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• W2316405747 abstract "The vascular endothelium is no longer regarded as a biologically inert lining of blood vessels, but is now recognized as a biologically highly active tissue which is crucially involved in the regulation of vascular function and structure. An intact endothelium controls vascular tone by the release of the vasorelexant mediators, nitric oxide and prostacyclin, which also exert significant anti-thrombotic properties. In arterial hypertension, the balance between vasorelaxant and vasoconstrictive mediators is severely disturbed, which, at least in part, is due to blood pressure-induced alterations of endothelial cell function. The common clinical observation that the main vascular complications of arterial hypertension are ischaemic rather than haemorrhagic (also known as the ‘thrombotic paradox of hypertension’ or ‘Birmingham paradox') suggests that hypertension promotes a prothrombotic state, characterized by abnormalities of endothelial function, platelet activation and the coagulation system, respectively [1]. In addition to the release of the vasorelaxant and anti-aggregant mediators, prostacyclin and nitric oxide, the anti-platelet function of vascular endothelial cells also relies on the enzymatic degradation of extracellular ADP. Although ADP by itself is only a weak platelet agonist, it is an important enhancer of other aggregation-inducing agents, including collagen or thrombin [2]. On the molecular level, the stimulating effects of ADP on platelets are mediated by two different G-protein coupled receptors, termed P2Y1 and P2Y12 (previously termed P2YADP, P2TAC or P2cyc) [3]. Binding of ADP to the P2Y1 receptor activates Gq and phospholipase C (PLC)-β resulting in mobilization of intracellular Ca2+, whereas binding of ADP to the P2Y12 receptor results in adenylyl cyclase inhibition through activation of an inhibitory G protein (Gi). Activation of both signalling pathways is required for full platelet aggregation [4]. The enzyme which degrades extracellular ADP (and ATP) has been identified as membrane-associated ecto-ADPase (also known as NTPDase-1 or CD39) [5,6]. Importantly, endothelial cells treated with aspirin and deficient in NO synthesis are still capable of inhibiting platelet function [7]. Using recombinant DNA technology, it was demonstrated that a soluble form of ecto-ADPase was able to efficiently inhibit platelet aggregation in vitro, indicating a novel therapeutic approach for the treatment of thrombotic disease [8]. In this issue of the journal, Kishi et al. [9] report that treatment of cultured human umbilical vein endothelial cells (HUVEC) using the angiotensin-converting enzyme (ACE) inhibitor perindopril inhibited platelet aggregation in vitro, induced either by ADP or collagen. This effect was also observed in HUVEC which were pre-incubated with pharmacological inhibitors of cyclo-oxygenase (aspirin) or nitric oxide synthase (l-NNA) and also in HUVEC stimulated with tumour necrosis factor (TNF)-α. Furthermore, the authors demonstrated that perindopril modestly increased protein expression and enzymatic activity of ecto-ADPase under basal conditions and subsequent to TNF-α stimulation. Compared to perindopril, the AT1 antagonist candesartan neither affected platelet aggregation nor ecto-ADPase activity. This is the first report showing that a commonly prescribed cardiovascular drug was able to increase endothelial cell ecto-ADPase activity, providing a possible explanation for the anti-thrombotic properties of ACE inhibitors. The anti-platelet activity of perindopril reported in this study is in agreement with a previous study performed in vivo which reported that administration of the ACE inhibitor quinapril, but not of the AT1 antagonist losartan, resulted in delayed onset of thrombus formation and decreased platelet aggregation in a rat model of chemically-induced aortic thrombosis, which was related to suppression of superoxide formation [10]. The findings of Kishi and coworkers also appear to be supported by the results of a small clinical study showing that blood pressure lowering in older hypertensive patients, using quinapril alone or in combination with nifedipine, attenuated platelet hyperactivity ex vivo [11]. Furthermore, a 4-week treatment of hypertensive males with fosinopril was shown to attenuate ADP-induced, but not collagen-induced platelet aggregation in vitro [12]. The failure of fosinopril to inhibit collagen-induced platelet aggregation ex vivo when administered to patients differs from the corresponding data reported by Kishi et al. [9] and remains to be clarified. Several large clinical studies have demonstrated the beneficial effects of ACE inhibitors with regard to ischaemic cardiovascular events in patients at increased risk. Among the more recently finished large clinical trials investigating the effects of ACE inhibitors, the HOPE study has provided clear evidence that ramipril was capable of significantly reducing (ischaemic) cardiovascular events in high-risk patients, and that this effect was observed in any subgroup analysed in this study [13]. It has to be noted that the effect of ACE inhibitor treatment was manifest in a study population with 75% of patients receiving aspirin or other anti-platelet drugs. Because the beneficial effect of ramipril also was evident in the subgroup of patients who were not hypertensive, the observed decrease in cardiovascular events may be related to effects of ramipril independent of blood pressure reduction. Interpretation of the HOPE study data may permit the conclusion that administration of ACE inhibitors inhibits platelet aggregation by a mechanism working in addition to inhibition of platelet thromboxane synthesis by low-dose aspirin. Augmentation of endothelial ecto-ADPase activity by the ACE inhibitor ramipril, as suggested by Kishi et al. [9], provides one possible explanation. However, this hypothesis is questioned by the result of the PROGRESS study which investigated the effect of administration of the ACE inhibitor perindopril on secondary stroke prevention. Subgroup analysis revealed that only those patients who received perindopril in combination with the diuretic indapamide had a significant benefit, whereas patients receiving perindopril alone showed only marginal risk reduction [14]. Despite marked differences with regard to the study population, it has to be noted that the proportion of patients receiving aspirin or other anti-platelet drugs was similar in both studies. In general, a specific anti-platelet effect of a given anti-hypertensive drug is difficult to dissect from anti-thrombotic effects achieved by blood pressure lowering itself. Despite Kishi et al. [9] providing a plausible mechanistic explanation as to why ACE inhibitors may reduce the thrombotic risk of patients with cardiovacular disease, the clinical significance of the data reported in their study remains hypothetical because the concentration of perindopril used (1 μmol) is likely to be far beyond the plasma concentrations achieved by therapeutic administration of the drug. The plasma concentration of S9780, the active metabolite of perindopril, for half-maximal ACE inhibition was determined to be in the range of 1.5 to 5 ng/ml (approximately 4–12.5 nmol) in normotensive subjects and hypertensive patients, respectively [15,16]. Furthermore, it needs to be clarified whether the effects of perindopril on endothelial ecto-ADPase are a class-specific effect of ACE inhibitors or whether they are specific of perindopril. In addition, the mechanism by which perindopril exerts its effect on ecto-ADPase expression remains to be identified. Because the AT1 antagonist candesartan did not show any inhibitory effect, a bradykinin- dependent mechanism should also be investigated. Finally, experiments using a specific ecto-ADPase antagonist (currently unavailable according to the published literature) are required to precisely assess the contribution of this enzyme to endothelial anti-platelet effects." @default.
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• W2316405747 title "Anti-platelet function of human endothelial cells" @default.
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