Ramipril retards development of aortic valve stenosis in a rabbit model: Mechanistic considerations

Doan Ngo, Irene Stafford, Aaron Sverdlov, Weier Qi, Ronald Wuttke, Yuan Zhang, Darren Kelly, Helen Weedon, Malcolm Smith, Jennifer Kennedy, John Horowitz

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    Abstract

    Background and Purpose: Aortic valve stenosis (AVS) is associated with significant cardiovascular morbidity and mortality. To date, no therapeutic modality has been shown to be effective in retarding AVS progression. We evaluated the effect of angiotensin-converting enzyme inhibition with ramipril on disease progression in a recently developed rabbit model of AVS. Experimental Approach: The effects of 8 weeks of treatment with either vitamin D 2 at 25 000 IU for 4 days a week alone or in combination with ramipril (0.5 mg•kg -1) on aortic valve structure and function were examined in New Zealand white rabbits. Echocardiographic aortic valve backscatter (AV BS) and aortic valve : outflow tract flow velocity ratio were utilized to quantify changes in valve structure and function. Key Results: Treatment with ramipril significantly reduced AV BS and improved aortic valve : outflow tract flow velocity ratio. The intravalvular content of the pro-oxidant thioredoxin-interacting protein was decreased significantly with ramipril treatment. Endothelial function, as measured by asymmetric dimethylarginine concentrations and vascular responses to ACh, was improved significantly with ramipril treatment. Conclusions and Implications: Ramipril retards the development of AVS, reduces valvular thioredoxin-interacting protein accumulation and limits endothelial dysfunction in this animal model. These findings provide important insights into the mechanisms of AVS development and an impetus for future human studies of AVS retardation using an angiotensin-converting enzyme inhibitor.

    Original languageEnglish
    Pages (from-to)722-732
    Number of pages11
    JournalBritish Journal of Pharmacology
    Volume162
    Issue number3
    DOIs
    Publication statusPublished - 2011

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    Ngo, D., Stafford, I., Sverdlov, A., Qi, W., Wuttke, R., Zhang, Y., Kelly, D., Weedon, H., Smith, M., Kennedy, J., & Horowitz, J. (2011). Ramipril retards development of aortic valve stenosis in a rabbit model: Mechanistic considerations. British Journal of Pharmacology, 162(3), 722-732. https://doi.org/10.1111/j.1476-5381.2010.01084.x