on October 5, 2006
Published online before print October 5, 2006, doi: 10.1161/01.ATV.0000249407.92147.12
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Submitted on March 16, 2006
Accepted on September 21, 2006
Soluble Guanylyl Cyclase Activation With HMR1766 Attenuates Platelet Activation in Diabetic Rats
Andreas Schäfer *;
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.
* To whom correspondence should be addressed. 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.
Key words: guanylyl cyclase • platelet activation • diabetes
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