Selective inhibition of endothelium-dependent vasodilator capacity by Escherichia coli endotoxemia.

Abstract

Increased release of endothelium-derived relaxing factor/nitric oxide has been proposed as the final common pathway for vasodilator responses to gram-negative lipopolysaccharide (endotoxin). To test this hypothesis, we examined endothelium-dependent and endothelium-independent vasodilator agents in vascular smooth muscle isolated from guinea pigs 16 hours after injection of saline (control group) or induction of Escherichia coli endotoxemia; aortic rings (approximately 1 mm in diameter) were studied with standard isometric tension techniques. Endotoxemia resulted in a significant loss of vasodilator responses to the endothelium-dependent receptor agonists acetylcholine (10(-10)-10(-5) M) and ADP (10(-8)-10(-5) M). In contrast, endotoxemia did not affect vasodilator responses to either the endothelium-dependent receptor agonist substance P (10(-11)-10(-7) M), the endothelium-dependent and receptor-independent agonist A23187 (10(-9)-10(-6) M), or the endothelium-independent agonist nitroprusside (10(-10)-10(-4) M). The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) inhibited the vasodilator response to acetylcholine more in vessels from lipopolysaccharide-injected than control guinea pigs. Unexpectedly, L-NAME converted the endothelium-dependent vasodilator action of ADP to an endothelium-dependent vasoconstrictor response that was blocked individually by the cyclooxygenase inhibitor indomethacin, the thromboxane synthase inhibitor dazoxiben, and the thromboxane A2 receptor antagonist SQ29548. We conclude that in vivo endotoxemia inhibits the constitutive isoform of nitric oxide synthase in endothelial cells by selectively disrupting receptor-coupled activation mechanisms shared by acetylcholine and ADP. Furthermore, since L-NAME unmasks a thromboxane A2-mediated vasoconstrictor action of the endogenous purinoceptor agonist ADP, drugs that inhibit nitric oxide synthase could exacerbate sepsis-induced vasoconstriction and ischemia by synergizing with lipopolysaccharide-induced inhibition of endothelial nitric oxide synthase.

High Doses of Vitamin C Reverse Escherichia coli Endotoxin–Induced Hyporeactivity to Acetylcholine in the Human Forearm

“…Selective impairment of endothelium-dependent vasodilation by LPS was first demonstrated in vitro. 19,20 In humans in vivo, this was first confirmed by Bhagat et al 3 in veins. Subsequently, Hingorani et al 4 demonstrated reduced endothelium-dependent vasodilation of resistance and conduit vessels after vaccination with Salmonella typhi in healthy volunteers.…”

Simvastatin Prevents Vascular Hyporeactivity During Inflammation

“…Impairment of endotheliumdependent vasodilation is present in inflammation and was demonstrated in vitro 23,24 and in resistance arteries of healthy humans challenged by different inflammatory stimuli. 13,25 Consistent with previous studies, LPS impaired the FBF response to ACh and NE, with preservation of the dilation to the vascular smooth muscle relaxant NTG.…”

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

“…These include the vasodilators, including NO and prostacyclin, and the vasoconstrictors, including endothelin, thromboxane A2, and platelet-activating factor (Wanecek et al, 2000). Impaired endothelium-dependent relaxations have been shown in blood vessels from endotoxemic animals (Parker and Adams, 1993;Umans et al, 1993;Myers et al, 1995;Wiel et al, 2000). Apart from anatomical injuries, such impairment observed in endotoxemic blood vessels may result from several mechanisms: alteration in endothelial cell surface receptors; modified signal transduction pathways such as receptor-eNOS uncoupling; altered function and expression of eNOS; changes in the pathways that lead to release of NO;…”