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0031-6997/08/6004-418-469$7.00
Pharmacol Rev 60:418-469, 2008

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Chemistry and Antihypertensive Effects of Tempol and Other Nitroxides

Christopher S. Wilcox and Adam Pearlman

Division of Nephrology and Hypertension and Hypertension, Kidney and Vascular Disorder Center, Georgetown University, Washington DC

Abstract
I. Introduction
    A. Development of Knowledge Concerning Nitroxides
    B. Biochemistry of Nitroxides
    C. Interaction with Reactive Oxygen Species
    D. Pro-Oxidant Actions
    E. Structure-Activity Relationships
    F. Metabolism and Pharmacokinetics
    G. Modified Nitroxides
II. Mechanistic Basis of the Blood Pressure-Lowering Effect of Tempol
    A. Signaling Studies in Cells and Tissues
        1. Protein Kinase G and cGMP.
        2. Protein Kinase A and cAMP.
        3. Mitogen-Activated Protein Kinases.
        4. Nuclear Factor kappaB.
        5. Rho and Rho Kinase.
        6. Protein Kinase C.
    B. Antihypertensive Action in Animal Models
        1. Overview of Antihypertensive Response to Tempol.
        2. Action in Animal Models of Hypertension.
            a. Spontaneously Hypertensive Rat.
            b. Renovascular Effects.
            c. Angiotensin II-Infused and Angiotensin II-Dependent Hypertension.
            d. Deoxycorticosterone Acetate- or Aldosterone-Salt Hypertension.
            e. Dahl Salt-Sensitive Rat.
            f. Endothelin Models.
            g. Lead- and Zinc-Induced Hypertension.
            h. Nitric-Oxide Synthase Inhibitor Hypertension.
            i. Reduced Renal Mass Models.
            j. Catecholaminergic and Dopaminergic Hypertension.
            k. Hypoxia.
            l. Blood Pressure Programming.
            m. Oxidant Protocols.
            n. Other Hypertensive Models.
        3. Mechanism of Antihypertensive Response to Acute Administration of Tempol.
        4. Mechanism of Antihypertensive Response to Prolonged Tempol.
            a. Studies of Dose, Duration, and Route of Administration.
            b. Relationships to Antioxidant Action.
            c. Interaction with Endogenous Oxidant/Antioxidant Pathways.
            d. Role of Nitric-Oxide Synthase.
    C. Vascular Actions of Tempol
        1. Endothelium-Dependent Relaxant Factor/Nitric Oxide.
        2. Endothelium-Dependent Hyperpolarizing Factor/Hydrogen Peroxide.
        3. Endothelium-Dependent Contracting Factor.
        4. Endothelin-1.
        5. Potassium Channels.
        6. Contractility.
        7. Cyclooxygenase, Vasoconstrictor Prostaglandins, and Thromboxanes.
        8. Comparison with Other Antioxidants.
    D. Sympatholytic Actions
        1. Afferent Actions.
        2. Peripheral Sympathetic Nervous System.
        3. Baroreflex Inhibition.
        4. Central Actions.
    E. Renal Actions
        1. Renal Hemodynamics and Autoregulation.
        2. Afferent Arteriole and Tubuloglomerular Feedback Response.
        3. Glomerulus and Podocyte.
        4. Salt and Fluid Reabsorption and Excretion and Salt Sensitivity.
        5. Renin-Angiotensin-Aldosterone System.
        6. Dopamine Receptor Signaling.
        7. Adenosine.
        8. Renal and Systemic Oxygenation and Hypoxia-Inducible Factor.
III. Toxicity of Tempol
IV. Conclusions Concerning Blood Pressure-Lowering Actions of Tempol
Nitroxides can undergo one- or two-electron reduction reactions to hydroxylamines or oxammonium cations, respectively, which themselves are interconvertible, thereby providing redox metabolic actions. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol) is the most extensively studied nitroxide. It is a cell membrane-permeable amphilite that dismutates superoxide catalytically, facilitates hydrogen peroxide metabolism by catalase-like actions, and limits formation of toxic hydroxyl radicals produced by Fenton reactions. It is broadly effective in detoxifying these reactive oxygen species in cell and animal studies. When administered intravenously to hypertensive rodent models, tempol caused rapid and reversible dose-dependent reductions in blood pressure in 22 of 26 studies. This was accompanied by vasodilation, increased nitric oxide activity, reduced sympathetic nervous system activity at central and peripheral sites, and enhanced potassium channel conductance in blood vessels and neurons. When administered orally or by infusion over days or weeks to hypertensive rodent models, it reduced blood pressure in 59 of 68 studies. This was accompanied by correction of salt sensitivity and endothelial dysfunction and reduced agonist-evoked oxidative stress and contractility of blood vessels, reduced renal vascular resistance, and increased renal tissue oxygen tension. Thus, tempol is broadly effective in reducing blood pressure, whether given by acute intravenous injection or by prolonged administration, in a wide range of rodent models of hypertension.

Address correspondence to: Dr. Christopher S. Wilcox, Division of Nephrology and Hypertension, Georgetown University Medical Center, 6 PHC, Suite F6003, 3800 Reservoir Rd., NW, Washington DC 20007. E-mail: wilcoxch{at}georgetown.edu






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