Nitric Oxide and the Autonomic Nervous System

• Sponsor: Vanderbilt University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00178919
• Collaborator: (none)
• Enrollment: 112
• Location: 1
• Arms: 2
• Duration (Months): 72
• Patients Per Site Per Month: 1.6

Study Details

Study Description

Brief Summary

The amount of blood flowing to the different parts of the body is regulated by the autonomic (automatic) nerves and by local factors produced by the blood vessels. Nitric oxide (NO) is one of the most important of these metabolic factors. If the production of NO is slowed or stopped the amount of blood to the different parts of the body is decreased. There is increasing knowledge that NO mechanisms are impaired in a number of medical conditions. NO function is reduced in patients with risk factors for atherosclerosis (hardening of the arteries) such as hypercholesterolemia (patients with high cholesterol), or diabetes mellitus, and is also impaired in smokers. This NO "deficiency" is believed to contribute to the greater cardiovascular risk that marks these patient populations. This study is designed to examine if endothelial nitric oxide is an important control mechanism of blood pressure under normal conditions, and if impairment of nitric oxide contributes to hypertension.

Condition or Disease	Intervention/Treatment	Phase
Hypertension; Pure Autonomic Failure	Drug: L-NMMA; Drug: Trimethaphan	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 112 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Official Title: Cardiovascular Regulation: Autonomic/Metabolic Mechanisms PO1 HL56693, Project 4: Cardiovascular Regulation: Autonomic/Metabolic Mechanisms
• Study Start Date: Aug 1, 2002
• Actual Primary Completion Date: Aug 1, 2008
• Actual Study Completion Date: Aug 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Autonomic Failure Patients To compare the effects of NO inhibition during intact and transient pharmacological blockade of the autonomic nervous system in Patients with Autonomic Failure.	Drug: L-NMMA; IV infusion of 125, 250 and 500 mcg/Kg/min for 15 minutes each dose. The main outcome is the maximal increase in blood pressure produced at the end of the infusions or a maximal systolic blood pressure of 160 mm Hg. It could be achieved after the first dose or the third.; Drug: Trimethaphan; IV infusion for the duration of the study at 4-6 mg/min depending on autonomic blockade. This is only to produce transient pharmacological blockade of the autonomic nervous system in order to allow the full expression of the inhibition of nitric oxide synthase. There is no direct outcome associated with this intervention.
Experimental: Controls and hypertensives To compare the effects of NO inhibition during intact and transient pharmacological blockade of the autonomic nervous system in normal volunteers and hypertensive subjects.	Drug: L-NMMA; IV infusion of 125, 250 and 500 mcg/Kg/min for 15 minutes each dose. The main outcome is the maximal increase in blood pressure produced at the end of the infusions or a maximal systolic blood pressure of 160 mm Hg. It could be achieved after the first dose or the third.; Drug: Trimethaphan; IV infusion for the duration of the study at 4-6 mg/min depending on autonomic blockade. This is only to produce transient pharmacological blockade of the autonomic nervous system in order to allow the full expression of the inhibition of nitric oxide synthase. There is no direct outcome associated with this intervention.

Outcome Measures

Primary Outcome Measures

1. Change in Systolic Blood Pressure [At the end of the highest tolerated dose of IV infusion of L-NMMA]

   L-NMMA (nitric oxide synthase inhibitor) was infused intravenously at different doses for 15 minutes each, after blocking the autonomic nervous system with trimethaphan. The change in systolic blood pressure at the end of the highest tolerated dose is the main outcome. Trimethaphan infused intravenously was used to produce transient blockade of the autonomic nervous system to allow for a full response to nitric oxide inhibition (in the absence of the baroreflex.

2. Systolic Blood Pressure in Response to Systemic Nitric Oxide Inhibition [End of 15 minutes of infusion of L-NMMA at the highest tolerated dose]

   Systolic blood pressure at the highest tolerated dose of IV infusion of L-NMMA during autonomic nervous system blockade with trimethaphan. Trimethaphan, infused intravenously was used to produce transient blockade of the autonomic nervous system to allow for a full response to nitric oxide inhibition (in the absence of the baroreflex.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Adult subjects.

• 18 to 85 years.

• Non-smokers or long term smokers for specific aim 6.

• Drug-free.

• Long term hypertension in specific substudy 3, patients with autonomic failure in specific aims 4 and 5, diabetes mellitus in specific aim 5.

Exclusion Criteria:

• Being on any medication other than antihypertensives (for hypertensives), autonomic medications (for autonomic failure [AF] patients), insulin or other treatment for diabetes (for diabetic patients).

