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

Abstract

Background-Acute inflammation causes endothelial vasodilator dysfunction that may be mediated by oxidative stress. Methods and Results-In this randomized, double-blind, crossover study, forearm blood flow responses to acetylcholine (ACh) (endothelium-dependent dilator) and glyceryl-trinitrate (GTN) (endothelium-independent dilator) were assessed before and after induction of acute systemic inflammation by low doses of Escherichia coli endotoxin (LPS) (20 IU/kg IV) in 8 healthy volunteers. The acute effect of intra-arterial vitamin C (24 mg/min) or placebo was studied 4 hours after LPS, respectively. Vitamin C alone was administered in control experiments. LPS administration caused systemic vasodilation, increased white blood count, elevated body temperature, and reduced vitamin C plasma concentrations. LPS decreased the responses of forearm blood flow to ACh by 30% (PϽ0.05) but not to GTN. Vitamin C completely restored the response to ACh, which was comparable with that observed under baseline conditions. Vitamin C had no effect on basal blood flow or ACh-or GTN-induced vasodilation in control subjects. Conclusions-Our data demonstrate that impaired endothelial vasodilation caused by E coli endotoxemia can be counteracted by high doses of antioxidants in vivo. Oxidative stress may play an important role in the pathogenesis of endothelial dysfunction during inflammation.

Simvastatin Prevents Vascular Hyporeactivity During Inflammation

“…In previous studies, we have demonstrated that increased oxidative stress plays an important role in vascular dysfunction during inflammation. In those studies, 14,15 LPS-induced hyporeactivity to ACh and to different vasoconstrictors could be reversed by intra-arterial infusion of high doses of the antioxidant vitamin C. Despite the lack of a direct antioxidative effect, statins may inhibit key proteins involved in generation of reactive oxygen species. Experimental studies revealed that statins inhibit production of superoxide via the NADPH oxidase system in monocytes, 26 neutrophils, 27 and endothelial cells, 28 because activation of NADPH oxidase is dependent on an isoprenoid group, ie, geranyl geraniol, which derives from HMG-CoA and is thus inhibited by statins.…”

“…Injection of LPS to humans has been established by other groups and at our institution as a model to study cardiovascular responses to acute systemic inflammation. 13,14,16,17 This dose of LPS impairs the vascular responses to adrenergic vasoconstrictors and endotheliumdependent vasodilators, with maximum clinical effect and vascular hyporeactivity Ϸ4 hours after LPS administration. 13,14 Therefore, FBF experiments were repeated at 4 hours after LPS administration.…”

“…13,14,16,17 This dose of LPS impairs the vascular responses to adrenergic vasoconstrictors and endotheliumdependent vasodilators, with maximum clinical effect and vascular hyporeactivity Ϸ4 hours after LPS administration. 13,14 Therefore, FBF experiments were repeated at 4 hours after LPS administration. Tympanic temperature (Thermoscan pro, Braun AG) was measured at frequent intervals; ECG, pulse rate, and blood pressure were recorded with an automated device (Hewlett Packard CMS patient monitor).…”

“…11,12 We have previously demonstrated that acute systemic inflammation, as induced by low doses of Escherichia coli lipopolysaccharide (LPS), results in marked endothelial dysfunction and impaired responsiveness to vasoconstrictors, 13 which is associated with oxidative stress. 14,15 To characterize the vasoprotective properties of simvastatin during inflammation, we studied whether LPS-induced hyporeactivity to the endothelium-dependent vasodilator acetylcholine (ACh) and the vasoconstrictor norepinephrine (NE) in the human forearm vasculature could be prevented by short-term treatment with high therapeutic doses of simvastatin.…”

Inflammation, endothelial dysfunction, and the risk of high blood pressure: epidemiologic and biological evidence

“…66 Actually, higher levels of oxidized LDL have been associated to endothelial-dependent vascular dysfunction in patients with coronary heart disease 6 and in patients with cardiovascular risk factors. 78 Moreover, Pleiner et al 79 have shown that IEDD induced by the administration of lipopolysaccharide in normal subjects can be restored by the local administration of high doses of Vitamin C, a free-radical scavenger. This suggests that oxidative stress may play an important role in inflammation-induced IEDD.…”