The Role of Nitrite in Preconditioning Mediated Tolerance to Ischemic Stress

Overview

Many studies have shown that if the human body is stressed by a lack of blood flow for a short period of time, the body develops defenses to make the body more resistant to a future stress from lack of blood flow. This natural defense system is called preconditioning. Finding medications that have a preconditioning effect to protect against damage from loss of blood flow would be of great help in the treatment of diseases such as heart attacks and stroke that occur because of blockages of blood flow. Predicting future heart attacks or strokes is very difficult and makes it difficult to study medications that could have a preconditioning effect. However, it has recently been recognized that we can mimic the preconditioning effect in the human arm, by blocking blood flow using a blood pressure cuff under pressure. Here, blowing up the cuff for 5 minutes and then letting the pressure out for 5 minutes and repeating this process twice more (a way to precondition the arm), has been shown to improve blood vessel function in response to a longer period of blood pressure cuff inflation (20 minutes). As nitrite, a naturally occurring blood substance, has biological effects suggesting that it may mimic preconditioning. The main objective of this study is to assess whether nitrite is equivalent to preconditioning in its capacity to protect the forearm blood flow in response to a 20 minute blockage of blood flow by blood pressure cuff inflation of the forearm. We hypothesize that in human subjects the ischemic preconditioning program works through activation of the pool of nitrite in the blood stream. Moreover, we propose that nitrite treatment will improve (1) blood vessel recovery (2) skeletal muscle blood flow and (3) skeletal muscle mitochondrial function and (4) reduce the activation of inflammation in response to the 20 minute stress of blood pressure cuff inflation.

Many studies have shown that if the human body is stressed by a lack of blood flow for a short period of time, the body develops defenses to make the body more resistant to a future stress from lack of blood flow. This natural defense system is called preconditioning. Finding medications that have a preconditioning effect to protect against damage from loss of blood flow would be of great help in the treatment of diseases such as heart attacks and stroke that occur because of blockages of blood flow. Predicting future heart attacks or strokes is very difficult and makes it difficult to study medications that could have a preconditioning effect. However, it has recently been recognized that we can mimic the preconditioning effect in the human arm, by blocking blood flow using a blood pressure cuff under pressure. Here, blowing up the cuff for 5 minutes and then letting the pressure out for 5 minutes and repeating this process twice more (a way to precondition the arm), has been shown to improve blood vessel function in response to a longer period of blood pressure cuff inflation (20 minutes). As nitrite, a naturally occurring blood substance, has biological effects suggesting that it may mimic preconditioning. The main objective of this study is to assess whether nitrite is equivalent to preconditioning in its capacity to protect the forearm blood flow in response to a 20 minute blockage of blood flow by blood pressure cuff inflation of the forearm. We hypothesize that in human subjects the ischemic preconditioning program works through activation of the pool of nitrite in the blood stream. Moreover, we propose that nitrite treatment will improve (1) blood vessel recovery (2) skeletal muscle blood flow and (3) skeletal muscle mitochondrial function and (4) reduce the activation of inflammation in response to the 20 minute stress of blood pressure cuff inflation.