744-6 Impaired Arteriolar Responsiveness to Endothelin-1 in Septic Rats is Reversed by NG-Methyl-L-Arginine

Abstract

Persistent vasodilation refractory to pressor agents is a characteristic hemodynamic abnormality in septic shock. Induction of nitric oxide synthase (NOS) by cytokines has been hypothesized to playa role in this refractory vasodilation. To investigate this pathogenetic mechanism, we used in vivo videomicroscopy to measure responses of resistance arterioles (15–20 μ m) to topical suffusion of the endogenous vasoconstrictor, endothelin-l (ET). Rats made septic by cecal ligation and puncture were compared to controls that underwent sham ligation. Responses to topically suffused ET were assessed in rat cremaster muscle of septic and control rats before and after superfusion of the muscle with the NOS inhibitor N G– methyl-L-arginine (NMA). Arteriolar Vasoconstriction (% maximal contraction) Group ET 1 nM ET 10 nM ET 100 nM Sham 12.0 ± 3.7 28.9 ± 9.5 89.6 ± 7.2 Septic 3.2 ± 1.7 * 8.3 ± 2.7 * 40.9 ± 8.8 * Sham + NMA 10.6 ± 2.8 28.5 ± 3.3 912 ± 5.8 Septic + NMA 9.7 ± 1.9 31.2 ± 4.5 78.3 ± 7.2 Septic + NMA + L-arginine 1.8 ± 1.2 * 6.1 ± 2.5 * 32.4 ± 11.2 * * p < 0.05 compared to Sham and Septic + NMA groups. n = 8 rats/group Vascoconstriction in response to ET in resistance arterioles in vivo was decreased in septic rats compared to sham controls. Taken together with similar results using norepinephrine in this model, these findings suggest a generalized abnormality in vasoconstrictor responsiveness of resistance arterioles in sepsis. Vascular responsiveness to ET in septic rats was restored by NOS inhibition, and the effect was reversed with superfusion of excess (1 mM) L-arginine. These studies suggest that nitric oxide may represent the common mechanism of the refractory vasodilation seen in patients with septic shock.