Aldehyde dehydrogenase, nitric oxide synthase and superoxide in ex vivo nitrate tolerance in rat aorta.
The role of aldehyde dehydrogenase (ALDH) in ex vivo tolerance to transdermal glyceryl trinitrate was explored in rat aorta. ALDH activity, measured by aldehyde-induced NADH formation, was strongly depressed in the tolerant arteries. ALDH inhibitors, chloral hydrate (0.3 mM) and cyanamide (0.1-1 mM) inhibited relaxation to glyceryl trinitrate in non-tolerant and tolerant arteries. The inhibition differed from tolerance in that (a) the glyceryl trinitrate concentration-response curve was sigmoidal cf. biphasic in tolerance, (b) the potentiating effect of nitric oxide synthase (eNOS) inhibition was unchanged cf. increased in tolerance and (c) superoxide inhibited the response cf. no significant effect in tolerant or non-tolerant arteries. Hence, reduced ALDH activity does not account fully for ex vivo tolerance. The discrepancies are consistent with evidence that (a) organic nitrates, unlike chloral and cyanamide, irreversibly inactivate ALDH (hence reduced enzyme saturability can explain the biphasic curve) and (b) eNOS contributes to tolerance by a mechanism independent of glyceryl trinitrate metabolism.
Cardiology Unit, The Queen Elizabeth Hospital Campus, North Western Adelaide Health Service, The University of Adelaide, 28 Woodville Road, Woodville South, South Australia, 5011, Australia.
Ivan S
IS
de la Lande
Jacqueline M
JM
Stepien
Andrew C
AC
Philpott
Patrick A
PA
Hughes
Irene
I
Stafford
John D
JD
Horowitz
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005996:Nitroglycerin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D004791:Enzyme Inhibitors; D013481:Superoxides; D019001:Nitric Oxide Synthase; D000444:Aldehyde Dehydrogenase; D005996:Nitroglycerin