Ramipril sensitizes platelets to nitric oxide: Implications for therapy in high-risk patients

Scott Willoughby, Sharmalar Rajendran, Wai Chan, Nathan Procter, Susan Leslie, Elizabeth Liberts, Tamila Heresztyn, Yuliy Chirkov, John Horowitz

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    39 Citations (Scopus)

    Abstract

    Using 2 sequential studies in HOPE (Heart Outcomes Prevention Evaluation) studytype patients, the aims of this study were: 1) to test the hypothesis that ramipril improves platelet nitric oxide (NO) responsiveness: and 2) to explore biochemical and physiological effects of ramipril in a cohort selected on the basis of platelet NO resistance. Ramipril prevents cardiovascular events, but the bases for these effects remain uncertain. NO resistance at both the platelet and vascular levels is present in a substantial proportion of patients with diabetes or ischemic heart disease and is an independent risk factor for cardiovascular events. Study 1 was a double-blind, randomized comparison of ramipril (10 mg) with placebo in a cohort of patients (n = 119) with ischemic heart disease or diabetes plus additional coronary risk factor(s), in which effects on platelet responsiveness to NO were compared. Study 2 was a subsequent short-term evaluation of the effects of ramipril in a cohort of subjects (n = 19) with impaired platelet NO responsiveness in whom additional mechanistic data were sought. In study 1, ramipril therapy increased platelet responsiveness to NO relative to the extent of aggregation (p < 0.001), but this effect occurred primarily in patients with severely impaired baseline NO responsiveness (n = 41). In study 2, ramipril also improved platelet NO responsiveness (p < 0.01), and this improvement was correlated directly with increased NO-stimulated platelet generation of cyclic guanosine monophosphate (p < 0.02) but not with changes in plasma thrombospondin-1 levels. Ramipril ameliorates platelet NO resistance in HOPE studytype patients, with associated increases in soluble guanylate cyclase responsiveness to NO. This effect is likely to contribute to treatment benefit and define patients in whom ramipril therapy is particularly effective.

    Original languageEnglish
    Pages (from-to)887-894
    Number of pages8
    JournalJournal of The American College of Cardiology
    Volume60
    Issue number10
    DOIs
    Publication statusPublished - 4 Sep 2012

    Keywords

    • asymmetric dimethylarginine (ADMA)
    • cGMP
    • nitric oxide resistance
    • platelet aggregation
    • ramipril

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