In:
Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 3, No. 1 ( 2014-01-27)
Abstract:
We tested the hypothesis that direct renin inhibition with aliskiren protects against myocardial ischemia/reperfusion (I/R) injury in spontaneously hypertensive rats ( SHR ), and examined the mechanism by which this occurs. Methods and Results Male SHR were treated (orally, 4 weeks) with saline or aliskiren (30 or 60 mg kg −1 day −1 ) and subjected to 30 minutes of left anterior descending coronary artery occlusion followed by 6 or 24 hours of reperfusion. Only the higher dose significantly lowered systolic blood pressure, the lower dose causing a smaller apparent lowering that was nonsignificant. Despite this difference in blood pressure‐lowering effect, both doses increased the ejection fraction and fractional shortening and reduced myocardial infarct size equally. I/R decreased cardiac expression of phosphatidylinositol 3‐kinase (PI3K), phospho‐Akt and phospho‐endothelial nitric oxide synthase (phospho‐ eNOS ), but increased expression of inducible nitric oxide synthase ( iNOS ); these changes were all abrogated by aliskiren. Moreover, aliskiren decreased superoxide anion generation and increased cyclic guanosine‐3′,5′‐monophosphate, an index of bioactive nitric oxide, in myocardium. It also decreased the expression of myocardial matrix metalloproteinase‐2, matrix metalloproteinase‐9, and tissue inhibitor of metalloproteinases‐1 ( TIMP ‐1) following I/R. In a L angendorff heart preparation, the detrimental cardiac effects of I/R were abrogated by aliskiren, and these protective effects were abolished by NOS or PI3K inhibition. In a parallel study, although specific iNOS inhibition reduced plasma malondialdehyde and myocardial superoxide anion generation, it did not affect the deleterious effects of I/R on myocardial structure and function. Conclusions Direct renin inhibition protects against myocardial I/R injury through activation of the PI3K‐Akt‐ eNOS pathway.
Type of Medium:
Online Resource
ISSN:
2047-9980
DOI:
10.1161/JAHA.113.000606
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2014
detail.hit.zdb_id:
2653953-6
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