NITRIC-OXIDE SYNTHASE INHIBITION REVERSES ARTERIOLAR HYPORESPONSIVENESS TO ENDOTHELIN-1 IN SEPTIC RATS

Persistent vasodilation refractory to vasopressor agents is the hemody namic 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 evalu ate the mechanism of vasodilation in sepsis, we used in vivo videomicr oscopy to measure responses of resistance arterioles (15-20 mu m) to t opical suffusion of the potent vasoconstrictor, endothelin-1 (ET-1), i n rat cremaster muscle. Rats made septic by cecal ligation and punctur e were compared with controls that underwent sham ligation. Responses to topically suffused ET-1 were assessed in septic and control rats be fore and after superfusion of the muscle with the NOS inhibitor N-G-mo nomethyl-L-arginine (L-NMMA). Sepsis produced a decrease in ET-1-induc ed vasoconstriction; the ET-1 concentration-response curve was shifted to the right in septic rats (P < 0.05). Contractions at ET-1 concentr ations of 1, 10, and 100 nM were 20, 28, and 32%, respectively, of sha m controls. Superfusion of the muscle with L-NMMA restored arteriolar responsiveness to ET-1 in the septic rats, significantly increasing ar teriolar constriction at 1 and 10 nM. This effect was reversed with su perfusion of excess L-arginine (1 mM). This study demonstrates that im paired vasoconstriction in response to ET-1 in resistance arterioles o f septic rats in vivo is reversed by NOS inhibition. Taken together wi th previous studies showing sepsis-induced impairment of vasoconstrict ion with norepinephrine, a vasopressor with a mechanism of action diff erent from ET-1, these findings suggest a generalized abnormality in t he responsiveness of resistance arterioles in sepsis. Reversal of hypo responsiveness to both of these vasopressor agents by NOS inhibition s uggests an important role for nitric oxide as a mediator of refractory vasodilation in sepsis.