Adenosine is a naturally occurring purine nucleoside that forms from the breakdown of adenosine triphosphate (ATP). ATP is the primary energy source in cells for transport systems and many enzymes. Most ATP is hydrolyzed to ADP, which can be further dephosphorylated to AMP. Most ADP and AMP that form in the cell is rephosphorylated in the mitochondria by enzymatic reactions requiring oxygen. If there are large amounts of ATP hydrolyzed, and especially if there is insufficient oxygen available (i.e., hypoxia), then some of the AMP can be further dephosphorylated to adenosine by the cell membrane associated enzyme, 5'-nucleotidase.
Adenosine can bind to purinergic receptors in different cell types where it can produce a number of different physiological actions. One important action is vascular smooth muscle relaxation, which leads to vasodilation. This is a particularly important mechanism for matching coronary blood flow to the metabolic needs of the heart. In coronary vascular smooth muscle, adenosine binds to adenosine type 2A (A2A) receptors, which are coupled to the Gs-protein. Activation of this G-protein stimulates adenylyl cyclase (AC in figure), increases cAMP and causes protein kinase activation. This stimulates KATP channels, which hyperpolarizes the smooth muscle, causing relaxation. Increased cAMP also causes smooth muscle relaxation by inhibiting myosin light chain kinase, which leads to decreased myosin phosphorylation and a decrease in contractile force. There is also evidence that adenosine inhibits calcium entry into the cell through L-type calcium channels. Since calcium regulates smooth muscle contraction, reduced intracellular calcium causes relaxation. In some types of blood vessels, there is evidence that adenosine produces vasodilation through increases in cGMP, which leads to inhibition of calcium entry into the cells as well as opening of potassium channels.
In cardiac tissue, adenosine binds to type 1 (A1) receptors, which are coupled to Gi-proteins. Activation of this pathway opens potassium channels, which hyperpolarizes the cell. Activation of the Gi-protein also decreases cAMP, which inhibits L-type calcium channels and therefore calcium entry into the cell. In cardiac pacemaker cells located in the sinoatrial node, adenosine acting through A1 receptors inhibits the pacemaker current (If), which decreases the slope of phase 4 of the pacemaker action potential thereby decreasing its spontaneous firing rate (negative chronotropy). Inhibition of L-type calcium channels also decreases conduction velocity (negative dromotropic effect) particularly at the atrioventricular (AV) nodes. Finally, adenosine by acting on presynaptic purinergic receptors located on sympathetic nerve terminals inhibits the release of norepinephrine. In terms of its electrical effects in the heart, adenosine decreases heart rate and reduces conduction velocity, especially at the AV node, which can produce atrioventricular block. Note, however, that when adenosine is infused into humans, heart rate increases because of baroreceptor reflexes caused by systemic vasodilation and hypotension.
DISCLAIMER: These materials are for educational purposes only, and are not a source of medical decision-making advice.