Ramipril sensitizes platelets to nitric oxide: implications for therapy in high-risk patients.
OBJECTIVE
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.
Cardiology Unit, The Basil Hetzel Institute, The Queen Elizabeth Hospital, Discipline of Medicine, University of Adelaide, Adelaide, Australia.
Scott R
SR
Willoughby
Sharmalar
S
Rajendran
Wai P
WP
Chan
Nathan
N
Procter
Sue
S
Leslie
Elizabeth A
EA
Liberts
Tamila
T
Heresztyn
Yuliy Y
YY
Chirkov
John D
JD
Horowitz
D000244:Adenosine Diphosphate / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism*; D015331:Cohort Studies; D006152:Cyclic GMP / Q000378:metabolism; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006162:Guanylate Cyclase / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D008875:Middle Aged; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism*; D009599:Nitroprusside / Q000378:metabolism*; D018384:Oxidative Stress; D010974:Platelet Aggregation / Q000187:drug effects; D017257:Ramipril / Q000008:administration & dosage / Q000494:pharmacology*; D019700:Thrombospondin 1 / Q000097:blood
D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; D019700:Thrombospondin 1; D009599:Nitroprusside; D009569:Nitric Oxide; D008315:Malondialdehyde; D000244:Adenosine Diphosphate; C018524:N,N-dimethylarginine; D001120:Arginine; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D017257:Ramipril