also necessary on combinations of aspirin and other antithrombotic drugs, such as heparin or ketanserin (Tanaka et al, 1993; Bolte et al, 1994; North et al, 1994). North et al (1994) demonstrated that treatment of women with severe renal disease with heparin plus aspirin reduced the prevalence of superimposed pre-eclampsia, compared with no treatment or aspirin alone. Next to low-dose aspirin, there appear to be several new and promising pharmaceutical approaches for reducing the consequences of EC dysfunction. Among these are selective TXA2-synthetase or TXA2-receptor antagonists, Serotonin2-receptor blockers, stable PGI2 analogues and NO donors.
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PMID:The pharmacological prevention of pre-eclampsia. 884 53

Reduced nerve conduction velocity (NCV) in experimental diabetes can be prevented by evening primrose oil (EP), which is rich in gamma-linolenic acid (GLA). This study examined the efficacy of natural GLA sources, blackcurrant (BC), borage (BO) and fungal (FU) oils, compared with EP, in correcting motor and sensory NCV deficits in streptozotocin-diabetic rats, and any potential contribution of thromboxane (TX) A2 synthesis using the TX antagonist, ZD1542, alone and jointly with GLA-rich oils. Sciatic motor NCV, 20% reduced by 8 weeks of diabetes, was partially (16%) corrected by 2 weeks ZD1542 treatment. 1% BC, BO, FU and EP dietary supplementation caused 11%, 32%, 41% and 53% NCV ameliorations, respectively. A 2% EP diet, more closely matching the GLA intake from the other oils, caused 67% correction. Joint oil/ZD1542 treatment produced further motor NCV improvements for BC and, particularly, BO. A 13% sensory saphenous NCV deficit in diabetic rats was ameliorated by 31%, 24%, 49%, 81%, 70% and 94% for ZD1542, BC, BO, FU, EP and 2% EP, respectively. Joint ZD1542-oil treatment further improved NCV, particularly for BO. Therefore, efficacy against experimental diabetic neuropathy is not predictable from the GLA content of natural oils, EP consistently outperforming BC, BO and FU. Increased TXA2 with diabetes made a minor contribution to NCV deficits, but blockade improved the response to BO.
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PMID:Effectiveness of natural oils as sources of gamma-linolenic acid to correct peripheral nerve conduction velocity abnormalities in diabetic rats: modulation by thromboxane A2 inhibition. 893 Nov 13


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