Acetylcholine-mediated vasodilatation in CFS/ME patients: the role of nitric oxide, prostacyclin and endothelium-derived hyperpolarising factor
Dr Faisel Khan
Investigator
Dr Faisel Khan
Institution
Vascular Diseases Research Unit, The Institute of Cardiovascular Research, Ninewells Hospital and Medical School, Dundee, UK
Aims
In three separate studies, we have demonstrated abnormalities of the acetylcholine-mediated vasodilator pathway in ME/CFS patients. We found enhanced sensitivity, which was specific for acetylcholine and not other, similar endothelium-dependent vasodilators or the endothelium-independent vasodilator, sodium nitroprusside. This sensitivity is unusual and might be important to the underlying pathophysiology of the illness. Sensitivity to acetylcholine was also restricted to those patients within the CFS construct, but not those with Gulf War Syndrome or those exposed to organophosphate compounds. Because of this research, we wish to carry out a set of experiments that will help to elucidate the reason for the unusual finding of acetylcholine sensitivity in the ME/CFS patient group.
We aim to examine the roles of nitric oxide, prostacyclin and endothelium-derived hyperpolarising factor (EDHF) in the response to acetylcholine in 15 ME/CFS patients and 15 age and gender-matched subjects. To achieve this we will use a variety of chemicals to block the activity of nitric oxide, prostaglandins, and the role of EDHF in the residual vasodilator response to acetylcholine. The understanding gained from this study will enable us to clarify the origin of the endothelial sensitivity to acetylcholine exhibited by ME/CFS patients. In the future, it might be possible to target drug therapy at correcting endothelial dysfunction through changes in EDHF activity.
Methods
We shall recruit 15 ME/CFS patients and 15 normal age and sex-matched healthy patients. Subjects will attend on 3 occasions, and forearm vascular responses will be measured. At visit 1, baseline vascular responses to iontophoretic application of acetylcholine and sodium nitroprusside will be assessed using laser Doppler imaging as described previously in our publications. Additionally, we will measure forearm vascular responses by strain gauge plethysmography to infusions of acetylcholine to determine whether the observed sensitivity to acetylcholine in the skin microvessels is also present in the forearm muscle vessels. At visits 2 and 3, vascular responses to iontophoretic application of acetylcholine and sodium nitroprusside will be assessed during infusions of an inhibitor of cytochrome enzymes. At visit 3, infusions will be repeated after inhibition of prostaglandins. These experiments have been designed to assess the contribution of the various pathways in the sensitivity to acetylcholine found in CDC-1994 patients. Vascular responses on the 3 visits will be compared using two-way analysis of variance with repeated measures.