• Having pulmonary, renal, hematopoietic, hepatic and/or cardiac disease.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Autonomic Dysfunction Center	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

• Vanderbilt University

Investigators

• Principal Investigator: Italo Biaggioni, M.D., Vanderbilt University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Italo Biaggioni, Professor of Medicine, Vanderbilt University
• ClinicalTrials.gov Identifier: NCT00178919
• Other Study ID Numbers: 010876; NIH 1RO1HL71172
• First Posted: Sep 15, 2005
• Last Update Posted: Jun 4, 2013
• Last Verified: May 1, 2013

• Keywords provided by Italo Biaggioni, Professor of Medicine, Vanderbilt University: Endothelial Nitric Oxide; L-NMMA; Trimethaphan; Autonomic Nervous System; Nitric Oxide Inhibition
• Additional relevant MeSH terms: Pure Autonomic Failure; Trimethaphan; Trimethaphan camsylate

Study Results

Participant Flow

Arm/Group Title	Autonomic Failure Patients	Hypertensives and Controls
Arm/Group Description	The NO synthase inhibitor L-NMMA was infused intravenously at different doses (125, 250 and 500 mcg/kg/min) until a systolic blood pressure of 150 mm Hg was reached.	The NO synthase inhibitor L-NMMA was infused intravenously at different doses (250, 500 mcg/kg/min) for 15 minutes each dose after acute transient pharmacological blockade of the autonomic nervous system with trimethaphan (4 mg/min) or with the autonomic nervous system intact.
Period Title: Overall Study
STARTED	19	93
COMPLETED	19	68
NOT COMPLETED	0	25

Baseline Characteristics

Arm/Group Title	Autonomic Failure Patients	Hypertensives and Controls	Total
Arm/Group Description	To compare the effects of NO inhibition during intact and transient pharmacological blockade of the autonomic nervous system.	To compare the effects of NO inhibition during intact and transient pharmacological blockade of the autonomic nervous system	Total of all reporting groups
Overall Participants	19	93	112
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	13 68.4%	93 100%	106 94.6%
>=65 years	6 31.6%	0 0%	6 5.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62 (10.4)	37 (11.8)	41 (14.8)
Sex: Female, Male (Count of Participants)
Female	9 47.4%	51 54.8%	60 53.6%
Male	10 52.6%	42 45.2%	52 46.4%
Region of Enrollment (participants) [Number]
United States	19 100%	93 100%	112 100%

Outcome Measures

1. Primary Outcome

Title	Change in Systolic Blood Pressure
Description	L-NMMA (nitric oxide synthase inhibitor) was infused intravenously at different doses for 15 minutes each, after blocking the autonomic nervous system with trimethaphan. The change in systolic blood pressure at the end of the highest tolerated dose is the main outcome. Trimethaphan infused intravenously was used to produce transient blockade of the autonomic nervous system to allow for a full response to nitric oxide inhibition (in the absence of the baroreflex.
Time Frame	At the end of the highest tolerated dose of IV infusion of L-NMMA

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Autonomic Failure Patients	Hypertensives and Controls
Arm/Group Description	To compare the effects of NO inhibition during intact and transient pharmacological blockade of the autonomic nervous system.	To compare the effects of NO inhibition during intact and transient pharmacological blockade of the autonomic nervous system
Measure Participants	19	68
Mean (Standard Error) [mm Hg]	43 (6.2)	21 (8.4)

2. Primary Outcome

Title	Systolic Blood Pressure in Response to Systemic Nitric Oxide Inhibition
Description	Systolic blood pressure at the highest tolerated dose of IV infusion of L-NMMA during autonomic nervous system blockade with trimethaphan. Trimethaphan, infused intravenously was used to produce transient blockade of the autonomic nervous system to allow for a full response to nitric oxide inhibition (in the absence of the baroreflex.
Time Frame	End of 15 minutes of infusion of L-NMMA at the highest tolerated dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Autonomic Failure Patients	Hypertensives and Controls
Arm/Group Description	To compare the effects of NO inhibition during intact and transient pharmacological blockade of the autonomic nervous system.	To compare the effects of NO inhibition during intact and transient pharmacological blockade of the autonomic nervous system
Measure Participants	19	68
Mean (Standard Deviation) [mm Hg]	152 (6.8)	136 (13.8)

Adverse Events

Arm/Group Title	Autonomic Failure Patients		Hypertensives and Controls
Arm/Group Description	The NO synthase inhibitor L-NMMA was infused intravenously at different doses (125, 250 and 500 mcg/kg/min) until a systolic blood pressure of 150 mm Hg was reached.		The NO synthase inhibitor L-NMMA was infused intravenously at different doses (250, 500 mcg/kg/min) for 15 minutes each dose after acute transient pharmacological blockade of the autonomic nervous system with trimethaphan (4 mg/min) or with the autonomic nervous system intact.
All Cause Mortality
	Autonomic Failure Patients		Hypertensives and Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Autonomic Failure Patients		Hypertensives and Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/93 (0%)
Other (Not Including Serious) Adverse Events
	Autonomic Failure Patients		Hypertensives and Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/93 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.