Evidence that an l‐arginine/nitric oxide dependent elevation of tissue cyclic GMP content is involved in depression of vascular reactivity by endotoxin

Abstract

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 4h after intraperitoneal administration of bacterial endotoxin (E.coli. lipopolysaccharide, LPS, 20mg 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, 10uM), 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, NG-nitro-L-arginine methyl ester (L-NAME, 300PM), 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.

Role of Kupffer Cells in Vasoregulatory Gene Expression During Endotoxemia

“…In intact liver under basal conditions, NO is produced by eNOS in sinusoidal endothelial cells (Shah et al, 1997). LPS is a potent inducer of iNOS in multiple cell types in the liver, most of all in Kupffer cells, but also in hepatocytes and HSC (Fleming et al, 1991). In our experiment, we observed 32-fold increase in iNOS mRNA expression in total liver of endotoxemic rats.…”

Methylene Blue for Distributive Shock: A Potential New Use of an Old Antidote

“…The overproduction of NO by iNOS in sepsis results in increased production of cGMP contributing to the refractory hypotension observed with septic shock. Numerous animal studies demonstrate large increases of NO after exposure to lipopolysaccharide (i.e., endotoxin) with resultant hypotension [62][63][64][65][66][67].…”

Vascular biology in sepsis: pathophysiological and therapeutic significance of vascular dysfunction

“…Finally, iNOS deficient mice have been found to be resistant to vascular hypocontractility (Gunnett et al, 1998). Accordingly, iNOS, which generates large amounts of NO, is likely to be a critical mediator of the diminished vascular contractility in sepsis (Fleming et al, 1991;Griffiths et al, 1995;Hom et al, 1995).…”