Autonomic Control of the Circulation and the Venous Distension Reflex

In humans, two-thirds of the blood volume is contained within the venous vasculature. Because
of this, changes in peripheral blood volume and alterations in the mechanical properties of
peripheral veins can greatly impact cardiac filling, cardiac output and blood pressure
responses to physiologic stress. Work from our laboratory over the past seven years has
showed that local upper limb venous distension via volume infusion into an occluded arm (i.e.
volume infusion model) or applying negative pressure to an occluded leg (limb suction
experimental model) leads to acute and dramatic increases in Muscle Sympathetic Nerve
Activity (MSNA; an index of sympathetic activity directed to skeletal muscle) and blood
pressure (BP) in humans. Since this venous distension reflex (VDR) differs physiologically
from the other reflex systems and because this system may play a critical role in orthostatic
BP control, the investigators believe that it is a significant area of study.

These experimental models "selectively" alter peripheral venous volume as the investigators
measure sympathetic reflex responses. This approach is innovative and allows examination of a
previously overlooked autonomic reflex in conscious humans. If these studies confirm the
hypotheses, the obtained data would challenge the present teaching regarding how the
sympathetic nervous system is engaged in humans during postural stress.

A number of thin afferent fibers (Group III and IV) end directly within the adventitia of the
small venous vessels. Their discharge can be increased in response to both distention evoked
by venous occlusion and the infusion of vasodilatory agents. The investigators postulate that
limb venous distension causes the release of substance(s) from vascular walls and/or the
surrounding tissues, and in turn stimulates these thin fiber afferents. Previous animal
studies show that metabolic products of the cyclooxygenase (COX) enzyme system (i.e.
prostaglandins) play an important role in activating Group III and IV afferents during muscle
contraction. Of note, colleagues have shown that COX blockade attenuates the rise in BP seen
with venous distention in a rat model.

In this protocol, the investigators will examine the role played by metabolic products of
arachidonic acid in evoking this reflex. First, the investigators speculate that
prostaglandins may cause engagement of the VDR by direct stimulation of afferents as seen
during muscle contraction. Second, some of prostaglandins such as prostaglandin I2 (PGI2) and
prostaglandin E2 (PGE2) are vasoactive substances, that may induce vasodilation. Thus, the
investigators speculate that prostaglandins could cause engagement of the VDR either by
direct stimulation of afferents or by inducing vessel dilation, that in turn stimulates
afferents. To examine this issue, the investigators propose studies to examine the effects of
COX inhibition on venous size measured with 3 Tesla (3T) MRI (Magnetic Resonance Imaging) as
peripheral veins are distended in human subjects.

The investigators have published several reports on VDR. However, the investigators have no
data regarding if the VDR is still active AFTER COX blockade, if the reflex will be
attenuated, or if COX blockade will alter the size of the veins during the venous distension
procedure.

Inclusion Criteria:

- Are capable of giving informed consent

- Are any race or ethnicity

- Are fluent in written and spoken English

- Have a satisfactory history and physical exam to meet inclusion/exclusion criteria

- Are free of acute or chronic medical conditions

- Are 21 - 35 years of age (inclusive)

- Weigh over 50 kg

Exclusion Criteria:

- Are less than 21 or over 35 years of age

- Are Pregnant or nursing woman

- Are prisoner or institutionalized individual or unable to consent

- Any chronic diseases (hypertension, heart, lung, neuromuscular disease, kidney
disease, diabetes or cancer).

- Are taking medications that may affect their cardiovascular or nervous system

- Has taken an NSAID within 48 hours of any visit (visit will need to be rescheduled)

- Has never taken an NSAID and therefore would not know if they were allergic to it

- Have a supine blood pressure >140/90 mmHg

- Have known allergy to ibuprofen-like drugs (NSAIDS) or aspirin

- Have history of asthma or nasal polyps

- Have history of GI bleeding or ulcers

- Subjects with ferromagnetic metal implants

- Subjects who are claustrophobic