title: Acute antihypertensive action of nitroxides in the spontaneously hypertensive rat.
abstract: Tempol is an amphipathic radical nitroxide (N) that acutely reduces blood pressure (BP) and heart rate (HR) in the spontaneously hypertensive rat (SHR). We investigated the hypothesis that the response to nitroxides is determined by SOD mimetic activity or lipophilicity. Groups (n = 6-10) of anesthetized SHRs received graded intravenous doses of Ns: 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, AT is positively charged and cell-permeable, and 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. T and AT reduced mean arterial pressure (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 Ns correlated with SOD activity (r = -0.94), whereas their ED(50) correlated with lipophilicity (r = 0.89). SOD and L-SOD did not lower BP acutely but reduced it after 90 min (-32 +/- 5 and -31 +/- 6 mmHg; P < 0.05 vs. vehicle). Pyrrolidine nitroxides are ineffective antihypertensive agents. The antihypertensive response to piperidine Ns is predicted by SOD mimetic action, and the sensitivity of response is by hydrophilicity. SOD exerts a delayed hypotensive action that is not enhanced by liposome encapsulation, suggesting it must diffuse to an extravascular site.
authors.affiliation: Georgetown University, Division of Nephrology and Hypertension, 3800 Reservoir Rd., NW, PHC F6003, Washington, DC 20007, USA. wilcoxch@georgetown.edu
authors.forename: Kinjal
authors.initials: K
authors.lastname: Patel
authors.forename: Yifan
authors.initials: Y
authors.lastname: Chen
authors.forename: Kathryn
authors.initials: K
authors.lastname: Dennehy
authors.forename: Jonathan
authors.initials: J
authors.lastname: Blau
authors.forename: Stephanie
authors.initials: S
authors.lastname: Connors
authors.forename: Margarida
authors.initials: M
authors.lastname: Mendonca
authors.forename: Margaret
authors.initials: M
authors.lastname: Tarpey
authors.forename: Murali
authors.initials: M
authors.lastname: Krishna
authors.forename: James B
authors.initials: JB
authors.lastname: Mitchell
authors.forename: William J
authors.initials: WJ
authors.lastname: Welch
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Wilcox
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000378:metabolism*; D015394:Molecular Structure; D051381:Rats; D011918:Rats, Inbred SHR; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D003497:Cyclic N-Oxides; D013482:Superoxide Dismutase