Ramipril Sensitizes Platelets to Nitric Oxide: Implications for Therapy in High-Risk Patients

Willoughby, Scott R., Rajendran, Sharmalar, Chan, Wai P., Procter, Nathan, Leslie, Sue, Liberts, Elizabeth A., Heresztyn, Tamila, Chirkov, Yuliy Y. and Horowitz, John D. (2012) Ramipril Sensitizes Platelets to Nitric Oxide: Implications for Therapy in High-Risk Patients. Journal of the American College of Cardiology, 60 (10). pp. 887-894. ISSN 0735-1097

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Abstract

Objectives: Using 2 sequential studies in HOPE (Heart Outcomes Prevention Evaluation) study–type 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. Background: 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. Methods: 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. Results: 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. Conclusions: Ramipril ameliorates platelet NO resistance in HOPE study–type 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.

Item Type: Article
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: LivePure Connector
Date Deposited: 19 Nov 2018 12:30
Last Modified: 22 Apr 2020 07:14
URI: https://ueaeprints.uea.ac.uk/id/eprint/68941
DOI: 10.1016/j.jacc.2012.01.066

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