The effect of tempol on endothelium-dependent vasodilatation and blood pressure.
High blood pressure is associated with increased oxidative stress and increased amounts of reactive oxygen species in the vascular wall which results in impairment of endothelial function and a proinflammatory state (with accelerated development of atherosclerosis). One consequence of this is a reduced nitric oxide (NO)-mediated vasodilatation which is also a prognostic marker of the severity of cardiovascular disease. Thus, improvement in endothelium-dependent vasodilatation may be an important goal in antihypertensive treatment. The present review focuses on possible mechanisms of action for the nitroxide tempol with reference to NO-dependent endothelial function and blood pressure lowering effects. Tempol is a water-soluble and cell permeable superoxide dismutase mimetic which scavenges free radicals such as superoxide ions and hydroxyl radicals, but other mechanisms (including K channel opening) may also contribute to the effect of this drug. Indeed, tempol can: (i) normalize the NO-dependent vasodilatation induced by acetylcholine in aorta; and (ii) restore the NO-dependent vasodilatation in smaller resistance arteries from hypertensive rats. Furthermore, both short-term and long-term administrations of tempol reduce blood pressure in hypertensive rats and mini-pigs, and the drug may even prevent the development of high blood pressure. The in vivo effect of tempol may, in addition to scavenging superoxide, inhibit the sympathetic nervous system. The toxicity of tempol in rodents seems limited but, apart from external application, there are no reports of administration of the drug to humans. In summary, lowering of the oxidative stress by scavenging of free radicals may offer a new antihypertensive treatment strategy.
Simonsen
Ulf
U
Department of Pharmacology, Faculty of Health Sciences, University Park 240, University of Aarhus, 8000 Aarhus C, Denmark. us@farm.au.dk
Christensen
Frank Holden
FH
Buus
Niels Henrik
NH
D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D018716:Molecular Mimicry; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology; D013113:Spin Labels; D014664:Vasodilation / Q000187:drug effects*
D000959:Antihypertensive Agents; D000975:Antioxidants; D003497:Cyclic N-Oxides; D017382:Reactive Oxygen Species; D013113:Spin Labels; C001803:tempol