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Nitric oxide is an autacoid produced from arginine in the body, and the active metabolite of drugs that release it (NO donors); it is available as a drug in itself (NO gas). It interacts with iron in hemoglobin and can be inhibited by hemoglobin.


Nitric oxide (NO) is a product of the metabolism of arginine in many tissues. It is thought to be an important paracrine vasodilator, and it may also play a role in cell death and in neurotransmission; it therefore qualifies as an autacoid. NO is also released from several important vasodilator drug molecules.

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Endothelium-derived relaxing factor, EDRFA mixture of nitric oxide and other vasodilator substances synthesized in vascular endothelium
Nitric oxide donorA molecule from which nitric oxide can be released (eg, arginine, nitroprusside, nitroglycerin)
cNOS, iNOS, eNOSNaturally occurring isoforms of nitric oxide synthase: respectively, constitutive (NOS-1), inducible (NOS-2), and endothelial (NOS-3) isoforms

Endogenous NO is synthesized by a family of enzymes collectively called nitric oxide synthase (NOS), Figure 19–1. These intracellular enzymes are activated by calcium influx or by cytokines. Arginine, the primary substrate, is converted by NOS to citrulline and NO. Three forms of NO synthase are known: isoform 1 (bNOS, cNOS, or nNOS, a constitutive form found in epithelial and neuronal cells); isoform 2 (iNOS or mNOS, an inducible form found in macrophages and smooth muscle cells); and isoform 3 (eNOS, a constitutive form found in endothelial cells). NOS can be inhibited by arginine analogs such as NG-monomethyl-L-arginine (L-NMMA). Under some circumstances (eg, ischemia), NO may be formed from endogenous nitrate ion. NO is not stored in cells. Because it is a gas at body temperature, NO very rapidly diffuses from its site of synthesis to surrounding tissues. Drugs that cause endogenous NO release do so by stimulating its synthesis by NOS. Such drugs include muscarinic agonists, histamine, and certain other vasodilators (bradykinin, hydralazine).

Figure 19–1

The pathway for nitric oxide (NO) synthesis and release from NO-containing drugs and the mechanism of stimulation of cGMP (cyclic guanosine monophosphate) synthesis. The action of cGMP on smooth muscle relaxation is shown in Figure 12–3.

NO is released from several important drugs, including nitroprusside (Chapter 11), nitrates (Chapter 12), and nitrites. Release from nitroprusside occurs spontaneously in the blood in the presence of oxygen, whereas release from nitrates and nitrites is intracellular and requires the presence of the mitochondrial enzyme ALD2 and thiol compounds such as cysteine (see Chapter 12). Tolerance may develop to nitrates and nitrites if endogenous thiol compounds are depleted.

(See Chapter 6)

List the noninnervated receptors found in blood vessels and describe their second-messenger mechanisms of action. The Skill Keeper Answer ...

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