• Heart rate [ Time Frame: Duration of the intervention ] [ Designated as safety issue: No ]
  

• Blood Pressure [ Time Frame: Duration of the intervention ] [ Designated as safety issue: No ]
  

In Specific Aim 1 we will use state-of-the-art measurements of sympathetic activity (response to trimethaphan, direct nerve sympathetic traffic recordings with microneurography, plasma norepinephrine and intraneuronal metabolites), inflammatory mediators (C-reactive protein, IL-6) and oxidative stress (isoprostanes) in patients with CFS-P. It is important that appropriate control groups be included, and we will also study patients with CFS without orthostatic tachycardia, patients with POTS without CFS, and normal controls.

We have documented abnormalities in volume regulation in POTS patients. Hypovolemia can contribute to sympathetic activation and, vice versa, sympathetic activation can contribute to hypovolemia. Interrupting this vicious circle with acute saline infusion is the most effective treatment to improve symptoms in POTS patients. Not surprisingly, many POTS patients followed by us, and CFS patients followed by our collaborator David Bell, are using saline pulse therapy as a way to alleviate symptoms. However, the efficacy and safety of this approach has not been proven. We propose to validate this treatment in Specific Aim 2.

Our studies show that nitric oxide is arguably the most important metabolic factor involved in cardiovascular regulation. Abnormalities in nitric oxide have been proposed to contribute to CFS and POTS, but proving this has been challenging in part due to its interaction with the sympathetic nervous system. In Specific Aim 3 we propose to investigate the importance of nitric oxide in CFS-P patients using an experimental approach developed in our laboratory to eliminate nitric oxide / autonomic interactions.

Finally, in Specific Aim 4 we propose a proof-of-concept study to test the hypothesis that sympathetic activation contributes to many of the abnormalities found in CFS patients. If our hypothesis is correct, inhibition of sympathetic tone will result in improvement of the abnormalities described in volume, inflammation and oxidative stress. More importantly, it will result in symptomatic improvement in these patients. We believe, therefore, that the studies proposed in this application will improve our understanding of the pathophysiology of CFS, and provide a rationale approach to the treatment of this disabling condition.

Inclusion Criteria:

• Meet CDC diagnostic criteria of CFS (Fukuda et al., 1994)
• Meet diagnostic criteria of POTS (Raj et al., 2005)
• Age between 18-65 years
• Male and female are eligible (although the majority of patients with CFS-P are female)

Exclusion Criteria:

• Presence of medical conditions that can explain postural tachycardia (e.g., dehydration, medications)
• Presence of medical or psychiatric conditions known to cause fatigue (Fukuda et al., 1994). Inability to give, or withdrawal of, informed consent
• Inability to acquire or maintain adequate long-term intravenous access (peripheral indwelling catheter, PIC)
• Pregnancy
• Other factors which in the investigator's opinion would prevent the subject from completing the protocol.
• Patients who are bedridden or chair-ridden.