- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02425566
Role of Sympathetic Activity and Splanchnic Capacitance in Hypertension
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Estimated)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
Tennessee
-
Nashville, Tennessee, United States, 37232
- Autonomic Dysfunction Center
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Other
- Allocation: Non-Randomized
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 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.
|
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.
Other Names:
|
Experimental: 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
|
Sublingual nitroglycerin (0.3-0.6 mg) will be given after baseline measurements.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Splanchnic venous capacitance
Time Frame: after 10 minutes of autonomic blockade
|
The primary outcome will be the splanchnic capacitance, defined as the pressure-venous curve (P-V curve), during trimethaphan infusion adjusted for its baseline values.
For analysis, the Y-intercept (volume) and the slope of the P-V relationship during autonomic blockade adjusted by their corresponding baseline values will be compared between groups.
|
after 10 minutes of autonomic blockade
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Systolic Blood Pressure
Time Frame: after 10 minutes of autonomic blockade
|
Changes from baseline in blood pressure.
|
after 10 minutes of autonomic blockade
|
Stroke volume
Time Frame: after 10 minutes of autonomic blockade
|
Changes from baseline in stroke volume.
|
after 10 minutes of autonomic blockade
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Italo Biaggioni, MD, Vanderbilt University
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Cardiovascular Diseases
- Vascular Diseases
- Hypertension
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Antihypertensive Agents
- Vasodilator Agents
- Autonomic Agents
- Peripheral Nervous System Agents
- Cholinergic Antagonists
- Cholinergic Agents
- Adjuvants, Anesthesia
- Ganglionic Blockers
- Nicotinic Antagonists
- Nitroglycerin
- Trimethaphan
- Trimethaphan camsylate
Other Study ID Numbers
- 141218
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Hypertension
-
National Taiwan University Hospital Hsin-Chu BranchRecruitingHypertension,Essential | Hypertension, MaskedTaiwan
-
University of Alabama at BirminghamTroy UniversityCompletedHypertension | Hypertension, Resistant to Conventional Therapy | Uncontrolled Hypertension | Hypertension, White CoatUnited States
-
BayerCompletedPrimary HypertensionChina
-
Addpharma Inc.Completed
-
Columbia UniversityAgency for Healthcare Research and Quality (AHRQ)Active, not recruitingWhite Coat Hypertension | Hypertension,EssentialUnited States
-
Universidade Federal de Santa MariaCompletedHealthy Volunteers | Hypertension, EssentialBrazil
-
Sulaiman AlRajhi CollegesUnknownHypertension, Essential | β-hydroxybutyrate
-
Centre Chirurgical Marie LannelongueUnknownChronic Thrombo-embolic Pulmonary Hypertension and Pulmonary Arterial HypertensionFrance
-
Cytos Biotechnology AGCompletedMild Essential Hypertension | Moderate Essential HypertensionSwitzerland
Clinical Trials on Trimethaphan
-
Vanderbilt UniversityActive, not recruitingMultiple System Atrophy | Orthostatic Hypotension | Supine HypertensionUnited States
-
Vanderbilt UniversityCompletedChronic Fatigue Syndrome | Orthostatic Intolerance | Postural Tachycardia SyndromeUnited States
-
Vanderbilt University Medical CenterWithdrawn
-
Vanderbilt UniversityCompleted
-
Vanderbilt University Medical CenterNational Heart, Lung, and Blood Institute (NHLBI)CompletedHypertension | ObesityUnited States
-
Vanderbilt UniversityCompleted
-
Vanderbilt UniversityTerminatedHypertension | Hypertension, EssentialUnited States
-
Vanderbilt UniversityCompletedOBESITY | HYPERTENSION | PURE AUTONOMIC FAILURE | SHY-DRAGER SYNDROMEUnited States
-
Vanderbilt UniversityCompleted