Nitric OxidePhase 2NCT00048477
Effects of Nitrite on Blood Vessel Dilation in Normal Volunteers
A Phase 2 study testing L-NMMA and Sodium Nitrite in people with Nitric Oxide and Endothelium-Derived Relaxing Factor, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
Trial summary
Nitric oxide gas is important in regulating blood vessel dilation, and consequently, blood flow. This gas is continuously produced by endothelial cells, which line the blood vessels. This study will examine whether nitrite, a molecule that normally circulates in the blood stream, can also dilate blood vessels. Read more about this study
- Who is it for?
- Any ageHealthy volunteers can take part
- Conditions the study is for
- Nitric Oxide, Endothelium-Derived Relaxing Factor, Healthy
- What is being tested?
- L-NMMA and Sodium Nitrite
- How many people
- 42 participants
- Where
- 1 siteUnited States
- Study dates
- Oct 2002to Nov 2003
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Who may be able to join
- All volunteer subjects must be at least 21 years of age in good health and have provided informed, written consent for participation in this study.
Who cannot join
- Subjects with a history or evidence of present or past hypertension (blood pressure greater than 145/95 mmHg), hypercholesterolemia (LDL cholesterol greater than 130 mg/dL), diabetes mellitus (fasting blood glucose greater than 130 mg/dL), smoking within two years, cardiovascular disease, peripheral vascular disease, coagulopathy, or any other disease predisposing to vasculitis or Raynaud's phenomenon.
- All subjects will be tested for red blood cell G6PD deficiency; levels below the lower limits of normal will result in exclusion from participation in the study.
- Subjects with a known cytochrome B5 deficiency will not participate in this study.
- Subjects with a history of reaction to a medication or other substance characterized by dyspnea and cyanosis will not participate in this study.
- Subjects with a baseline methemoglobin level greater than 1% will not receive nitrite infusions.
- Lactating and pregnant females.
- No volunteer subject will be allowed to take any medication (oral contraceptive agents are allowed), vitamin supplements, herbal preparations, nutriceuticals or other 'alternative therapies' for at least one month prior to study and will not be allowed to take aspirin for one week prior to study.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Heart, Lung and Blood Institute (NHLBI)
Bethesda, Maryland, 20892
About this study
Official title: Determination of Nitrite as a Source of Bioactive Nitric Oxide in Human Subjects
Nitric oxide gas is important in regulating blood vessel dilation, and consequently, blood flow. This gas is continuously produced by endothelial cells, which line the blood vessels. This study will examine whether nitrite, a molecule that normally circulates in the blood stream, can also dilate blood vessels. The results of this study may be valuable in developing treatments for people with conditions associated with impaired endothelial production of nitric oxide, including high blood pressure, high blood cholesterol, diabetes, estrogen deficiency, and others.
Healthy, non-smoking normal volunteers 21 years of age or older may be eligible for this study. People who lack the enzyme G6PD or cytochrome B5 in their red blood cells may not participate. Absence of these enzymes can lead to episodes of sudden shortness of breath and cyanosis (blueness of the skin due to lack of sufficient oxygen). Participants will undergo the procedures described in study Parts A and B, as follows:
- Part A - After numbing the skin, small tubes are placed in the artery and vein at the inside of the elbow of the dominant arm (right- or left-handed) and a small tube is placed in a vein of the other arm. The tubes are used for infusing saline (salt water) and for drawing blood samples. A pressure cuff is placed around the upper part of the dominant arm, and a rubber band device called a strain gauge is also placed around the arm to measure blood flow. When the cuff is inflated, blood flows into the arm, stretching the strain gauge at a rate proportional to the flow. Grip-strength of the dominant arm is measured with a dynamometer to determine maximum grip-strength. Then, several measurements of blood flow, nitrite, hemoglobin, and handgrip are made before and after administration of L-NMMA, a drug that blocks endothelial production of nitric oxide.
