Abstract 5141: Guanylyl Cyclase Activation Using HMR1766 Improves Endothelial Function and Reduces Platelet Activation in Congestive Heart Failure
Background: Endothelial dysfunction and platelet activation are part of the cardiovascular phenotype of severe congestive heart failure(CHF). An association between reduced endothelium-dependent NO-bioavailability and platelet activation has been described in experimental CHF. We investigated, whether chronic activation of soluble guanylyl cyclase using HMR1766 increases vascular NO-bioavailability and reduces platelet activation in experimental CHF.
Methods and results: Chronic myocardial infarction was induced in male Wistar rats by coronary ligation. Rats were randomised to placebo or HMR1766 (10mg/kg twice daily). After 10 weeks, haemodynamics were measured and endothelial function was assessed in organ bath studies. Only animals were included in the CHF groups, when left-ventricular infarct size was >45% and left-ventricular end-diastolic pressure was >15 mmHg. Endothelium-dependent, acetylcholine-induced and NO-mediated relaxation of the aorta was significantly attenuated in CHF-Placebo compared to Sham-operated rats (Rmax: Sham 83.9±1.4%, CHF-Placebo 56.9±5.9%, p<0.01) and markedly improved in CHF-HMR1766 (Rmax 75.4±4.6% p<0.01 vs. CHF-Placebo). Basal NO-bioavailability in vivo was determined by the extent of phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in platelets from whole blood fixed in formaldehyde immediately following collection. Platelet in vivo-VASP phosphorylation was attenuated in CHF-Placebo compared to Sham animals (mean fluorescence intensity: Sham 16.4±1.0%, CHF-Placebo 13.4±0.3%, p<0.05), and normalised by HMR1766 treatment (17.1±1.2% p<0.05 vs. CHF-Placebo). Activation of circulating platelets was determined measuring P-selectin surface-expression on platelets by flow-cytometry. P-selectin surface-expression was significantly increased in CHF-Placebo (mean fluorescence intensity: Sham 14.2±0.4%, CHF-Placebo 16.0±0.4%, p<0.05) and reduced following treatment with HMR1766 (14.5±0.3% p<0.05 vs. CHF-Placebo).
Conclusion: Chronic guanylyl cyclase activation using HMR1766 significantly improved endothelial function, enhanced systemic NO-bioavailability and reduced platelet activation in CHF rats.