Tempol (T) is an amphipathic radical nitroxide (N) that acutely reduces blood pressure (BP) and heart rate (HR) in the SHR. We investigated the hypothesis that the response to nitroxides is determined by superoxide dismutase (SOD) mimetic activity or lipophilicity. Methods: Groups (n=6-10) of anesthetized SHR received graded iv doses of N's: tempol (T), 4-amino-tempo (AT), 4-oxo-tempo (OT), 4-trimethylammonium-2,2,6,6-tetramethylpiperidine-1-oxyl iodide (CAT-1), 3-carbamoyl-proxyl (3-CP) or 3-carboxy-proxyl (3-CTPY). Others received native or liposomal (L) Cu/Zn SOD. T and OT are uncharged, whereas AT is positively charged and cell permeable whereas CAT-1 is positively charged and cell-impermeable. 3-CP and 3-CTPY have five-member pyrrolidine rings, whereas T, AT, OT, and CAT-1 have six-member piperidine rings. Results: T and AT reduced MAP similarly (-48±2 mmHg and -55±8 mmHg) but more (p<0.05) than OT and CAT-1. 3-CP and 3-CTPY were ineffective. The group mean change in MAP with piperidine N's correlated with SOD activity (r=-0.94) whereas their ED₅₀ correlated with lipophilicity (r=0.89). SOD and L-SOD did not lower BP acutely, but reduced it after 90 mins (-32±5 and -31±6 mmHg; p<0.05 vs. vehicle). Conclusions: Pyrrolidine nitroxides are ineffective antihypertensive agents. The antihypertensive response to piperidine N's is predicted by SOD mimetic action and the sensitivity of response by hydrophilicity. SOD exerts a delayed hypotensive action that is not enhanced by liposome encapsulation, suggesting it must diffuse to an extravascular site.