Changes in vascular responsiveness to a thromboxane mimetic in endotoxin tolerance

Area of Science:

• Physiology
• Immunology
• Pharmacology

Background:

• Endotoxin tolerance in rats affects macrophage activation and hemodynamic responses.
• Previous studies suggest altered signal transduction pathways in endotoxin tolerance.
• Vascular hyporesponsiveness to thromboxane A2 (TxA2) mimetics is observed in tolerant rats.

Purpose of the Study:

• To investigate the mechanisms underlying vascular hyporesponsiveness to TxA2 mimetics in endotoxin-tolerant rats.
• To test if endotoxin tolerance alters TxA2 receptor function, G protein activity, or second messenger production.
• To determine the role of G protein-coupled signal transduction in altered vascular responsiveness.

Main Methods:

• Rats were rendered endotoxin tolerant using escalating doses of Salmonella enteritidis endotoxin.
• Aortic rings were used to assess contractile responses to the TxA2 agonist U46619.
• Scatchard analysis was performed to evaluate I-BOP binding to TxA2 receptors in aortic membranes.
• GTPase activity and U46619-stimulated phosphoinositide production were measured in aortic membranes.

Main Results:

• Endotoxin-tolerant rats showed significantly reduced contractile responses to U46619 compared to control rats.
• No significant differences were found in TxA2 receptor number (Bmax) or affinity (Kd) between control and tolerant rats.
• GTPase activity was significantly reduced in aortic membranes from tolerant rats, indicating impaired G protein function.
• U46619-stimulated phosphoinositide production was similar in both groups.

Conclusions:

• Vascular hyporesponsiveness to TxA2 mimetics in endotoxin tolerance is associated with decreased vascular G protein function.
• The observed hyporesponsiveness is not due to alterations in TxA2 receptor number or affinity.
• Changes in phosphatidylinositol metabolism do not account for the reduced contractile response in endotoxin-tolerant rats.