EVIDENCE THAT AN L-ARGININE NITRIC-OXIDE DEPENDENT ELEVATION OF TISSUE CYCLIC-GMP CONTENT IS INVOLVED IN DEPRESSION OF VASCULAR REACTIVITY BY ENDOTOXIN

1 The aim of this investigation was to study the relationship between contractile responsiveness, activation of the L-arginine pathway and tissue levels of guanosine 3':5-cyclic monophosphate (cylic GMP) in aortic rings removed from rats 4 h after intraperitoneal administration of bacterial endotoxin (E.coli. lipopolysaccharide, LPS, 20 mg kg-1). 2 LPS-treatment resulted in a reduction of the sensitivity and maximal contractile response to noradrenaline (NA). 3 Depression of the maximal contractile response was restored to control by 6-anilo-5,8-quinolinedione (LY 83583, 10-mu-M), which prevents activation of soluble guanylate cyclase. 4 Cyclic GMP levels in tissue from LPS-treated rats were 2 fold greater than cyclic GMP levels detected in tissue from control (saline-treated) rats. The LPS-induced increase in cyclic GMP content was observed both in the presence and absence of functional endothelium. 5 Addition of L-arginine (1 mM) to maximally contracted aortic rings produced significant relaxation of rings from LPS-treated rats but not rings from control animals. In the LPS-treated group, addition of L-arginine was also associated with a significant increase in cyclic GMP content. L-Arginine had no effect on the cyclic GMP content of control rings. D-Arginine (1 mM) was without effect. 6 In rings from LPS-treated rats, N(G)-nitro-L-arginine methyl ester (L-NAME, 300-mu-M), an inhibitor of nitric oxide (NO) production, increased the contractile response to NA and prevented the LPS-induced increase in cyclic GMP content. In control rings, L-NAME increased the NA sensitivity only when the endothelium remained intact and reduced the cyclic GMP content of these rings to that of control endothelium-denuded rings. 7 These results demonstrate that LPS-induced hyporeactivity to NA occurs secondarily to activation of the L-arginine pathway and subsequent activation of soluble guanylate cyclase in vascular tissue. In addition they suggest that LPS induces the production of an NO-like relaxing factor in non-endothelial cells.