The general objectives of this proposed research are to describe the hemodynamic state of peripheral vascular beds in the various stages of experimental hypertension, and to attempt to identify the chemical and/or physical factors responsible for these hemodynamics. Major hypotheses to be tested are: 1) vascular structural changes are of primary importance in elevating resistance even in early stages of hypertension; 2) there are important non-pressure-related influences on cardiovascular wall-thickening in hypertension; 3) these influences include humoral factors and growth factors produced by vascular wall cells; and 4) there are elevated levels of endogenous circulating cardiac glycoside-like factors in hypertension that have primary tropic effects on cardiovascular growth.
Specific aims are: 1) further qualitative assessment of the relative roles of structural and functional vascular changes in the early and chronic stages of volume-expanded hypertension; 2) further quantitative assessment of non-pressure-related changes in morphology and biochemistry of vascular walls in hypertension; 3) exploration for humoral substances involved in cardiovascular growth in hypertension; 4) exploration for growth factors produced by vascular wall tissues or associated cells in hypertension; and 5) investigation of the relationship of polyamine biosynthesis and endogenous Na-K pump inhibitors on cardiovascular growth in hypertension. Methodology to be used to achieve these aims includes: 1) measurement of resistance, norepinephrine dose-response curves and ouabain-induced shifts in these curves in maximally-vasodilated, pump-perfused (blood) hindlimb vascular beds of rats; 2) measurement of changes in water content, dry weight and quanitiative morphometry of cardiovascular tissue; and 3) tissue culture assay of serum and plasma fractions for humoral and/or endothelial cell growth factors. Identification of non-pressure-related factors promoting cardiovascular wall thickening in hypertension would lead to new therapeutic approaches. If vascular wall thickening in hypertension can be prevented or attenuated, it is likely that the hypertension cannot be sustained.
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