Role of Sympathetic Activity and Splanchnic Capacitance in Hypertension

NCT ID: NCT02425566

Last Updated: 2025-08-21

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-04-30
• Study Completion Date: 2026-08-31

Brief Summary

The purpose of this study is to better understand the role of the abdominal veins (splanchnic capacitance) and the sympathetic nervous system in human hypertension. The investigators will test the hypothesis that constriction of abdominal veins due to sympathetic activation contributes to human hypertension. Splanchnic capacitance will be assessed in normotensive and hypertensive subjects at baseline and during acute blockade of the autonomic nervous system.

Detailed Description

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.

Conditions

Hypertension

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Study day with trimethaphan

After baseline measurements, autonomic blockade will be induced by continuous intravenous infusion of trimethaphan starting at 0.5-1.0 mg/min and increasing by 1.0 mg/min every 2 to 6 minutes up to an infusion rate of 5 mg/min.

Group Type: EXPERIMENTAL

Trimethaphan

Intervention Type: DRUG

Trimethaphan is a Nn-nicotinic receptor antagonist that blocks sympathetic and parasympathetic transmission at the level of the autonomic ganglia. It will be administered as an acute intravenous infusion with doses ranging from 0.5 to 5.0 mg/min.

Radionuclide Study day with nitroglycerin

Sublingual nitroglycerin (0.3-0.6 mg) will be given after baseline measurements. Outcome measurements will be repeated within 10 min after the nitroglycerin has dissolved

Group Type: EXPERIMENTAL

Nitroglycerin

Intervention Type: DRUG

Sublingual nitroglycerin (0.3-0.6 mg) will be given after baseline measurements.

Interventions

Trimethaphan

Trimethaphan is a Nn-nicotinic receptor antagonist that blocks sympathetic and parasympathetic transmission at the level of the autonomic ganglia. It will be administered as an acute intravenous infusion with doses ranging from 0.5 to 5.0 mg/min.

Intervention Type: DRUG

Nitroglycerin

Sublingual nitroglycerin (0.3-0.6 mg) will be given after baseline measurements.

Intervention Type: DRUG

Other Intervention Names

Trimethaphan Camsylate; Nitroglycerin sublingual, nitrostat

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Vanderbilt University

OTHER

Sponsor Role: lead

Responsible Party

Italo Biaggioni

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Italo Biaggioni, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University

Locations

Autonomic Dysfunction Center

Nashville, Tennessee, United States

Countries

United States

References

Okamoto LE, Dupont WD, Biaggioni I, Kronenberg MW. Effect of nitroglycerin on splanchnic and pulmonary blood volume. J Nucl Cardiol. 2022 Dec;29(6):2952-2963. doi: 10.1007/s12350-021-02811-7. Epub 2021 Nov 2.

Reference Type: DERIVED

PMID: 34729682 (View on PubMed)

Other Identifiers

141218

Identifier Type: -

Identifier Source: org_study_id