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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2813.)
© 2006 American Heart Association, Inc.

Thrombosis

Soluble Guanylyl Cyclase Activation With HMR1766 Attenuates Platelet Activation in Diabetic Rats

Andreas Schäfer; Ulrike Flierl; Anna Kobsar; Martin Eigenthaler; Georg Ertl; Johann Bauersachs

From the Medizinische Klinik und Poliklinik I (A.S., U.F., G.E., J.B.), Universitätsklinikum Würzburg, Julius-Maximilians-Universität Würzburg, and the Institut für Klinische Biochemie und Pathobiochemie (A.K., M.E.), Julius-Maximilians-Universität Würzburg, Germany.

Correspondence to Andreas Schäfer, MD, Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany. E-mail a.schaefer{at}medizin.uni-wuerzburg.de

Objective— Platelet activation significantly contributes to cardiovascular morbidity and mortality in diabetes. An association between impaired NO-mediated platelet inhibition and platelet activation has recently been demonstrated in experimental diabetes. Guanylyl cyclase activation enhances the reduced signaling via the NO/cGMP pathway. We investigated whether chronic guanylyl cyclase activation would beneficially modulate platelet activation in experimental diabetes mellitus.

Methods and Results— Diabetes was induced by streptozotocin-injection in male Wistar rats. After 2 weeks, treatment with either placebo or the guanylyl cyclase activator HMR1766 (10 mg/kg twice daily by gavage) was initiated. Two weeks later, in vivo platelet activation and in vitro platelet reactivity were assessed. Chronic treatment with HMR1766 enhanced NO/cGMP-mediated signaling in platelets from diabetic rats determined by in vivo phosphorylation of platelet vasodilator-stimulated phosphoprotein (VASP) at Ser¹⁵⁷ and Ser²³⁹. In parallel, platelet-binding of fibrinogen, surface-expression of P-selectin, appearance of platelet-derived microparticles, and platelet-aggregates with other blood cells were significantly reduced by chronic treatment with HMR1766.

Conclusion— Chronic activation of soluble guanylyl cyclase in diabetic rats improved markers of platelet activation and is a rationale approach for prevention of adverse cardiovascular events in diabetes.

Diabetes is associated with progressive platelet activation in vivo and thromboembolic complications. Chronic treatment with the direct guanylyl cyclase activator HMR1766 in rats with diabetes improved NO/cGMP signaling and reduced platelet activation in vivo and in vitro.

Key Words: guanylyl cyclase • platelet activation • diabetes

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