title: Nitric oxide synthase inhibition reverses arteriolar hyporesponsiveness to endothelin-1 in septic rats.
abstract: Persistent vasodilation refractory to vasopressor agents is the hemodynamic abnormality characteristic of septic shock. Induction of nitric oxide synthase (NOS) by sepsis-induced cytokines has been hypothesized to play a pathogenetic role in this refractory vasodilation. To evaluate the mechanism of vasodilation in sepsis, we used in vivo videomicroscopy to measure responses of resistance arterioles (15-20 microm) to topical suffusion of the potent vasoconstrictor, endothelin-1 (ET-1), in rat cremaster muscle. Rats made septic by cecal ligation and puncture were compared with controls that underwent sham ligation. Responses to topically suffused ET-1 were assessed in septic and control rats before and after superfusion of the muscle with the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA). Sepsis produced a decrease in ET-1-induced vasoconstriction; the ET-1 concentration-response curve was shifted to the right in septic rats (P < 0.05). Contractions at ET-1 concentrations of 1, 10, and 100 nM were 20, 28, and 32%, respectively, of sham controls. Superfusion of the muscle with L-NMMA restored arteriolar responsiveness to ET-1 in the septic rats, significantly increasing arteriolar constriction at 1 and 10 nM. This effect was reversed with superfusion of excess L-arginine (1 mM). This study demonstrates that impaired vasoconstriction in response to ET-1 in resistance arterioles of septic rats in vivo is reversed by NOS inhibition. Taken together with previous studies showing sepsis-induced impairment of vasoconstriction with norepinephrine, a vasopressor with a mechanism of action different from ET-1, these findings suggest a generalized abnormality in the responsiveness of resistance arterioles in sepsis. Reversal of hyporesponsiveness to both of these vasopressor agents by NOS inhibition suggests an important role for nitric oxide as a mediator of refractory vasodilation in sepsis.
authors.affiliation: Section of Cardiology, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Hollenberg
authors.forename: M J
authors.initials: MJ
authors.lastname: Piotrowski
authors.forename: J E
authors.initials: JE
authors.lastname: Parrillo
mesh_terms: D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D002432:Cecum; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology*; D008297:Male; D018715:Microscopy, Video; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D018805:Sepsis / Q000503:physiopathology*; D014661:Vasoconstriction; D014664:Vasodilation; D019323:omega-N-Methylarginine / Q000494:pharmacology*
chemical_list: D019332:Endothelin-1; D019323:omega-N-Methylarginine; D019001:Nitric Oxide Synthase; D009638:Norepinephrine