Cardiovascular Physiology Concepts
                                    Richard E. Klabunde, Ph.D.

Metabolic Mechanisms of Vasodilation

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.

Several different mechanisms that may be involved in the metabolic regulation of blood flow are summarized below:

Hypoxia:

Decreased tissue pO₂ resulting from reduced oxygen supply or increased oxygen demand  causes vasodilation. Hypoxia-induced vasodilation may be direct (inadequate O₂ to sustain smooth muscle contraction) or indirect via the production of vasodilator metabolites. Note, however, that hypoxia induces vasoconstriction in the pulmonary circulation (i.e., hypoxic vasoconstriction), which likely involves the formation of reactive oxygen species, endothelin-1 or productions of arachidonic acid metabolism.

Tissue Metabolites and Ions:

Adenosine is formed from cellular AMP acted upon by 5'-nucleotidase. The AMP is derived from hydrolysis of intracellular ATP and ADP. Adenosine formation increases during hypoxia and increased oxygen consumption, especially if the latter is accompanied by inadequate oxygen delivery. Adenosine formation is a particularly important mechanism for regulating coronary blood flow.

Potassium ion is released by contracting cardiac and skeletal muscle. Small increases in extracellular K⁺ produces hyperpolarization of vascular smooth muscle and relaxation through stimulation of the electrogenic Na⁺/K⁺-ATPase pump and increasing membrane conductance to K⁺ (K⁺ activated K⁺ channels). Extracellular K⁺ increases when there is an increase in action potential frequency, because with each action potential K⁺, leaves the cell. Normally, the Na⁺/K⁺-ATPase pump is able to restore the ionic gradients; however, the pump does not keep up with rapid depolarizations (i.e., there is a time lag) during muscle contractions and this causes K⁺ to accumulate in the extracellular space. Potassium ion appears to play a significant role in causing active hyperemia in contracting skeletal muscle.

Carbon dioxide formation increases during states of increased oxidative metabolism. It readily diffuses from parenchymal cells in which it is produced to the vascular smooth muscle of blood vessels where it causes vasodilation. CO₂ plays a significant role in regulating cerebral blood flow.

Hydrogen ion increases when CO₂ increases or during states of increased anaerobic metabolism, which can produce metabolic acidosis. Like CO₂, increased H⁺ (decreased pH) causes vasodilation, particularly in the cerebral circulation.

Lactic acid, a product of anaerobic metabolism, is a vasodilator, although in large part because of its pH effect.

Inorganic phosphate is released by the hydrolysis of adenine nucleotides. It may have some vasodilatory activity in contracting skeletal muscle.

DISCLAIMER: These materials are for educational purposes only, and are not a source of medical decision-making advice.

© 1999-2008 Richard E. Klabunde, all rights reserved.