COLLAGEN CROSSLINKS IN HYPERTENSION OF AGING

We propose to investigate the role of glucose-derived arterial wall collagen crosslinking in the pathogenesis of age-related changes in blood pressure. The specific aims are to: I) Characterize the relationship between accumulated glucose-derived collagen crosslinks and arterial hypertension in normal, spontaneously hypertensive, alloxan-diabetic, and alloxan-diabetic spontaneously hypertensive rats as a function of increasing age; II) Evaluate the effect of aminoguanidine, an inhibitor of glucose-derived collagen crosslinking, on both quantity of accumulated advanced glycosylation products and development of hypertension in these four experimental groups of animals; III) Quantitate both advanced glycosylation product accumulation and collagen crosslinking in human arteries obtained at autopsy from normotensive and hypertensive subjects; IV) Quantitate both advanced glycosylation product accumulation and collagen crosslinking in skin punch biopsy specimens from defined groups of normotensive and hypertensive clinic patients. These studies will involve newly developed spectrofluorometric and radioimmunoassay techniques for measuring specific advanced glycosylation product crosslinks, and three newly adapted methods from collagen structural studies for determining the extent of collagen crosslinking. The availability of aminoguanidine, a recently described inhibitor of glucose-derived collagen crosslink formation, will make it possible to determine for the first time in these studies, the extent to which observed correlations between age-related glucose-derived collagen crosslink accumulation and the development of age-related hypertension are causally related.