Direct renin inhibition with aliskiren protects against myocardial ischemia/reperfusion injury by activating nitric oxide synthase signaling in spontaneously hypertensive rats.

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. 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 Langendorff 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. Direct renin inhibition protects against myocardial I/R injury through activation of the PI3K-Akt-eNOS pathway.