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

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dc.contributor.authorWilloughby, S.
dc.contributor.authorRajendran, S.
dc.contributor.authorChan, W.
dc.contributor.authorProcter, N.
dc.contributor.authorLeslie, S.
dc.contributor.authorLiberts, E.
dc.contributor.authorHeresztyn, T.
dc.contributor.authorChirkov, Y.
dc.contributor.authorHorowitz, J.
dc.date.issued2012
dc.description.abstract<h4>Objectives</h4>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.<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.
dc.description.statementofresponsibilityScott R. Willoughby, Sharmalar Rajendran, Wai P. Chan, Nathan Procter, Sue Leslie, Elizabeth A. Liberts, Tamila Heresztyn, Yuliy Y. Chirkov, John D. Horowitz
dc.identifier.citationJournal of the American College of Cardiology, 2012; 60(10):887-894
dc.identifier.doi10.1016/j.jacc.2012.01.066
dc.identifier.issn0735-1097
dc.identifier.issn2225-3653
dc.identifier.orcidRajendran, S. [0000-0001-7949-8873]
dc.identifier.orcidHorowitz, J. [0000-0001-6883-0703]
dc.identifier.urihttp://hdl.handle.net/2440/73673
dc.language.isoen
dc.publisherElsevier Science Inc
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1012729
dc.rightsCopyright © 2012 American College of Cardiology Foundation
dc.source.urihttps://doi.org/10.1016/j.jacc.2012.01.066
dc.subjectBlood Platelets
dc.subjectHumans
dc.subjectNitroprusside
dc.subjectNitric Oxide
dc.subjectMalondialdehyde
dc.subjectRamipril
dc.subjectGuanylate Cyclase
dc.subjectArginine
dc.subjectThrombospondin 1
dc.subjectCyclic GMP
dc.subjectAdenosine Diphosphate
dc.subjectAngiotensin-Converting Enzyme Inhibitors
dc.subjectDrug Administration Schedule
dc.subjectCohort Studies
dc.subjectDouble-Blind Method
dc.subjectOxidative Stress
dc.subjectPlatelet Aggregation
dc.subjectAged
dc.subjectAged, 80 and over
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectBiomarkers
dc.titleRamipril sensitizes platelets to nitric oxide: Implications for therapy in high-risk patients
dc.typeJournal article
pubs.publication-statusPublished

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