Vasovagal syncope (VVS, simple faint) is the most common cause of transient loss of consciousness and is the acute episodic form of orthostatic intolerance (OI). Postural tachycardia syndrome (POTS) is the common chronic form of OI. Both are defined by debilitating symptoms and signs while upright relieved by recumbency. Pathophysiological mechanisms have remained elusive although our past work shows that excessive upright central hypovolemia results from splanchnic blood pooling due to defective splanchnic arterial and venous constriction. Preliminary data support the hypothesis that production of nitric oxide (NO) is enhanced in these patients resulting in reduced sympathetic noradrenergic neurotransmission at pre-junctional and post-junctional sites. Our approach is two-fold: 1) We will use intradermal microdialysis and laser Doppler flowmetry (LDF) to delineate the microvascular mechanisms of NO modulation of noradrenergic neurotransmission free of confounding systemic reflex changes. 2) We will systemically apply this mechanism to a model of orthostatic stress, lower body negative pressure (LBNP), while measuring cardiac output by inert gas rebreathing, regional blood volume, and regional blood flow using plethysmographic techniques focusing on splanchnic changes, and muscle sympathetic nerve activity by peroneal microneurography. 30 each of VVS, POTS and control subjects ages 14-29 years will be recruited. We will use chemiluminescence to measure NO in microdialysate to test whether it is increased in OI. Pre-junctional neurotransmission will be assessed by step wise tyramine doses using HPLC analysis of microdialysate norepinephrine (NE). Post-junctional neurotransmission will be assessed by LDF responses to step-wise increases of NE after endogenous blockade with bretylium. Basal and local heat stimulated NO will be assessed. We will determine whether inhibition of neurotransmission is NO-specific by repeating studies after NOS inhibition with nitro-L-arginine (NLA) and after repletion of NO during perfusion with NLA+sodium nitroprusside (SNP). We will obtain skin biopsies for NOS isoform protein and expression. We will determine if systemic NO inhibits pre and post synaptic adrenergic activity in OI, altering the response to LBNP. Presynaptic neurotransmission will be assessed by step-wise increasing LBNP and measuring plasma NE response. Post-synaptic neurotransmission will be assessed by the systemic response to stepwise increasing phenylephrine doses. To confirm NO-specificity, studies will be repeated after NOS inhibition with L-NG-monomethyl Arginine(L-NMMA), after repletion of NO during perfusion with L-NMMA +SNP, and after low dose phenylephrine as a control for baseline shifts of MSNA and vasoconstriction. L-NMMA enters the CNS slowly over many hours. To ascertain its central effects we will measure MSNA at the end of experiments. Studies will establish the molecular mechanism for common and debilitating forms of OI in the cutaneous human surrogate model, and apply this knowledge to the integrative physiology of OI. This research will lead to targeted and effective medical therapy for important groups of OI patients.

Public Health Relevance

Vasovagal syncope (simple postural faint) is the most common cause of acute loss of consciousness. Postural tachycardia syndrome (POTS) is the most common chronic form of postural lightheadedness. Together they afflict many Americans, mostly young women, who are prevented from gainful employ or school attendance. The underlying mechanism is not known. Our past work suggests that a simple molecule, nitric oxide, acts to subvert normal blood flow controls causing blood to pool in the gut when standing. Our proposal will show the mechanism behind this problem and will indicate effective medical treatments.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL112736-02
Application #
8606885
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Maric-Bilkan, Christine
Project Start
2013-02-01
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$479,074
Indirect Cost
$170,272
Name
New York Medical College
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
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Del Pozzi, Andrew T; Schwartz, Christopher E; Tewari, Deepali et al. (2014) Reduced cerebral blood flow with orthostasis precedes hypocapnic hyperpnea, sympathetic activation, and postural tachycardia syndrome. Hypertension 63:1302-8
Medow, Marvin S; Sood, Shilpa; Messer, Zachary et al. (2014) Phenylephrine alteration of cerebral blood flow during orthostasis: effect on n-back performance in chronic fatigue syndrome. J Appl Physiol (1985) 117:1157-64
Del Pozzi, Andrew T; Pandey, Akash; Medow, Marvin S et al. (2014) Blunted cerebral blood flow velocity in response to a nitric oxide donor in postural tachycardia syndrome. Am J Physiol Heart Circ Physiol 307:H397-404
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