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

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.