Role of Sympathetic Activity and Splanchnic Capacitance in Hypertension

The splanchnic circulation contains a highly compliant venous bed which normally stores ~25%
of the blood volume, and receives up to 25% of the resting cardiac output. It is highly
innervated by the sympathetic nervous system, and this neural regulation results in large
volume shifts that modulate blood pressure (BP). The splanchnic circulation may play a role
in hypertension as suggested by studies showing that surgical splanchnic denervation
effectively lowered BP in hypertensive subjects without affecting renal function. Recently,
studies in animal models have shown that splanchnic sympathetic activation, particularly to
capacitance vessels, was critical to the development of hypertension. The clinical
translation of these findings to human hypertension has lagged behind because of limitations
in previously available experimental approaches. The investigators propose to use splanchnic
radionuclide plethysmography and sympathetic withdrawal with the ganglionic blocker
trimethaphan to overcome these limitations.

Several studies have shown that sympathetic activity contributes to hypertension.
Accordingly, our previous studies showed that sympathetic withdrawal with the ganglionic
blocker trimethaphan resulted in normalization of BP in hypertensive subjects. Interestingly,
this was caused mainly by a fall in stroke volume, rather than a decrease in arterial
vascular resistance suggesting that decreased venous return may play a major role, and that a
sympathetically mediated contraction of splanchnic capacitance contributes to the maintenance
of hypertension.

The investigators hypothesize that the decrease in BP induced by autonomic blockade with
trimethaphan results from an increase in splanchnic capacitance leading to a reduction in
venous return. To test this hypothesis, the investigators will compare the effect of
sympathetic withdrawal on splanchnic capacitance between hypertensive and normotensive
subjects. Splanchnic venous capacitance will be measured by radionuclide plethysmography.
Abdominal blood volumes will be measured using labeled red cells with technetium-99 while
applying different levels of continuous positive airway pressure.

In addition, the investigators will assess whether changes in splanchnic capacitance measured
by bioimpedance are similar to those measured by radionuclide imaging. For this purpose, the
investigators will compare the effects of nitroglycerin on splanchnic capacitance measured by
the two techniques.

Inclusion Criteria:

- Lean and obese, male and female subjects of all races between 18 and 65 years of age.

- Normotensive and hypertensive subjects will be enrolled. Hypertension will be defined
as a systolic BP ≥140 mm Hg and/or a diastolic BP ≥ 90 mm Hg, taken in the seated
position in at least 2 separate occasions. All subjects will be otherwise normal
volunteers.

- Subjects able and willing to provide informed consent.

Exclusion Criteria:

- Pregnancy.

- Subjects with morbid obesity (BMI > 40 kg/m2).

- Subjects with any chronic disease (other than hypertension) including diabetes,
cardiovascular disease, history of smoking, or if they take any medication that have
known effects autonomic functions, or other factors which in the investigator's
opinion would prevent the subject from completing the protocol including clinically
significant abnormalities in clinical, mental or laboratory testing.

- Current smokers or history of heavy smoking (>2 packs/day)

- Lean normotensive subjects will be excluded if they have a strong family history of
hypertension (both parents treated or diagnosed), diagnosis of sleep apnea or a high
score in the Berlin questionnaire for sleep apnea, or if they are highly trained
athletes.