Activation of soluble guanylyl cyclase by a factor other than nitric oxide or carbon monoxide contributes to the vascular hyporeactivity to vasoconstrictor agents in the aorta of rats treated with endotoxin.
We have examined the role of soluble guanylyl cyclase and possible mediators of its activation in the vascular hyporeactivity caused by bacterial endotoxin (lipopolysaccharide, LPS) ex vivo. Treatment of rats with E. coli LPS (10 mg/kg, i.v. for 3h) resulted in a significant reduction in the contractions elicited by norepinephrine (NE; 10(-9)-10(-6) M) in endothelium-denuded aortic rings ex vivo. Methylene blue or LY-83583, inhibitors of soluble guanylyl cyclase, completely restored contractions to NE, whereas the nitric oxide synthase (NOS) inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME), caused only a partial restoration. Zinc protoporphyrin-IX, an inhibitor of heme oxygenase, did not enhance NE-induced contraction in rings from LPS-treated rats, indicating that the production of carbon monoxide (CO) does not contribute to this vascular hyporeactivity. Indomethacin, an inhibitor of cyclooxygenase, further suppressed the contractions in rings from LPS-treated rats. These results suggest that hyporesponsiveness to NE caused by LPS is due to the activation of soluble guanylyl cyclase, which is partially mediated by N(O), but not by CO. Moreover, LPS may induce the production of another mediator(s) that activate soluble guanylyl cyclase in the vascular smooth muscle.
Wu
C C
CC
William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London, United Kingdom.
Szabó
C
C
Chen
S J
SJ
Thiemermann
C
C
Vane
J R
JR
D000818:Animals; D001011:Aorta; D002248:Carbon Monoxide / Q000494:pharmacology*; D004731:Endotoxins / Q000633:toxicity*; D004789:Enzyme Activation; D006162:Guanylate Cyclase / Q000378:metabolism*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000503:physiopathology*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D004731:Endotoxins; D008070:Lipopolysaccharides; D014662:Vasoconstrictor Agents; D009569:Nitric Oxide; D002248:Carbon Monoxide; D006162:Guanylate Cyclase; D009638:Norepinephrine; D007213:Indomethacin