Clinically‐Tested SOD Mimic, MnTnBuOE‐2‐PyP5+, Acutely Decreases Blood Pressure via Sympathoinhibition and Vasodilation

Abstract

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, and thus, provides hope for the use of SOD mimics in the clinical setting. Considering the extensive evidence indicating that scavenging of O2•− decreases hypertensive blood pressures, we tested the hypothesis that the SOD mimic, BuOE, decreases blood pressure in normotensive and angiotensin II (AngII)‐induced hypertensive mice. First, using electron paramagnetic resonance (EPR) spectroscopy and hypoxanthine (HX) + xanthine oxidase (XO) to generate O2•− in a cell‐free system, we confirmed the ability of BuOE to scavenge O2•−. Superoxide produced by HX + XO yielded an EPR spectrum amplitude of 5.6×106 ± 1.3×105 EPR arbitrary units (au), which was significantly (p < 0.05) attenuated by 50 nM BuOE (3.3×106 ± 4.2×104 au). In normotensive and AngII‐induced hypertensive mice, BuOE (1 mg/kg, IP), significantly (p<0.05) decreased mean arterial pressure (MAP), as measured by radiotelemetry, within 25 minutes post‐injection (normotensive ⊗ MAP: vehicle −3.3 ± 2.8; BuOE −27 ± 5.4 mmHg; hypertensive ⊗ MAP: vehicle 3.1 ± 7.2; BuOE −60 ± 14 mmHg). To explore the mechanism(s) by which BuOE decreases MAP, renal sympathetic nerve activity (RSNA) was recorded in normotensive rats injected with BuOE (0.1 mg/kg, IV). Immediately following BuOE injection, RSNA significantly (p < 0.01) decreased by 35 ± 7.0% of baseline, followed by a significant (p < 0.01) decrease in MAP (46 ± 13 mmHg). Additionally, to explore the impact of BuOE on vascular reactivity, video myography was performed on isolated skeletal muscle arterioles from normotensive rats. BuOE (2 μM) induced significant (p < 0.05) vasodilation (31 ± 10%) that was attenuated by pretreating arterioles with the endothelial nitric oxide synthase (eNOS) inhibitor, L‐NAME (1 mM); thus, suggesting that enhanced nitric oxide bioavailability mediates BuOE‐induced vasodilation. Collectively, these data indicate that BuOE, a SOD mimic currently in clinical trials in cancer patients, acutely decreases blood pressure in both normotensive and hypertensive conditions by decreasing sympathetic nerve activity and inducing vasodilation.Support or Funding InformationUniversity of Nebraska Medical Center Graduate Student Assistantship/Fellowship