Nitric oxide synthase inhibition reverses arteriolar hyporesponsiveness to catecholamines in septic rats.
Induction of nitric oxide synthase by cytokines has been hypothesized as a mechanism of the hyporesponsiveness to catecholamines that occurs in clinical septic shock. We measured responses of resistance arterioles in rat cremaster muscle to topically suffused norepinephrine in vivo with the use of image-shearing videomicroscopy. Rats made septic by cecal ligation and puncture were compared with controls that underwent sham ligation. The norepinephrine concentration-response curve was shifted to the right in septic rats [50% effective concentration (EC50) 9.1 +/- 5.4 vs. 0.10 +/- 0.02 microM, P < 0.05]. Contractions at doses of 10(-9), 10(-8), and 10(-7) M norepinephrine were 26, 41, and 38%, respectively, of sham controls. Superfusion of the muscle with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine at 100 microM restored the arteriolar responsiveness of the septic rats (EC50 0.14 +/- 0.07 vs. 6.8 +/- 3.1 microM, P < 0.05). This effect was reversed with superfusion of excess (1 mM) L-arginine. These experiments demonstrate impaired vasoconstriction in response to norepinephrine in resistance arterioles of septic rats in vivo. NG-monomethyl-L-arginine reversed this hyporesponsiveness, implying that nitric oxide synthase may mediate the decreased catecholamine responsiveness associated with sepsis.
Hollenberg
S M
SM
Critical Care Medicine Department, National Institute of Child Health and Development, National Institutes of Health, Bethesda, Maryland 20892.
Cunnion
R E
RE
Zimmerberg
J
J
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001160:Arterioles / Q000187:drug effects* / Q000201:enzymology; D007239:Infections / Q000503:physiopathology*; D008297:Male; D009132:Muscles / Q000098:blood supply; D019001:Nitric Oxide Synthase; D009638:Norepinephrine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019323:omega-N-Methylarginine
D019323:omega-N-Methylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D009638:Norepinephrine