Vascular tolerance to nitroglycerin in ascorbate deficiency.
OBJECTIVE
Nitroglycerin (GTN) acts through release of a nitric oxide (NO)-related activator of soluble guanylate cyclase in vascular smooth muscle. Besides enzymatic GTN bioactivation catalysed by aldehyde dehydrogenase, non-enzymatic reaction of GTN with ascorbate also results in the formation of a bioactive product. Using an established guinea pig model of ascorbate deficiency, we investigated whether endogenous ascorbate contributes to GTN-induced vasodilation.


RESULTS
Guinea pigs were fed either standard or ascorbate-free diet for 2 or 4 weeks prior to measuring the GTN response of aortic rings and isolated hearts. The effects of ascorbate on GTN metabolism were studied with purified mitochondrial aldehyde dehydrogenase (ALDH2) and isolated mitochondria. Ascorbate deprivation led to severe scorbutic symptoms and loss of body weight, but had no (2 weeks) or only slight (4 weeks) effects on aortic relaxations to a direct NO donor. The EC(50) of GTN was increased from 0.058 +/- 0.018 to 0.46 +/- 0.066 and 5.5 +/- 0.9 microM after 2 and 4 weeks of ascorbate-free diet, respectively. Similarly, coronary vasodilation to GTN was severely impaired in ascorbate deficiency. The potency of GTN was reduced to a similar extent by ALDH inhibitors in control and ascorbate-deficient blood vessels. Up to 10 mM ascorbate had no effect on GTN metabolism catalysed by purified ALDH2 or liver mitochondria isolated from ascorbate-deficient guinea pigs.


CONCLUSIONS
Our results indicate that prolonged ascorbate deficiency causes tolerance to GTN without affecting NO/cyclic GMP-mediated vasorelaxation.
Wölkart
Gerald
G
Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Universitätsplatz 2, A-8010 Graz, Austria.
Wenzl
M Verena
MV
Beretta
Matteo
M
Stessel
Heike
H
Schmidt
Kurt
K
Mayer
Bernd
B
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D001205:Ascorbic Acid / Q000494:pharmacology; D001206:Ascorbic Acid Deficiency / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology; D005996:Nitroglycerin / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D012614:Scurvy / Q000503:physiopathology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
D014665:Vasodilator Agents; D000444:Aldehyde Dehydrogenase; D005996:Nitroglycerin; D001205:Ascorbic Acid