Acute antihypertensive action of Tempol in the spontaneously hypertensive rat.
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 micromol/kg; DeltaMAP, -57+/- 3 mmHg; and DeltaHR, -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(omega)-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.
Chen
Xueguang
X
Division of Nephrology and Hypertension, Georgetown University, 3800 Reservoir Road N.W., Washington, DC 20007, USA.
Patel
Kinjal
K
Connors
Stephanie G
SG
Mendonca
Margarida
M
Welch
William J
WJ
Wilcox
Christopher S
CS
D000640:Amitrole / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002374:Catalase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019806:Cromakalim / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005730:Ganglionic Blockers / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism; D018738:Hexamethonium / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007262:Infusions, Intravenous; D054086:KATP Channels / Q000187:drug effects* / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D013113:Spin Labels; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors
D000959:Antihypertensive Agents; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D005730:Ganglionic Blockers; D054086:KATP Channels; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008665:Metalloporphyrins; D010455:Peptides; D026902:Potassium Channel Blockers; D013113:Spin Labels; D019806:Cromakalim; C055421:tin mesoporphyrin; D009569:Nitric Oxide; D018738:Hexamethonium; D019328:Buthionine Sulfoximine; C064719:iberiotoxin; D002374:Catalase; D005979:Glutathione Peroxidase; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing); D005905:Glyburide; C001803:tempol; D019331:NG-Nitroarginine Methyl Ester; D000640:Amitrole