Acute antihypertensive action of Tempol in the spontaneously hypertensive rat

• Published in: American journal of physiology. Heart and circulatory physiology 2007-12, Vol.293 (6), p.H3246-H3253
• Main Authors: Chen, Xueguang, Patel, Kinjal, Connors, Stephanie G, Mendonca, Margarida, Welch, William J, Wilcox, Christopher S
• Format: Article
• Language: English
• Subjects: Amitrole - pharmacology; Animals; Antihypertensive Agents - administration & dosage; Antihypertensive Agents - pharmacology; Blood pressure; Blood Pressure - drug effects; Buthionine Sulfoximine - pharmacology; Cardiology; Cardiovascular system; Catalase - antagonists & inhibitors; Catalase - metabolism; Cromakalim - pharmacology; Cyclic N-Oxides - administration & dosage; Cyclic N-Oxides - pharmacology; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Ganglionic Blockers - pharmacology; Glutathione Peroxidase - antagonists & inhibitors; Glutathione Peroxidase - metabolism; Glyburide - pharmacology; Heart rate; Heart Rate - drug effects; Heme Oxygenase (Decyclizing) - antagonists & inhibitors; Heme Oxygenase (Decyclizing) - metabolism; Hexamethonium - pharmacology; Hypertension; Hypertension - drug therapy; Hypertension - metabolism; Hypertension - physiopathology; Infusions, Intravenous; KATP Channels - drug effects; KATP Channels - metabolism; Large-Conductance Calcium-Activated Potassium Channels - antagonists & inhibitors; Large-Conductance Calcium-Activated Potassium Channels - metabolism; Male; Metalloporphyrins - pharmacology; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide - metabolism; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Peptides - pharmacology; Potassium Channel Blockers - pharmacology; Rats; Rats, Inbred SHR; Rodents; Spin Labels; Sympathetic Nervous System - drug effects; Sympathetic Nervous System - metabolism; Sympathetic Nervous System - physiopathology; Time Factors
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00957.2007

Division of Nephrology and Hypertension, Clinical Pharmacology, and Angiogenesis Program, Lombardi Cancer Institute and Cardiovascular Kidney Hypertension Institute, Georgetown University, Washington, District of Columbia Submitted 16 August 2007 ; accepted in final form 9 October 2007 Acute intravenous Tempol reduces mean arterial pressure (MAP) and heart rate (HR) in spontaneously hypertensive rats. 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, and/or the peripheral or central sympathetic nervous systems (SNSs). Tempol caused dose-dependent reductions in MAP and HR (at 174 µmol/kg; MAP, –57± 3 mmHg; and HR, –50 ± 4 beats/min). The antihypertensive response was unaffected by the infusion of a pegylated catalase or by the 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 Ca 2+ -activated potassium channels with iberiotoxin. However, the antihypertensive response was significantly ( P < 0.01) blunted by 48% by the activation of adenosine 5'-triphosphate-sensitive potassium (K ATP ) channels with cromakalim during maintenance of blood pressure with norepinephrine and by 31% by the blockade of these channels with glibenclamide, by 40% by the blockade of nitric oxide synthase with N -nitro- L -arginine methyl ester ( L -NAME), and by 40% by the blockade of ganglionic autonomic neurotransmission with hexamethonium. L -NAME and hexamethonium were additive, but glibenclamide and hexamethonium were less than additive. The 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 SNS that involves the activation of K ATP channels. superoxide dismutase; nitric oxide synthase; sympathetic nervous system; catalase; adenosine 5'-triphosphate-activated potassium channels Address for reprint requests and other correspondence: C. S. Wilcox, Georgetown Univ., Div. of Nephrology and Hypertension, 3800 Reservoir Rd. NW, PHC F6003, Washington, DC 20007 (e-mail: wilcoxch{at}georgetown.edu )