Guanylyl cyclase activator ataciguat improves vascular function and reduces platelet activation in heart failure.
BACKGROUND
Endothelial dysfunction and platelet activation due to impaired endogenous platelet inhibition by nitric oxide (NO) are part of the cardiovascular phenotype in congestive heart failure (CHF). We investigated whether chronic activation of the NO target enzyme soluble guanylyl cyclase (sGC) would beneficially modulate vascular function and platelet activation in experimental CHF.


METHODS
Chronic myocardial infarction was induced by coronary ligation in male Wistar rats. Animals were either treated with placebo or the sGC activator ataciguat (10 mg/kg/twice daily by gavage). After 10 weeks, hemodynamic assessment was performed and only animals with impaired left-ventricular end-diastolic pressures of more than 15 mmHg were included in the analysis. Vasomotor function was determined in organ bath studies. NO bioavailability was assessed by in vivo platelet vasodilator-stimulated phosphoprotein (VASP) phosphorylation. P-selectin was determined as a marker of platelet degranulation.


RESULTS
Endothelium-dependent, NO-mediated vasorelaxation as well as vascular sensitivity to exogenous NO were significantly impaired in aortic rings from CHF rats and normalised by ataciguat. In parallel, in vivo VASP phosphorylation reflecting NO bioavailability was significantly attenuated in platelets from CHF rats and normalised by ataciguat. Platelet activation, which was increased in CHF, was reduced by treatment with ataciguat.


CONCLUSIONS
Chronic sGC activation improved vasomotor function and reduced platelet activation in CHF rats.
Schäfer
Andreas
A
Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg, Bayerische Julius-Maximilians-Universität Würzburg, Germany. a.schaefer@medizin.uni-wuerzburg.de
Fraccarollo
Daniela
D
Werner
Lennart
L
Bauersachs
Johann
J
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000032:analysis; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006162:Guanylate Cyclase / Q000378:metabolism; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins / Q000032:analysis; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010750:Phosphoproteins / Q000032:analysis; D015539:Platelet Activation / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D050705:Receptors, Guanylate Cyclase-Coupled / Q000819:agonists* / Q000378:metabolism / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase; D013449:Sulfonamides / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology; D062367:ortho-Aminobenzoates / Q000494:pharmacology*; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D014665:Vasodilator Agents; D062367:ortho-Aminobenzoates; D000098662:Vasodilator-Stimulated Phosphoprotein; D013481:Superoxides; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D050705:Receptors, Guanylate Cyclase-Coupled; D000071756:Soluble Guanylyl Cyclase; C515616:5-chloro-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide