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Cardiovascular-Kidney Interactions in Health and Disease

Acute antihypertensive action of nitroxides in the spontaneously hypertensive rat

¹Division of Nephrology and Hypertension, Georgetown University, Washington, DC; ²Anesthesiology Research Division, University of Alabama, Birmingham, Alabama; and ³Radiation Oncology Branch, Clinical Oncology Program, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Submitted 30 June 2005 ; accepted in final form 13 September 2005

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 ED₅₀ 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.

tempol; superoxide dismutase; blood pressure; nitric oxide; hypertension

This article has been cited by other articles:

				C. S. Wilcox and A. Pearlman Chemistry and Antihypertensive Effects of Tempol and Other Nitroxides Pharmacol. Rev., December 1, 2008; 60(4): 418 - 469. [Abstract] [Full Text] [PDF]

				X. Chen, K. Patel, S. G. Connors, M. Mendonca, W. J. Welch, and C. S. Wilcox Acute antihypertensive action of Tempol in the spontaneously hypertensive rat Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3246 - H3253. [Abstract] [Full Text] [PDF]

				Y. Chen, A. Pearlman, Z. Luo, and C. S. Wilcox Hydrogen peroxide mediates a transient vasorelaxation with tempol during oxidative stress Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2085 - H2092. [Abstract] [Full Text] [PDF]

				C. S. Wilcox Special feature: cardiovascular-kidney interactions in health and disease Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R34 - R36. [Full Text] [PDF]