Potentiation of nitric oxide-mediated vascular relaxation by SC52608, a superoxide dismutase mimic.
Nitric oxide (NO) produced by the vascular endothelium is an endogenous contributor to the regulation of vascular relaxation and the maintenance of blood pressure. The effective half-life of NO and the relaxation of aortic rings by NO is enhanced by a reduction in the concentration of superoxide radicals with superoxide dismutase (SOD). In the current study, SC52608, a newly synthesized SOD mimic with a manganese core, was tested for its ability to potentiate the activity of NO both in vitro and in vivo. SC52608 relaxation of rat aortic segments was endothelium dependent as well as concentration dependent. The maximum relaxation following KCl contraction was 44% with 300 microM SC52608. Cyclic GMP concentrations in the segments were increased 1.6- and 3.2-fold with 5 and 300 microM SC52608, respectively. N-monomethyl-I-arginine pretreatment of aortic rings abolished the relaxation and cyclic GMP accumulation mediated by SC52608. In a smooth muscle cell reporter system of nitric oxide synthase activity, SC52608 potentiated the increase in cyclic GMP elicited by NO in a concentration-dependent manner with a maximum increase of 5.2-fold at 100 microM. Injection of SC52608 into conscious, restrained rats resulted in a dose-dependent decrease of blood pressure. Therefore, the data suggest that SC52608 potentiates the actions of nitric oxide on vascular tone, cyclic GMP, and blood pressure by enhancing the half-life of NO through a mechanism that mimics the action of SOD.
Kasten
T P
TP
Monsanto Corporate Research, St. Louis, Missouri 63167.
Settle
S L
SL
Misko
T P
TP
Riley
D P
DP
Weiss
R H
RH
Currie
M G
MG
Nickols
G A
GA
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001013:Aorta, Thoracic; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002712:Chlorides / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D017895:Manganese Compounds / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D009942:Organometallic Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*; D019323:omega-N-Methylarginine
D000975:Antioxidants; D002712:Chlorides; D017895:Manganese Compounds; D009942:Organometallic Compounds; C089774:SC 52608; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D013482:Superoxide Dismutase; D006152:Cyclic GMP; C025340:manganese chloride; D007213:Indomethacin