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


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 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.


CONCLUSIONS
Direct renin inhibition protects against myocardial I/R injury through activation of the PI3K-Akt-eNOS pathway.
Key Laboratory of Cardiovascular Disease and Molecular Intervention, State Key Laboratory of Reproductive Medicine, Atherosclerosis Research Centre, Nanjing Medical University, Nanjing, China.
Wen
W
Zhang
Yi
Y
Han
Guoliang
G
Meng
Wenli
W
Bai
Liping
L
Xie
Hui
H
Lu
Yongfeng
Y
Shao
Lei
L
Wei
Shiyang
S
Pan
Suming
S
Zhou
Qi
Q
Chen
Albert
A
Ferro
Yong
Y
Ji
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005650:Fumarates / Q000494:pharmacology*; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013318:Stroke Volume / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects; D000092502:Renin Inhibitors
D000577:Amides; D000959:Antihypertensive Agents; D006152:Cyclic GMP; D005650:Fumarates; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D058539:Phosphatidylinositol 3-Kinase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012083:Renin; D013481:Superoxides; D019715:Tissue Inhibitor of Metalloproteinase-1; D000092502:Renin Inhibitors; C576839:TIMP1 protein, rat; C446481:aliskiren; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; C522363:Mmp2 protein, rat; C572337:Mmp9 protein, rat
aliskiren; ischemia; myocardial infarction; nitric oxide synthase; reperfusion