Orthostatic intolerance, also known as the postural tachycardia syndrome (POTS), is the most common cause of chronic fatigue syndrome (CFS) in the young. Our lab has demonstrated that many CFS/POTS patients have a redistributive form of central hypovolemia that is associated with splanchnic hyperemia and hypervolemia also known as "splanchnic pooling". Furthermore, cutaneous studies have provided separate evidence for nitric oxide (NO) excess although it remains unclear which nitric oxide synthase (NOS) isoforms are involved. We hypothesize that CFS/POTS is caused by either increased neuronal NOS activity (nNOS, NOS-1) or increased inducible NOS (INOS, NOS-2), that there is evidence for increased NOS expression at tissue level, and that inhibition of NO-dependent vasodilation can reduce splanchnic hyperemia and improve orthostatic tolerance. To explore these hypotheses, 20 CFS/POTS patients, 20 CFS patients without POTS (CFS/~POTS), and 20 control subjects will be studied in order to accomplish the following Specific Aims: 1) We will determine the isoform dependence of increased cutaneous NO in CFS/POTS by measuring NO-dependent local heating and acetylcholine cutaneous blood flow responses combined with isoform selective NOS inhibitors. 2) We will determine whether protein and mRNA expression of NOS isoforms are increased in white blood cells and skin biopsies of CFS/POTS, compared to CFS/~POTS, and controls using Western blot and RT- PCR techniques. 3) We will test the hypothesis that the guanylate cyclase inhibitor methylene blue versus phenylephrine differentially decreases splanchnic pooling in CFS/POTS patients compared to healthy control subjects. Relevance: Chronic orthostatic intolerance, or the inability to remain upright, affects a large number of Americans, making it impossible for these individuals to study or maintain jobs. This condition is also known as the postural tachycardia syndrome and is the main cause of chronic fatigue syndrome in the young. We have evidence that many POTS patients have excessive pooling of blood in the gut circulation when upright that is related to a small yet potent fundamental molecule called nitric oxide (NO). In the proposed studies, we will demonstrate the origin of the excess in NO, and while using an already approved medication, we will test whether we can improve our patients so that they can effectively return to work and school.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30HL097380-04
Application #
8309987
Study Section
Special Emphasis Panel (ZRG1-F10-S (21))
Program Officer
Meadows, Tawanna
Project Start
2009-08-01
Project End
2013-05-24
Budget Start
2012-08-01
Budget End
2013-05-24
Support Year
4
Fiscal Year
2012
Total Cost
$42,628
Indirect Cost
Name
New York Medical College
Department
Physiology
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Ross, Amanda J; Ocon, Anthony J; Medow, Marvin S et al. (2014) A double-blind placebo-controlled cross-over study of the vascular effects of midodrine in neuropathic compared with hyperadrenergic postural tachycardia syndrome. Clin Sci (Lond) 126:289-96
Medow, Marvin S; Aggarwal, Arun; Baugham, Ila et al. (2013) Modulation of the axon-reflex response to local heat by reactive oxygen species in subjects with chronic fatigue syndrome. J Appl Physiol (1985) 114:45-51
Schwartz, Christopher E; Medow, Marvin S; Messer, Zachary et al. (2013) Spontaneous fluctuation indices of the cardiovagal baroreflex accurately measure the baroreflex sensitivity at the operating point during upright tilt. Am J Physiol Regul Integr Comp Physiol 304:R1107-13
Stewart, Julian M; Medow, Marvin S; Messer, Zachary R et al. (2012) Postural neurocognitive and neuronal activated cerebral blood flow deficits in young chronic fatigue syndrome patients with postural tachycardia syndrome. Am J Physiol Heart Circ Physiol 302:H1185-94
Ocon, Anthony J; Messer, Zachary R; Medow, Marvin S et al. (2012) Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome. Clin Sci (Lond) 122:227-38
Ocon, Anthony J; Messer, Zachary; Medow, Marvin S et al. (2011) Increased pulsatile cerebral blood flow, cerebral vasodilation, and postsyncopal headache in adolescents. J Pediatr 159:656-62.e1
Medow, Marvin S; Bamji, Natasha; Clarke, Debbie et al. (2011) Reactive oxygen species (ROS) from NADPH and xanthine oxidase modulate the cutaneous local heating response in healthy humans. J Appl Physiol 111:20-6
Stewart, Julian M; Ocon, Anthony J; Medow, Marvin S (2011) Ascorbate improves circulation in postural tachycardia syndrome. Am J Physiol Heart Circ Physiol 301:H1033-42
Ocon, Anthony J; Medow, Marvin S; Taneja, Indu et al. (2011) Respiration drives phase synchronization between blood pressure and RR interval following loss of cardiovagal baroreflex during vasovagal syncope. Am J Physiol Heart Circ Physiol 300:H527-40
Stewart, Julian M; Rivera, Eileen; Clarke, Debbie A et al. (2011) Ventilatory baroreflex sensitivity in humans is not modulated by chemoreflex activation. Am J Physiol Heart Circ Physiol 300:H1492-500

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