Differential involvement of guanylate cyclase and potassium channels in nitric oxide-induced hyporesponsiveness to phenylephrine in endotoxemic rats.
This study evaluated the involvement of nitric oxide (NO), guanylate cyclase, and potassium channels in the long-lasting vascular hyporesponsiveness to phenylephrine induced by Escherichia coli lipopolysaccharide (LPS) in vitro and in vivo. Experiments in rat aorta rings with endothelium incubated with LPS (10 microg/mL) for 12 h showed that the hyporesponsiveness depends on guanylate cyclase activity and tetraethylammonium-sensitive, but not voltage- or ATP-dependent, potassium channels. Pressor responses to phenylephrine were reduced by 50% in rats injected 8 and 24 h before with LPS (10 mg/kg, intraperitoneally). Pretreatment with NO synthase inhibitors (iNOS; Nomega-nitro-L-arginine methyl ester [L-NAME], 55 micromol/kg or aminoguanidine, 244 micromol/kg, intraperitoneally) fully prevented LPS-induced hyporesponsiveness. When administered just before phenylephrine, L-NAME (11 micromol/kg, intravenously) reversed the hyporesponsiveness in rats injected 8 h, but not in those injected 24 h before with LPS, whereas 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1 (ODQ, 11 micromol/kg, intravenously) reversed the hyporesponsiveness in animals injected 24 h, but not in those injected 8 h before with LPS. Tetraethylammonium (360 micromol/kg, intravenously) reestablished normal responses to phenylephrine in rats injected 8 and 24 h before with LPS. Again, neither voltage- nor ATP-dependent potassium channels appears to be involved. Western blot showed that iNOS expression peaked at 8 h, decreasing to low levels 24 h after LPS injection. Therefore, NO is important in initiating LPS-induced hyporesponsiveness to vasoconstrictors, but not in maintaining it for long periods. Once NO has exerted its effects and even when iNOS expression is minimal, the long-lasting hyporesponsiveness appears to depend on a complex interplay between guanylate cyclase and potassium channel activation.
da Silva-Santos
José Eduardo
JE
Department of Pharmacology, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
Terluk
Marcia Ribeiro
MR
Assreuy
Jamil
J
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000201:enzymology* / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D019789:Tetraethylammonium / Q000494:pharmacology; D013997:Time Factors
C116907:1H-(1,2,4)oxadiazolo(4,3-a)-quiloxalin-1-one; D008070:Lipopolysaccharides; D010069:Oxadiazoles; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D010656:Phenylephrine; D009569:Nitric Oxide; D019789:Tetraethylammonium; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D019331:NG-Nitroarginine Methyl Ester