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

• Published in: British journal of pharmacology Vol. 103; no. 1; pp. 1047 - 1052
• Main Authors: Fleming, Ingrid, Julou‐Schaeffer, Géraldine, Gray, Gillian A., Parratt, James R., Stoclet, Jean‐Claude
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-05-1991; Nature Publishing
• Subjects: Aminoquinolines - pharmacology; Animal poisons toxicology. Antivenoms; Animals; Arginine - analogs & derivatives; Arginine - metabolism; Arginine - pharmacology; Biological and medical sciences; cyclic GMP; Cyclic GMP - metabolism; endotoxin (LPS); Endotoxins - pharmacology; Enzyme Activation - drug effects; Guanylate Cyclase - metabolism; In Vitro Techniques; isolated arteries; Lipopolysaccharides - pharmacology; Male; Medical sciences; Muscle Contraction - drug effects; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; NG‐nitro‐l‐arginine methyl ester (l‐NAME); Nitric oxide; Nitric Oxide - pharmacology; Nitroarginine; Rats; Rats, Inbred Strains; SRS-A - antagonists & inhibitors; Toxicology; Intraperitoneal administration; Escherichia coli; 3',5'-GMP; Smooth muscle; Muscle contraction; Endotoxin; Artery; Arginine; Microbial origin; Animal; Nitrogen monoxide; Lipopolysaccharide; Bacteria; Circulatory system; Mechanism of action; Enterobacteriaceae
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1991.tb12298.x

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 μm), 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, 300 μm) 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.