Mechanism of the Superoxide Dismutase Mimic MnTnBuOE-2-PyP5+ and its Nanoformulation on Blood Pressure Regulation
Doctor of Philosophy (PhD)
Integrative Physiology & Molecular Medicine
Dr. Matthew C. Zimmerman
It is well-established that reactive oxygen species (ROS), particularly superoxide (O2·-), produced in the vasculature and brain contribute to the pathogenesis of hypertension. We, and others, have previously reported that in vivo scavenging of O2·- via overexpression of superoxide dismutase (SOD) protein or SOD mimics decreases blood pressure in hypertensive animals. While few SOD mimics have transitioned to clinical trials, MnTnBuOE-2-PyP5+ (BuOE), a manganese porphyrin SOD mimic, is currently in clinical trials for normal tissue protection in cancer patients exposed to radiation therapy. Furthermore, our collaborators developed a nanoformulated BuOE (nanoBuOE) in which BuOE is coated with mesoporous silica nanoparticles and a lipid bilayer to allow for slow, sustained in vivo release of the drug. After confirming BuOE’s ability to scavenge O2·- via Electron Paramagnetic Resonance (EPR) spectroscopy, we tested the hypothesis that BuOE, but not nanoBuOE, decreases normotensive and hypertensive blood pressures. In normotensive and angiotensin II (AngII)-induced hypertensive mice, BuOE, but not nanoBuOE, significantly decreased blood pressures, as measured by radiotelemetry. To explore the mechanism(s) by which BuOE decreases blood pressures, renal sympathetic nerve activity (RSNA) was recorded in normotensive and hypertensive rats injected with BuOE or nanoBuOE. Immediately following BuOE, but not nanoBuOE, injection, RSNA significantly decreased, followed by a significant decrease in blood pressure. Additionally, to explore the impact of BuOE and nanoBuOE on vascular reactivity, video myography was performed on isolated femoral arteries from normotensive and hypertensive mice. BuOE induced significant vasodilation that was attenuated by pretreating arteries with the endothelial nitric oxide synthase inhibitor, L-NAME; thus, suggesting that enhanced nitric oxide bioavailability mediates BuOE-induced vasodilation. Doppler imaging of the superior mesenteric artery of normotensive and hypertensive mice demonstrated BuOE-induced vasodilation in vivo, confirming the myography data. Collectively, these data indicate that BuOE, but not nanoBuOE, acutely decreases blood pressure in both normotensive and hypertensive conditions by decreasing sympathetic nerve activity and inducing vasodilation.
Schlichte, Sarah L., "Mechanism of the Superoxide Dismutase Mimic MnTnBuOE-2-PyP5+ and its Nanoformulation on Blood Pressure Regulation" (2021). Theses & Dissertations. 561.
Available for download on Sunday, July 30, 2023