This is an second amended new application R01 to examine the role of polyamines in the pathogenesis of hypertension. It is based on the observation by Soltis that difluoromethylornithine (DFMO) prevents the development of hypertension in the DOCA-salt model. The investigator provides preliminary data showing that DFMO likewise prevents the elevation of arterial pressure in the RRM model. The investigator provides additional preliminary data showing a variety of abnormalities in vascular structure and function in the RRM model and evidence showing that some of these abnormalities can be prevented by application of DFMO. The proposal is to examine various structural and functional aspects of blood vessels in the RRM model and to determine whether polyamines play a role in the development of these changes, and finally to establish whether or not these changes participate in the causation of hypertension or whether they are secondary to hypertension.
The specific aims are: 1) To determine whether elevated polyamines contribute to changes in vascular reactivity and in the passive mechanical characteristics of isolated resistance arteries; 2) To determine whether structural changes in resistance articles or microvascular rarefaction are mediated by polyamine level of biosynthesis; and 3) To evaluate the role of altered polyamine biosynthesis vs. elevated blood pressure in contributing to structural and functional alterations in the vasculature in the RRM model.