- Part B - Part A testing is repeated, except that sodium nitrite dissolved in a saline solution is infused into the artery of the forearm for a few minutes before and during the hand-grip exercises. In addition, blood samples are drawn before and after each handgrip exercise to measure methemoglobin, a substance that, at excessive levels, can cause adverse side effects.
Read the detailed description
Nitric oxide (NO) is a soluble gas continuously synthesized by the endothelium and contributes importantly to vasodilator tone of the coronary and systemic circulations by activating guanylyl cyclase in vascular smooth muscle, causing relaxation. Although regional synthesis of NO by the endothelium contributes to local vasodilator tone, we have shown previously that NO may be transported in blood, and have biological effects at a distance from the site of entry into the circulation. Thus, we found that NO may be transported bound to heme iron in red blood cells and released at vascular sites of deficient NO synthesis, restoring vasodilator tone. Another potential source of bioactive NO is via nitrite, formed by the auto-oxidation of NO. This study is designed to determine the contribution of nitrite transported in blood to forearm microvascular dilator tone in healthy subjects at rest and during regional hypoxia associated with forearm exercise stress, with measurements made before and after regional blockade of endothelial NO synthesis. Findings in this study may be relevant to understanding the physiological contribution and therapeutic potential of nitrite in the regulation of vasodilator tone in diseases and conditions associated with regional endothelial dysfunction and reduced endothelial NO bioactivity (e.g., hypertension, diabetes mellitus, hypercholesterolemia, cigarette smoking, estrogen deficiency).
- Conditions
- Nitric Oxide, Endothelium-Derived Relaxing Factor, Healthy
- Being tested
- L-NMMA and Sodium Nitrite
- Keywords
- Endothelium, Vasodilation, Exercise, Hemoglobin, Blood Flow, Healthy Volunteer, HV
- Medical subject headings
- Aneurysm, Motor Activity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-NMMA and Sodium NitriteDrug
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Nov 2002 (estimated)
- Study startOct 2002
- Study completionNov 2003
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Nitric OxideStudies of the same condition, open and under way.
- More trials run by National Heart, Lung, and Blood Institute (NHLBI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Enrolment
- 42 participants
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00048477
- Sponsor's protocol ID
- 030020
- Other IDs
- 03-H-0020
- Status last verified
- Nov 2003
- First submitted
- 31 Oct 2002
- Last updated
- 4 Mar 2008
- Results posted
- No
Publications
Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980 Nov 27;288(5789):373-6. doi: 10.1038/288373a0.
PubMed 6253831Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987 Jun 11-17;327(6122):524-6. doi: 10.1038/327524a0.
PubMed 3495737Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988 Jun 16;333(6174):664-6. doi: 10.1038/333664a0.
PubMed 3131684
Study at a glance
From the registry record, last updated by the sponsor on 4 Mar 2008. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Determination of Nitrite as a Source of Bioactive Nitric Oxide in Human Subjects
- ClinicalTrials.gov ID
- NCT00048477
- Acronym / sponsor ID
- 030020
- Conditions
- Nitric Oxide, Endothelium-Derived Relaxing Factor, Healthy
- Keywords
- Endothelium, Vasodilation, Exercise, Hemoglobin, Blood Flow, Healthy Volunteer, HV
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 42 participants
- Lead sponsor
- National Heart, Lung, and Blood Institute (NHLBI)US National Institutes of Health
- Study start
- Oct 2002
- Study completion
- Nov 2003
- First posted
- 1 Nov 2002 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Nitric oxide gas is important in regulating blood vessel dilation, and consequently, blood flow. This gas is continuously produced by endothelial cells, which line the blood vessels. This study will examine whether nitrite, a molecule that normally circulates in the blood stream, can also dilate blood vessels. The results of this study may be valuable in developing treatments for people with conditions associated with impaired endothelial production of nitric oxide, including high blood pressure, high blood cholesterol, diabetes, estrogen deficiency, and others.
