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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Maric-Bilkan, Christine
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York Medical College
Schools of Medicine
United States
Zip Code
Stewart, Julian M; Boris, Jeffrey R; Chelimsky, Gisela et al. (2018) Pediatric Disorders of Orthostatic Intolerance. Pediatrics 141:
Jardine, David L; Wieling, Wouter; Brignole, Michele et al. (2018) The pathophysiology of the vasovagal response. Heart Rhythm 15:921-929
Rowe, Peter C; Underhill, Rosemary A; Friedman, Kenneth J et al. (2017) Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: A Primer. Front Pediatr 5:121
Stewart, Julian M; Sutton, Richard; Kothari, Mira L et al. (2017) Nitric oxide synthase inhibition restores orthostatic tolerance in young vasovagal syncope patients. Heart 103:1711-1718
Medow, Marvin S; Merchant, Sana; Suggs, Melissa et al. (2017) Postural Heart Rate Changes in Young Patients With Vasovagal Syncope. Pediatrics 139:
Stewart, Julian M; Medow, Marvin S; Sutton, Richard et al. (2017) Mechanisms of Vasovagal Syncope in the Young: Reduced Systemic Vascular Resistance Versus Reduced Cardiac Output. J Am Heart Assoc 6:
Medow, Marvin S; Kothari, Mira L; Goetz, Amanda M et al. (2017) Decreasing cerebral oxygen consumption during upright tilt in vasovagal syncope. Physiol Rep 5:
Gutkin, Michael; Stewart, Julian M (2016) Orthostatic Circulatory Disorders: From Nosology to Nuts and Bolts. Am J Hypertens 29:1009-19
Stewart, Julian M; Suggs, Melissa; Merchant, Sana et al. (2016) Postsynaptic ?1-Adrenergic Vasoconstriction Is Impaired in Young Patients With Vasovagal Syncope and Is Corrected by Nitric Oxide Synthase Inhibition. Circ Arrhythm Electrophysiol 9:
Wieling, Wouter; Jardine, David L; de Lange, Frederik J et al. (2016) Cardiac output and vasodilation in the vasovagal response: An analysis of the classic papers. Heart Rhythm 13:798-805

Showing the most recent 10 out of 29 publications