Hypertension, Pure Autonomic Failure
Conditions
Keywords
Endothelial Nitric Oxide, L-NMMA, Trimethaphan, Autonomic Nervous System, Nitric Oxide Inhibition
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.
Interventions
DRUGL-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.
DRUGTrimethaphan
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.
Sponsors
Vanderbilt University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Autonomic Failure Patients To compare the effects of NO inhibition during intact and transient pharmacological blockade of the autonomic nervous system. | 19 |
| Hypertensives and Controls To compare the effects of NO inhibition during intact and transient pharmacological blockade of the autonomic nervous system | 93 |
| Total | 112 |
Baseline characteristics
| Characteristic | Hypertensives and Controls | Autonomic Failure Patients | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 6 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 93 Participants | 13 Participants | 106 Participants |
| Age Continuous | 37 years STANDARD_DEVIATION 11.8 | 62 years STANDARD_DEVIATION 10.4 | 41 years STANDARD_DEVIATION 14.8 |
| Region of Enrollment United States | 93 participants | 19 participants | 112 participants |
| Sex: Female, Male Female | 51 Participants | 9 Participants | 60 Participants |
| Sex: Female, Male Male | 42 Participants | 10 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 19 | 0 / 93 |
| serious Total, serious adverse events | 0 / 19 | 0 / 93 |
Outcome results
Primary
Change in Systolic Blood Pressure
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Autonomic Failure Patients | Change in Systolic Blood Pressure | 43 mm Hg | Standard Error 6.2 |
| Hypertensives and Controls | Change in Systolic Blood Pressure | 21 mm Hg | Standard Error 8.4 |
Primary
Systolic Blood Pressure in Response to Systemic Nitric Oxide Inhibition
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Autonomic Failure Patients | Systolic Blood Pressure in Response to Systemic Nitric Oxide Inhibition | 152 mm Hg | Standard Deviation 6.8 |
| Hypertensives and Controls | Systolic Blood Pressure in Response to Systemic Nitric Oxide Inhibition | 136 mm Hg | Standard Deviation 13.8 |