Healthy, non-smoking normal volunteers 21 years of age or older may be eligible for this study. People who lack the enzyme G6PD or cytochrome B5 in their red blood cells may not participate. Absence of these enzymes can lead to episodes of sudden shortness of breath and cyanosis (blueness of the skin due to lack of sufficient oxygen). Participants will undergo the procedures described in study Parts A and B, as follows:
- Part A - After numbing the skin, small tubes are placed in the artery and vein at the inside of the elbow of the dominant arm (right- or left-handed) and a small tube is placed in a vein of the other arm. The tubes are used for infusing saline (salt water) and for drawing blood samples. A pressure cuff is placed around the upper part of the dominant arm, and a rubber band device called a strain gauge is also placed around the arm to measure blood flow. When the cuff is inflated, blood flows into the arm, stretching the strain gauge at a rate proportional to the flow. Grip-strength of the dominant arm is measured with a dynamometer to determine maximum grip-strength. Then, several measurements of blood flow, nitrite, hemoglobin, and handgrip are made before and after administration of L-NMMA, a drug that blocks endothelial production of nitric oxide.
- Part B - Part A testing is repeated, except that sodium nitrite dissolved in a saline solution is infused into the artery of the forearm for a few minutes before and during the hand-grip exercises. In addition, blood samples are drawn before and after each handgrip exercise to measure methemoglobin, a substance that, at excessive levels, can cause adverse side effects.
Detailed description
Nitric oxide (NO) is a soluble gas continuously synthesized by the endothelium and contributes importantly to vasodilator tone of the coronary and systemic circulations by activating guanylyl cyclase in vascular smooth muscle, causing relaxation. Although regional synthesis of NO by the endothelium contributes to local vasodilator tone, we have shown previously that NO may be transported in blood, and have biological effects at a distance from the site of entry into the circulation. Thus, we found that NO may be transported bound to heme iron in red blood cells and released at vascular sites of deficient NO synthesis, restoring vasodilator tone. Another potential source of bioactive NO is via nitrite, formed by the auto-oxidation of NO. This study is designed to determine the contribution of nitrite transported in blood to forearm microvascular dilator tone in healthy subjects at rest and during regional hypoxia associated with forearm exercise stress, with measurements made before and after regional blockade of endothelial NO synthesis. Findings in this study may be relevant to understanding the physiological contribution and therapeutic potential of nitrite in the regulation of vasodilator tone in diseases and conditions associated with regional endothelial dysfunction and reduced endothelial NO bioactivity (e.g., hypertension, diabetes mellitus, hypercholesterolemia, cigarette smoking, estrogen deficiency).
Study design
- Primary purpose
- Treatment
Who may qualify
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (1 listed)
- All volunteer subjects must be at least 21 years of age in good health and have provided informed, written consent for participation in this study.
Key exclusion criteria (7 listed)
- Subjects with a history or evidence of present or past hypertension (blood pressure greater than 145/95 mmHg), hypercholesterolemia (LDL cholesterol greater than 130 mg/dL), diabetes mellitus (fasting blood glucose greater than 130 mg/dL), smoking within two years, cardiovascular disease, peripheral vascular disease, coagulopathy, or any other disease predisposing to vasculitis or Raynaud's phenomenon.
- All subjects will be tested for red blood cell G6PD deficiency; levels below the lower limits of normal will result in exclusion from participation in the study.
- Subjects with a known cytochrome B5 deficiency will not participate in this study.
- Subjects with a history of reaction to a medication or other substance characterized by dyspnea and cyanosis will not participate in this study.
- Subjects with a baseline methemoglobin level greater than 1% will not receive nitrite infusions.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| L-NMMA and Sodium Nitrite | Drug | – |
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Mar 2008.
- Background: PubMed 6253831Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980 Nov 27;288(5789):373-6. doi: 10.1038/288373a0.
- Background: PubMed 3495737Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987 Jun 11-17;327(6122):524-6. doi: 10.1038/327524a0.
- Background: PubMed 3131684Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988 Jun 16;333(6174):664-6. doi: 10.1038/333664a0.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing L-NMMA and Sodium Nitrite in people with Nitric Oxide and Endothelium-Derived Relaxing Factor, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Mar 2008. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00048477, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Mar 2008.