Soluble guanylyl cyclase activation with HMR1766 attenuates platelet activation in diabetic rats.
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.


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.


CONCLUSIONS
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.
Schäfer
Andreas
A
Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany. a.schaefer@medizin.uni-wuerzburg.de
Flierl
Ulrike
U
Kobsar
Anna
A
Eigenthaler
Martin
M
Ertl
Georg
G
Bauersachs
Johann
J
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D020536:Enzyme Activators / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000378:metabolism*; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D013449:Sulfonamides / Q000494:pharmacology; D013927:Thrombosis / Q000378:metabolism / Q000517:prevention & control; D062367:ortho-Aminobenzoates / Q000494:pharmacology; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D020536:Enzyme Activators; D008840:Microfilament Proteins; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D062367:ortho-Aminobenzoates; D000098662:Vasodilator-Stimulated Phosphoprotein; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; C515616:5-chloro-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide