The Venous Distension Reflex and Orthostatic Hypertension

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 (BP)
responses to physiologic stress. Work from our laboratory over the past seven years has shown
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 an acute and dramatic increase in Muscle Sympathetic Nerve Activity (MSNA; an
index of sympathetic activity directed to skeletal muscle) and BP in humans. Since this
venous distension reflex (VDR) differs physiologically from the other reflex systems, and
since this system may play a critical role in orthostatic BP control, we believe that it is a
significant area of study.

The investigators speculate that VDR from lower limbs contributes to the autonomic adjustment
to orthostatic stress. To examine the VDR in lower limbs, an arterial occlusion cuff on the
mid-thigh was inflated (250 mm mercury; Hg). Then, limb suction (-100 mmHg) was applied
~10-15 cm below the level of arterial occlusion (i.e. below the knee). MSNA was measured in
the opposite control limb. When suction was applied below the level of arterial occlusion
(i.e. occlusion + suction), both MSNA and mean arterial BP (MAP) increased. In control
trials, arterial occlusion without limb suction (i.e. occlusion alone) did not increase MSNA.
Plethysmographic data showed calf circumference increased without detectable arterial
pulsations. Pilot data suggest that the fluid shifts from the occluded but non-depressurized
zone of the limb (i.e. between the cuff and knee) into the occluded and depressurized region
of the limb within the tank. Thus, the results suggest that the VDR was engaged with this
limb suction experimental model.

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.

In ~2.5-10% of the population, BP rises as the person stands. This has been termed
orthostatic hypertension, and is different from the "normal" sustained BP response when a
person stands. The incidence of orthostatic hypertension may increase with aging (~2.4% for
45-64 years old and ~8.7% for >70 years old). Orthostatic hypertension is a risk factor for
the development of stroke, left ventricular hypertrophy, and chronic kidney disease. It is
unclear why BP rises with standing in some individuals. Some investigators have speculated
that orthostatic hypertension is due to exaggerated baroreceptor withdrawal with standing.
Others have speculated that this response is due to an increase in sympathetic output. It has
been noted that some patients with orthostatic hypertension have increased venous pooling in
their lower legs. Based these data, the investigators postulate that heightened engagement of
the VDR reflexly increases MSNA and also serves to reset the aortic baroreflex. In this
protocol, the investigators will determine if the MSNA response to leg suction is heightened
in the individuals with elevated standing BP, and examine if the baroreflex is altered in
these individuals. The investigators will also examine if external pressure on lower limbs,
which limits the venous pooling in the lower limbs, will attenuate the increase in BP during
standing in those individuals.

Inclusion Criteria:

- Are capable of giving informed consent

- Are of any race or ethnicity

- Are fluent in written and spoken English

- Whose history and physical exam did not uncover any exclusion criteria

- Are 18 years of age

For subjects with elevated standing BP

- Systolic BP (SBP) during standing is at least 10 mmHg > the supine SBP

- Patients with a diagnosis of stage I hypertension without other chronic diseases may
be INCLUDED

For normal subjects without elevated standing BP

- The change in SBP by standing is within ± 5 mmHg from the supine SBP

- Matched gender, similar age and BMI (within 10%) to participants with elevated
standing BP

- Free of acute or chronic medical conditions

Exclusion Criteria:

- Age < 18 years of age

- Are a pregnant or nursing woman

- Are a prisoner or institutionalized individual or unable to consent

- Have chronic diseases (e.g. heart, lung, neuromuscular disease, or cancer) other than
stage I hypertension

- Have orthostatic hypotension or a history of syncope

- Current smoker

- History of blood clots