Incubation with endotoxin activates the L-arginine pathway in vascular tissue

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Rat aortic rings incubated with a low dose of endotoxin (100 ng ml −1) for 5 h exhibited depressed reactivity to norepinephrine (NE) which was independent of the presence of endothelium. An inhibitor of nitric oxide synthesis from L-arginine N Gmonomethyl-L-arginine (300 μM), but not the inactive D-enantiomer, restored the contractile response of endotoxin-treated rings to control. The effect of N Gmonomethyl-L-arginine was reversed by L-arginine (1 mM). In the absence of N Gmonomethyl-L-arginine, L-but not D-arginine relaxed endotoxin-treated rings but was without effect on control tissues. This response was reversed following inhibition of guanylate cyclase by methylene blue (3 μM). In addition, tissue cyclic GMP content was 10 times greater in endotoxin-treated compared to control tissue. These data indicate that endotoxin can act directly on vascular tissue to induce a hyporeactivity to NE which is secondary to the activation of the L-arginine pathway and subsequent activation of soluble guanylate cyclase.