Influence of a new stimulator of soluble guanylate cyclase on platelet aggregation and vascular endothelial function in experimental ischemic stroke against the background of arterial hypertension

Abstract

Background. Correction of endothelial dysfunction during arterial hypertension (AH) is an important measure in preventing cerebrovascular stroke. Drugs activating soluble guanylate cyclase (sGC) and 3’,5’-guanosine monophosphate (cGMP) production independently of nitric oxide (NO) were shown to be therapeutically useful in reducing the risk of stroke. The present work aims to study the antiaggregant and endothelium-protective activity of a new sGC stimulator, an indolinone derivative (2-[2-[(5RS)-5-(hydroxymethyl)-3-methyl-1,3-oxazolidine-2- yliden]-2-cyanoethylidene]-1H-indole-3(2H)-one (codename — GRS) in a model of ischemic stroke with AH. Prior studies have shown that GRS compound inhibits platelet aggregation, lowers blood pressure (BP) in spontaneouslyhypertensive SHR rats, prevents vascular occlusion in models of arterial and venous thrombosis. Antiplatelet drug clopidogrel, a P2Y12 receptor inhibitor, included in the standard of care for secondary prevention of ischemic stroke, was used as the reference drug.Objective. To assess the antiaggregant and endothelium-protective activity of a new indolinone derivative GRS, an sGC stimulator, compared to clopidogrel in a model of ischemic stroke concomitant with high arterial BP in spontaneously-hypertensive SHR rats.Design and methods. Focal brain ischemia/reperfusion was modelled in spontaneously-hypertensive SHR rats (n = 78). GRS in 10 mg/kg dose and clopidogrel in 10 mg/kg dose were administered orally once daily 3 days before modelling ischemia/reperfusion and for 5 days afterwards. Platelet aggregation and functioning of vascular endothelium were monitored.Results. Focal brain ischemia/reperfusion in SHR rats resulted in increased platelet aggregation and the development of endothelial dysfunction and disruption of vasodilatory function of endothelium. GRS compound and clopidogrel in repeated administration have prevented an increase in platelet aggregation (p < 0,05), GRS compound also alleviated endothelial dysfunction (p < 0,05).Conclusions. The indolinone derivative GRS, an sGC stimulator, inhibits increased platelet aggregation and prevents endothelial dysfunction in rats after focal brain ischemia/ reperfusion; the endothelium-protective effects of GRS aren’t related to its antiaggregant activity.