Blood flow is closely coupled to tissue metabolic activity in most organs of the body. For example, an increase in tissue metabolism, as occurs during muscle contraction or during changes in neuronal activity in the brain, leads to an increase in blood flow (active hyperemia). There is considerable evidence that actively metabolizing cells surrounding arterioles release vasoactive substances that cause vasodilation. This is termed the metabolic theory of blood flow regulation. Increases or decreases in metabolism lead to increases or decreases in the release of these vasodilator substances. These metabolic mechanisms ensure that the tissue is adequately supplied by oxygen and that products of metabolism (e.g., CO2, H+, lactate) are removed. Another mechanism that may couple blood flow and metabolism involves changes in the partial pressure of oxygen.