Nitrite Infusion Studies
|ClinicalTrials.gov Identifier: NCT00102271|
Recruitment Status : Completed
First Posted : January 26, 2005
Last Update Posted : July 2, 2017
This study will examine 1) how nitrite (a natural blood substance that relaxes blood vessels) increases blood flow and lowers blood pressure, and 2) how to increase the effects of nitrite on blood pressure.
Healthy volunteers between 21 and 40 years of age may be eligible for this study. They must be non-smokers and have no history of high blood pressure, high cholesterol, or diabetes. Candidates are screened with a medical history, physical examination, electrocardiogram, and blood tests. This study is either done in the NIH Clinical Center intensive care unit or on the general clinical ward. Participants are enrolled in Part A of the study. After completion of Part A participants will be enrolled in Part B of the study.
Participants lie in a reclining chair during the study. Small catheters (plastic tubes) are inserted into an artery and vein in the forearm. Another tube is placed in the vein of the opposite arm. Blood pressure cuffs are placed around the upper arm and wrist, and a strain gauge (a rubber band-like device) is placed around the forearm. This device helps us to measure blood flow through the arm. When the blood pressure cuffs are inflated, blood flows into the forearm, stretching the strain gauge at a rate proportional to the blood flow. Pressure cuffs and a strain gauge are also placed on the other arm. After 20 minutes, blood pressure and blood flow are measured in both forearms. Then blood is drawn from the tube in the right vein to measure blood counts, proteins, and other chemicals. Participants then are given small doses of either saline, ascorbic acid, or a medicine called oxypurinol, a form of a drug that is often taken to prevent gout. After 30 minutes, sodium nitrite is injected in increasing doses into the artery for 30 minutes. Blood flow is measured and blood is drawn every 5 minutes during the infusion. At the end of the 30 minutes, blood is drawn from the vein every 30 minutes for 3 hours. After 3 hours, sodium nitrite infusions are restarted for 2 hours and blood flow is measured and samples collected every 30 minutes during this period.
Part B: Participants lie in a reclining chair during the study. A small catheter (plastic tube) is placed in the artery of the left forearm to draw blood samples. A larger catheter called a central line is placed in a deeper vein in the neck. Another tube is advanced through the central line into the chambers of the heart, through the heart valve, and into the lung artery to measure pressures in the heart and lungs. Blood is drawn after 30 minutes to obtain baseline measurements. Then saline (sterile salt water) is put into the tube in the lung artery. Blood pressure cuffs are placed around the upper arm and wrist, and a strain gauge (a rubber band-like device) is placed around the forearm, which helps us to measure flow through the arm. When the cuffs are inflated, blood flows into the forearm, stretching the strain gauge at a rate proportional to the blood flow. Pressure cuffs and a strain gauge are also placed on the other arm. After 20 minutes, blood pressure and blood flow are measured in the forearm and blood samples are drawn from the tube in the left artery to measure blood counts, proteins, and other chemicals.
Subjects then breathe a mixture of oxygen and nitrogen through a facemask for 30 minutes, then room air for 30 minutes, and then the oxygen and nitrogen mixture for another 30 minutes. While breathing the mixture the second time, sodium nitrite is injected through the tube in the artery in three increasing doses for 5 minutes each. Every 5 minutes during the infusion blood is drawn from the tubes in the neck. Forearm blood flow is also measured every 5 minutes. After 30 minutes, the subject breathes room air for 3 hours and 15 minutes and then the sodium nitrite is injected again in three increasing doses for 5 minutes each. Every 5 minutes during the infusion blood is taken from the tube in the neck and forearm blood flow is measured
|Condition or disease||Intervention/treatment||Phase|
|Healthy||Drug: Oxypurinol Drug: Sodium Nitrite||Phase 1|
Although regional synthesis of nitric oxide (NO) by the endothelium contributes importantly to local vasodilator tone, we have previously shown that NO bioactivity may be transported in blood, and have biological effects at a distance from the site of entry into the circulation. These endocrine effects of NO are mediated by intravascular NO-stores - candidates are protein and heme-bound NO species (RXNO) in plasma or erythrocytes and the oxidative NO-metabolite nitrite. Cumulating evidence suggests that nitrite may serve as a major intravascular storage pool for NO. Recent studies by our group show that regional, intra-arterial infusion of nitrite elicits downstream vasodilator response. The mechanism of nitrite reduction in vivo may involve a number of pathways. We have observed that nitrite is reduced to NO by its reaction with deoxyheme proteins. This chemistry suggests a role for hemoglobin and other heme proteins as an oxygen dependent nitrite reductase and further that nitrite ions might contribute to systemic hypoxic vasodilation. Other research groups have proposed pH-dependent mechanisms, the involvement of electron donors such as ascorbic acid, or xanthinoxidase as a reducing agent.
The present study will be conducted in two stages (Parts A and B) with the following objectives: Part A will determine 1) whether systemic (intravenous) infusion of nitrite modulates vascular tone in the systemic circulation, 2) whether oxypurinol (a potent inhibitor of xanthine oxidase activity) lowers or ascorbic acid potentiates nitrite-induced vasodilation, 3) elucidate the pharmacokinetic profile of nitrite application in humans and 4) determine phase I data for dosing nitrite in human disease. Part B will determine whether the systemic and pulmonary vascular responses to nitrite infusion are potentiated under hypoxic conditions and are mediated by NO gas per se as measured by NO content in exhaled breath.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||36 participants|
|Official Title:||Evaluation of the Mechanism of NO Formation and Pharmacokinetics of Systemic Nitrite Infusion|
|Study Start Date :||January 19, 2005|
|Actual Study Completion Date :||April 12, 2011|
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00102271
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|