Acute intravenous tempol reduces mean arterial pressure (MAP) and heart rate (HR) in spontaneously hypertensive rats (SHR). We investigated the hypothesis that the antihypertensive action depends on generation of hydrogen peroxide, activation of heme oxygenase, glutathione peroxidase or potassium conductances, nitric oxide synthase (NOS), and/or the peripheral or central sympathetic nervous systems (SNSs). Tempol caused dose-dependent reductions in MAP and HR (at 174 µmol · kg ^-1 , MAP -57 ± 3 mmHg and HR -50 ± 4 min^-1). The antihypertensive response was unaffected by infusion of pegylated catalase or by inhibition of catalase with 3-aminotriazole, inhibition of glutathione peroxidase with buthionine sulfoximine, inhibition of heme oxygenase with tin mesoporphyrin, or inhibition of large-conductance Ca²⁺ -activated potassium channels with iberiotoxin. However, the antihypertensive response was significantly (p < 0.01) blunted by 48% by activation of adenosine triphosphate (ATP)-sensitive potassium channels (K_ATP) with cromakalim during maintenance of BP with norepinephrine and by 31% by blockade of these channels with glibenclamide, by 40% by blockade of NOS with L-nitroarginine methyl ester, and by 40% by blockade of preganglionic neurotransmission with hexamethonium. L-NAME and hexamethonium were additive, but glibenclamide and hexamethonium were less than additive. Central administration of tempol was ineffective. The acute antihypertensive action of tempol depends on the independent effects of potentiation of nitric oxide and inhibition of the peripheral sympathetic nervous system that involves the activation of K_ATP channels.