The hypothesis to be tested is that cardiac hypertrophy is promoted by humoral factors which are present in hypertension but are independent of blood pressure. There is evidence in the literature to suggest that angiotensin II (AII) plays a permissive role in the development of cardiac hypertrophy. Using the two-kidney-one-clip Goldblatt model (2K1C) of hypertension, preliminary studies showed that isolated myocyte size in the right and left ventricles and total heart weight increased in animals treated with hydralazine, a drug which has been associated with high AII levels. The proposed experiments examine in vivo the role of AII in the enlargement of myocytes.
Specific aims are to correlate AII levels with cardiac hypertrophy using a model which dissociates cardiac hypertrophy from hypertension (such as hydralazine-treated hypertensive rats), to prevent cardiac hypertrophy with captopril treatment of 2K1C and hydralazine-treated-2K1C hypertension, to produce cardiac hypertrophy with the infusion of low doses of AII, and to directly stimulate the growth of cultured myocytes with AII and with plasma from hypertensive animals. Dietary sodium has been shown to affect the concentration of AII and the atrial granules which contain a natriuretic hormone. The relationship of these variables to cardiac hypertrophy has not been established, so ultrastructural morphology of the atrium will be examined as an adjunct to the major studies on regional myocyte size. In vitro assays will involve established methods in the measurement of AII levels, and cultured myocytes will be used to evaluate the effects of AII and plasma from hypertensive animals upon DNA and protein synthesis in myocytes from several regions of the heart. Specific receptor mechanisms in cardiac hypertrophy will be the subject of long-term future studies, with special emphasis on AII receptors. If AII levels do not correlate with cardiac hypertrophy, then an alternative would be to study the effect of norepinephrine upon cardiac hypertrophy. Despite considerable literature on beta receptors, the effect of beta blockers on cardiac hypertrophy has been variable. The complex mechanisms which initiate the hypertrophic process have yet to be elucidated.
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| Smith, S H; Kirklin, J K; Geer, J C et al. (1987) Arteritis in cardiac rejection after transplantation. Am J Cardiol 59:1171-3 |
| Smith, S H; Bishop, S P (1986) Selection criteria for drug-treated animals in two-kidney, one clip renal hypertension. Hypertension 8:700-5 |
