EFFECTS OF ENDOTOXIN IN-VIVO ON ENDOTHELIAL AND SMOOTH-MUSCLE FUNCTION IN RABBIT AND RAT AORTA

In order to determine whether endotoxemia induced generalized defects in vascular contraction and endothelium-dependent relaxation, we studied the effect of in vivo endotoxin administration in Sprague-Dawley rats and New Zealand White rabbits on endothelial and arterial smooth-muscle responses of isolated thoracic aorta in vitro. Endotoxin treatment significantly decreased contractile responses to phenylephrine (PE), angiotensin II (All), serotonin (5-HT), and potassium chloride. This effect was not altered by indomethacin or endothelial denudation. Treatment of vessels with N-G-nitro-L-arginine (NNLA), an inhibitor of arginine-dependent nitric oxide biosynthesis, or with methylene blue, an inhibitor of soluble guanylate cyclase, resulted in significant improvement of the contractile defect in endotoxin treated vessels. The restorative effect of NNLA on contractile responses in endotoxin-treated aortic rings was similar in the presence or absence of an intact endothelium. Endothelium dependent relaxation in response to acetylcholine, substance P, or the calcium ionophore A23187 was markedly impaired in vessels from endotoxin-treated rabbits, while endothelium-independent relaxation in response to nitroprusside was similar in both groups. These results suggest that endotoxemia both induces basal, nonendothelial nitric oxide synthesis and impairs the agonist-stimulated release of endothelium-derived relaxing factor (EDRF). These findings may have mechanistic importance in the hemodynamic derangements of endotoxemia.