Abstract 12584: Combined Treatment With Irbesartan and Amlodipine Potently Prevents Acute Myocardial Infarction in Subtotally Nephrectomized Triple Nitric Oxide Synthases-Deficient Mice

Background: Since there are few experimentally useful models that develop acute myocardial infarction (AMI), research and development of therapeutic strategies for preventing AMI have made little progress. We have recently demonstrated that 2/3 nephrectomized (NX) triple nitric oxide synthases (NOSs)-deficient mice cause sudden death due to AMI as early as 4 months after the surgery, succeeding in the establishment of an experimentally useful AMI model ( JMCC 2014). In this study, we examined the effects of an angiotensin II type 1 receptor blocker, irbesartan (irbe), and a calcium channel antagonist, amlodipine (amlo), in this model. Method and Results: The 2/3NX triple NOSs-/- mice were treated with irbe (50 mg/ml/day in chow); amlo (250 mg/ml in drinking water); a combination of both; or an anti-hypertensive agent, hydralazine (0.25 mg/ml in drinking water) for 6 months (n=20-49). We used the clinical therapeutic dosage. In this model, the mono-treatment with irbe or amlo significantly reduced the incidence of AMI and mortality, while the co-treatment with irbe and amlo more potently suppressed them. The 2/3NX triple NOSs-/- mice exhibited cardiovascular risk factors (hypertension, hypercholesterolemia, and hyperglycemia), higher urinary 8-isoprostane levels (a marker of oxidative stress), and increased circulating bone marrow (BM)-derived vascular smooth muscle cell (VSMC) progenitor cells (a pro-arteriosclerotic factor). The sole treatment with irbe or amlo significantly improved these pro-arteriosclerotic parameters, while the simultaneous treatment with irbe and amlo more powerfully ameliorated them. Although the hydralazine treatment significantly lowered blood pressure to the same extent as the irbe/amlo treatment, it did not significantly affect any other pro-arteriosclerotic parameters, suggesting a minor role of an anti-hypertensive effect. Conclusions: Combined treatment with the clinical dosage of irbesartan and amlodipine potently prevented AMI and improved prognosis in the 2/3NX triple NOSs-/- mice via ameliorating cardiovascular risk factors, oxidative stress, and increased BM-derived VSMC progenitor cells. These results suggest the therapeutic importance of those agents to prevent AMI in humans.