NO donor and biological properties of different benzofuroxans.
OBJECTIVE
To investigate the effect of benzofusion on NO donor properties and related biological activities of the furoxan system. The biological properties considered were the ability to increase the cytosolic levels of cGMP in C6 cells and vasodilation.


METHODS
NO donor properties were investigated either in the presence or the absence of cysteine by using the Griess reaction, chemiluminescence, and gas chromatography. Increase of cytosolic cGMP levels were evaluated by radioimmunoassay. Vasodilating activity was assessed on rat aorta strips precontracted with noradrenaline, in the presence and the absence of oxyhemoglobin (HbO2) and methylene blue (MB), respectively.


RESULTS
Benzofuroxan and its methyl and cyano derivatives were unable to release NO under the experimental conditions. Generally these compounds displayed feeble vasodilating properties and were able to weakly stimulate soluble guanylate cyclase (sGC). By contrast, benzodifuroxan and benzotrifuroxan were able to produce both NO* and its reduced form NO- , the nitroxyl anion. They displayed potent vasodilating properties and were able to increase cytosolic levels of cGMP in a concentration-dependent manner.


CONCLUSIONS
The simple benzofuroxans considered here are devoid of the capability to release NO, they weakly stimulate sGC as well as manifest feeble vasodilating properties by a mechanism that does not involve a thiol-induced NO production. By contrast, benzodifuroxan and benzotrifuroxan behave as typical NO donor furoxans.
Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Italy.
C
C
Medana
A
A
Di Stilo
S
S
Visentin
R
R
Fruttero
A
A
Gasco
D
D
Ghigo
A
A
Bosia
D000818:Animals; D001011:Aorta; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006162:Guanylate Cyclase / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014664:Vasodilation / Q000187:drug effects; D010069:Oxadiazoles
D001583:Benzoxazoles; D006152:Cyclic GMP; D006162:Guanylate Cyclase; D009569:Nitric Oxide; D020030:Nitric Oxide Donors; D009638:Norepinephrine; C014354:benzofuroxan; D010069:Oxadiazoles