Effects of Nitrite on Blood Vessel Dilation in Normal Volunteers

Overview

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.

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).