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Eplerenone improves vascular function and reduces platelet activation in diabetic rats

100%

Schafer A., Vogt C., Fraccarollo D., Widder J., Flierl U., Hildemann S. K., Ertl G., Bauersachs J.

Journal of Physiology and Pharmacology

2010

tom 61

nr 1

45-52

Diabetes is associated with endothelial dysfunction and platelet activation, both of which contribute to increased cardiovascular risk. We investigated whether the selective mineralocorticoid receptor (MR) antagonist eplerenone improves endothelial dysfunction and reduces platelet activation in diabetic rats. Male Wistar-rats were injected with streptozotocin (50 mg/kg i.v.) to induce insulin-deficient diabetes. After 2 weeks, treatment with eplerenone (100 mg/kg/day) or vehicle was initiated for 2 weeks. Aortic superoxide production determined by lucigenin-enhanced chemiluminescence and 2-hydroxyethidium formation was significantly increased in rats with diabetes and reduced by treatment with eplerenone (chemiluminescence: control 2045±227, STZ-placebo 3977±340, p<0.05 vs. control, STZ-eplerenone 1762±307, p<0.05 vs. STZ-placebo). Endothelium-dependent vasorelaxation was significantly attenuated in diabetic rats and was normalized by eplerenone (maximum relaxation in % of precontraction: control 95±3, STZ-placebo 82±3, p<0.01 vs. control, STZ-eplerenone 99±1, p<0.01 vs. STZ-placebo). Treatment with the selective MR antagonist significantly reduced fibrinogen-binding on activated GPIIb/IIIa (immunofluorescence: control 161±7, STZ-placebo 208±16, p<0.05 vs. control, STZ-eplerenone 173±6, p<0.05 vs. STZ-placebo). Eplerenone improves endothelial function by reducing superoxide formation and increasing NO bioavailability in diabetic rats. Platelet activation was significantly reduced by eplerenone. Selective MR blockade may constitute a useful therapeutic approach for treatment of vascular dysfunction in diabetes.

The involvement of Naplus-Kplus-ATPase in the development of platelet procoagulant response

80%

Tomasiak M., Stelmach H., Rusak T., Ciborowski M., Radziwon P.

Acta Biochimica Polonica

2007

tom 54

nr 3

In circulation, platelets may come into contact with both exogenous (cardiac glycoside treatment) and endogenously produced inhibitors of Na+/K+-ATPase. We examined whether blocking of platelet Na+/K+-ATPase by ouabain results in generation of procoagulant activity. It was shown that an in vitro treatment of platelets with ouabain (20-200 µM for 20 to 60 min) is associated with an intracellular accumulation of sodium ([Na+]i), generation of a weak calcium signal, and expression of procoagulant activity. The ouabain-induced procoagulant response was dose- and time-related, less pronounced than that evoked by collagen and similar to that produced by gramicidin, not affected by EDTA or aspirin, and strongly reduced in the absence of extracellular Na+ or by hyperosmolality. Flow cytometry studies revealed that ouabain treatment results in a unimodal left shift in the forward and side scatter of the entire platelet population indicating morphological changes of the plasma membrane. The shift was dose related, weaker than that evoked by collagen and similar to that produced by gramicidin. Ouabain-treated platelets express phosphatidylserine (PS). The ouabain-evoked PS expression was dose- and time-dependent, weaker than that produced by collagen and similar to that evoked by gramicidin. Electronic cell sizing measurements showed a dose-dependent increase in mean platelet volume upon treatment with ouabain. Hypoosmotically-evoked platelet swelling resulted in the appearance of procoagulant activity. Thromboelastography measurements indicate that, in whole blood, nanomolar (50-1000 nM, 15 min) concentrations of ouabain significantly accelerate the rate of clot formation initiated by contact and high extracellular concentration of calcium. We conclude that inefficiently operating platelet Na+/K+-ATPase results in a rise in [Na+]i. An increase in [Na+]i and the swelling associated with it may produce PS exposure and a rise in membrane curvature leading to the generation of a procoagulant activity.

Sphingosine 1-phosphate is a blood constituent released from activated platelets, possibly playing a variety of physiological and pathophysiological roles

80%

Igarashi Y., Yatomi Y.

Acta Biochimica Polonica

1998

tom 45

nr 2

We have found that sphingosine 1-phosphate (Sph-1-P) acts as an autocrine stimulator of platelets, being abundantly stored in platelets and released extracellularly, and that its exogenous addition induces platelet activation (Yatomi et al., Blood 1995, 86, 193-202) through a specific receptor on the platelet surface (Yatomi et al., J. Biol. Chem. 1997, 272, 5291-5297). Very recently, we identified Sph-1-P as a normal constituent of human plasma and serum. Sph-1-P levels in plasma and serum were 191±79 and 484±82 pmol/ml (mean ±S.D., n = 8), respectively. Platelets are most likely the source of Sph-1-P discharged during blood clotting, since they abundantly store Sph-1-P as compared with other blood cells, and release considerable amounts of stored Sph-1-P extracellularly upon stimulation. The Sph-1-P released from activated platelets may be involved in a variety of physiological processes, including thrombosis, atherosclerosis, and wound healing. Moreover, we often observed that Sph-1-P injection into mice (iv., 10 mg/kg) caused immediate rigor and death. This may be related to the recent observations from an other laboratory that nanomolar concentrations of Sph-1-P affected atrial myocyte K+ channel. These observations taken together strongly suggest pathophysiological roles of the released Sph-1-P in the blood. As one example, we found that Sph-1-P content in the plasma of platelet concentrates correlated with poor platelet increments after transfusion and with the occurence of transfusion reactions in patients.

Ograniczanie wyników

2 Acta Biochimica Polonica

1 Journal of Physiology and Pharmacology

1 Bauersachs J.

1 Ciborowski M.

1 Ertl G.

1 Flierl U.

1 Fraccarollo D.

1 Hildemann S. K.

1 Igarashi Y.

1 Radziwon P.

1 Rusak T.

1 Schafer A.

1 Stelmach H.

1 Tomasiak M.

1 Vogt C.

1 Widder J.

1 Yatomi Y.

1 2010

1 2007

1 1998

Wyniki wyszukiwania

Eplerenone improves vascular function and reduces platelet activation in diabetic rats

The involvement of Naplus-Kplus-ATPase in the development of platelet procoagulant response

Sphingosine 1-phosphate is a blood constituent released from activated platelets, possibly playing a variety of physiological and pathophysiological roles