Project Number: 1F30HL097380-01
Principal Investigator (PI): OCON, ANTHONY JAMES
Title: Inhibition Of NO Dependent Splanchnic Hyperemia Improves CFS/POTS
Organization: NEW YORK MEDICAL COLLEGE
Abstract Text:
DESCRIPTION (provided by applicant): 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.
Other Information:
RFA/PA: PA-08-021
Study Section: ZRG1 Project Start Date: 1-AUG-2009 Project End Date:
31-JUL-2014
Fiscal Year: 2009 Budget Start Date: 1-AUG-2009 Budget End Date: 31-JUL-2010
Administering Institutes or Centers: NATIONAL HEART, LUNG, AND BLOOD
INSTITUTE
Project Funding Information for 2009: Total Funding: $27,784
Year Funding IC FY Total Cost by IC
2009 NATIONAL HEART, LUNG, AND BLOOD INSTITUTE $27,784
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