VASCULAR EXPRESSION OF INDUCIBLE NITRIC-OXIDE SYNTHASE IS ASSOCIATED WITH ACTIVATION OF CA-DEPENDENT K+ CHANNELS(+)

We tested the hypothesis that expression of inducible nitric oxide syn thase (NO-synthase) in response to endotoxin (lipopolysaccharide) prod uces activation of potassium channels. Contraction of the rat thoracic aorta in response to phenylephrine was measured in vitro after treatm ent in vivo for 15 hr with vehicle (control) or lipopolysaccharide (10 mg/kg i.p.). Impaired contraction in response to phenylephrine was us ed as an index of inducible NO-synthase expression, and activation of potassium channels was examined with specific inhibitors. Contraction in response to 10(-5) M phenylephrine (expressed as a percentage of co ntraction in response to 85 mM KCI) was markedly impaired in lipopolys accharide-treated rats, compared with control (15 +/- 5% vs. 131 +/- 1 0%, P < .05, mean +/- S.E.). Expression of inducible NO-synthase mRNA in the vessel wall in lipopolysaccharide-treated rats was confirmed us ing reverse transcription-polymerase chain reaction, Contraction of th e aorta in lipopolysaccharide-treated rats was restored to normal by 0 .3 mM aminoguanidine (an inhibitor of inducible NO-synthase). Contract ion of the aorta in response to phenylephrine, which was inhibited by lipopolysaccharide, was not affected by glibenclamide (an inhibitor of ATP-sensitive potassium channels) but was increased 2-fold (P < .05) by iberiotoxin (50 nM), an inhibitor of Ca++-dependent potassium chann els. Relaxation of the aorta in response to sodium nitroprusside, an e xogenous donor of nitric oxide, and 8-bromo-cyclic GMP was also inhibi ted by iberiotoxin. These findings suggest that nitric oxide produced by vascular expression of inducible NO-synthase activates calcium-depe ndent potassium channels and that this mechanism may contribute to imp aired vasoconstrictor responses during sepsis.