PROJECT SUMMARY/ABSTRACT The objective of this project is to identify the mechanisms by which the antioxidant MnTnBuOE-2-PyP5+ (BuOE) and its nanoformulation, nanoBuOE, decrease blood pressure. BuOE, a manganese porphyrin currently in clinical trials as a radioprotector in cancer patients, has properties similar to that of mammalian superoxide dismutase; that is, it scavenges superoxide (O2•-). The pathogenesis of hypertension, a major risk factor for several cardiovascular disorders such as heart failure and stroke, has been linked to elevated O2•-, as this reactive oxygen species (ROS) is known to activate the sympathetic nervous system and induce vasoconstriction, both of which drive hypertension. Preliminary studies reveal that native BuOE rapidly and acutely decreases blood pressure in mice to severe hypotensive levels, and that this hypotensive response is accompanied by a significant reduction in sympathetic output. The dramatic drop in blood pressure induced by BuOE has also been observed in cancer patients enrolled in the BuOE clinical trials. Interestingly, additional preliminary data suggest that nanoBuOE, which is formulated to slowly release the drug, does not acutely impact blood pressure in mice. This project is designed to test the hypotheses that: 1) native BuOE immediately and acutely decreases blood pressure by scavenging O2•- in brain nuclei known to regulate sympathetic nerve activity; and 2) the slow- releasing nanoBuOE accumulates in the vasculature over time to decrease O2•- and increase nitric oxide (NO•) resulting in vasodilation and a gradual/chronic decrease in blood pressure. Changes in blood pressure, sympathetic nerve activity, and vascular tone will be measured in hypertensive rats treated with native BuOE, nanoBuOE, or vehicle. Further, the mechanisms by which native BuOE and nanoBuOE decrease blood pressure will be investigated by manipulating levels of NO•, a known sympathoinhibitory molecule in the brain and vasodilator in the vasculature. Completion of these studies will provide mechanistic insight into a potentially new anti-hypertensive therapy for the improved treatment of hypertension. Additionally, this fellowship will support other critical aspects of the applicant’s predoctoral training including the mastering of multiple physiological methods and approaches, presentation of results at national conferences, publication of data, and professional development. Together with the applicant, the Sponsor and Co-Sponsor developed a training plan specifically tailored to the applicant and will provide a mentoring environment in which the applicant can flourish. As such, the research project and training plan will provide the applicant with the necessary training needed to become a critically-thinking, independent academic scientist.