Enhanced Cholinergically Mediated Vasodilatation

We could not determine why the patients with chronic fatigue syndrome have acetylcholine supersensitivity in the skin microcirculation. Recent evidence in mice treated with cholinesterase inhibitors suggests that cholinergic stimulation promotes changes in the genes regulating acetylcholine metabolism (9) and that such changes are facilitated by stress (10).

Whether such changes of cholinergic tone apply to the metabolism of acetylcholine in vascular endothelium, however, remains speculative. There are several ways that the acetylcholine-endothelial pathway could account for cholinergic supersensitivity.

Acetylcholine produces vasodilatation through a sequence of events beginning with its binding to muscarinic receptors on the endothelial cell surface. This activates G proteins, promoting the conversion of larginine to nitric oxide, which diffuses into the smooth muscle cells and stimulates guanylate cyclase to produce cyclic GMP, thereby causing relaxation. As vascular responses to sodium nitroprusside were not enhanced in patients with chronic fatigue syndrome, we suggest that the enhanced vasodilator activity to acetylcholine is situated at the muscarinic M3 receptor or along the muscarinic receptor/vascular smooth muscle pathway.

Many of the symptoms of chronic fatigue syndrome, such as temperature sensitivity, gastrointestinal difficulties, problems with sleep, and orthostatic intolerance, are consistent with altered cholinergic activity. Our findings of enhanced cholinergicallymediated vasodilatation are related only to the vasoactive properties of acetylcholine within the endothelium, which are distinct from its action as a neurotransmitter.

Nevertheless, the response of skin microvessels to acetylcholine is typical of blood vessels elsewhere in the body. Thus, our findings might have important implications for features of chronic fatigue syndrome that involve vascular integrity.