Although functional and structural changes of the vasculature have a critical role in the pathogenesis of deoxycorticosterone acetate-salt (DOCA-salt) hypertension, the specific intracellular signalling mechanisms by which these changes occur have not been clearly defined. One important transduction pathway involves the polyamines, a family of organic polycations essential for a number of cellular activities including growth, differentiation and stimulus-response coupling. Recent evidence demonstrates that the increase in blood pressure, vascular hyperresponsiveness and arterial medial thickening seen in the DOCA-salt animal are associated with elevations in vascular polyamines and can be blocked by inhibition of polyamine synthesis. The long-term objectives of this project are to delineate the specific mechanisms by which polyamines are elevated in the vasculature of DOCA-salt rats, how polyamines mediate the vascular functional and structural changes in this model and determine if polyamine regulatory pathways may serve as isolated targets for pharmacologic intervention in hypertension in general. The proposed research will test the working hypothesis that enhanced vascular polyamine contents comprise an obligatory link between the initiating stimuli and alterations in vascular structure and function which underlie the initiation, development and maintenance of DOCA-salt hypertension. Integrated studies conducted in intact rats, isolated vascular tissues and cultured arterial smooth muscle cells will address the following specific aims: 1) Provide rigorous confirmation that enhanced vascular polyamine contents are essential to the pathogenesis of DOCA-salt hypertension, 2) Delineate the mechanisms by which the initial hypertensive stimuli (DOCA and salt) increase vascular polyamine contents, and 3) Determine the role of neural and humoral factors in the elevation of vascular polyamine contents. Temporal relationships linking the elevation in blood pressure and altered vascular structure and function at the level of the resistance vessel to alterations in vascular polyamines will be determined. Alterations in the initial step of polyamine biosynthesis (ornithine decarboxylase activity) and transport regulatory mechanisms (uptake and efflux) will be assessed and the influence of neural and humoral factors on these mechanisms investigated in vascular tissues and cultured cells. This research will provide basic information on the mechanisms regulating vascular polyamines and how these processes are altered in hypertension.
