Nitric Oxide Signaling

Nitric oxide is a very unusual molecule to be playing a role in physiological regulation. It is a volatile gas that can freely diffuse across cell membranes, and it has a very short half-life in the circulation.

We have already briefly encountered nitric oxide in the context of phagolysosomes. Nitric oxide is a free radical, and it is synthesized in phagolysosomes to act along with oxygen radicals in killing phagocytized microbes. (See web page on Oxygen Radicals).

In certain places, nitric oxide serves as a neurotransmitter. However it is very different from other neurotransmitters in that it can easily diffuse short distances and affect more than one cell.

An important role for nitric oxide is as a paracrine in the circulatory system. Nitric oxide produced by endothelial cells causes relaxation in vascular smooth muscle, leading to blood vessel dilation.

Nitric oxide is produced through activity of the enzyme nitric oxide synthase (NOS). There are three different forms of NOS that are named according to their site of action: endothelial NOS, neuronal NOS, and inducible NOS (which acts in phagocytes).

The figure shows how nitric oxide functions as a regulatory molecule. In target cells, nitric oxide activates an intracellular enzyme, soluble guanylyl cyclase, to catalyze the formation of the second messenger cyclic GMP (cGMP). cGMP activates protein kinases and other proteins to cause the cellular effects. In smooth muscle cells, this leads to a decrease in Ca++ in the cytosol, to cause relaxation of the smooth muscle and blood vessel dilation.

Several important drug actions revolve around nitric oxide. Nitroglycerin is converted to nitric oxide in the blood, which is why it dilates blood vessels in the heart. The drugs such as sildenafil (Viagra ®) that are used to treat erectile dysfunction act as phosphodiesterase inhbitors. They are fairly specific for the phosphodiesterase that is found in the smooth muscle surrounding blood vessels in the erectile tissues of the penis. Blocking the phosphodiesterase allows more cGMP to be present. This causes vascular smooth muscle relaxation and blood flow into the erectile tissues, which promotes erection.

Quick Quiz

Fill in Answer Correct False Correct Answer
1. Name the enzyme that produces nitric oxide.
2. What type of cell produces nitric oxide to cause blood vessel dilation? 
3. What second messenger increases in response to nitric oxide?
4. Does nitric oxide lead to smooth muscle relaxation or smooth muscle contraction?
5. Which of the following enzymes is the target for the drug sildenafil? [nitric oxide synthase; guanylyl cyclase, phosphodiesterase]

(Spelling must be correct)