Nitric Oxide, Donors, & Inhibitors: Introduction
Nitric oxide is an autacoid produced within 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.
High-Yield Terms to Learn
Endothelium-derived relaxing factor, EDRF A mixture of nitric oxide and other vasodilator substances synthesized in vascular endothelium Nitric oxide donor A molecule from which nitric oxide can be released (eg, arginine, nitroprusside, nitroglycerin) cNOS, iNOS, eNOS Naturally occurring isoforms of nitric oxide synthase: respectively, constitutive (NOS-1), inducible (NOS-2), and endothelial (NOS-3) isoforms
Endogenous NO
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.
Exogenous NO Donors
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 enzymatic and intracellular and requires the presence of thiol compounds such as cysteine. Tolerance may develop to nitrates and nitrites if endogenous thiol compounds are depleted.
Skill Keeper: Noninnervated Receptors
(See Chapter 6)
List the noninnervated receptors found in blood vessels and describe their second-messenger mechanisms of action. The Skill Keeper Answer appears at the end of the chapter.
Effects of NO
Smooth Muscle
NO is a powerful vasodilator in all vascular beds and a potent relaxant in most other smooth muscle tissues. The mechanism of this effect involves activation of guanylyl cyclase (Figure 19-1) and the synthesis of cyclic guanosine monophosphate (cGMP). This cGMP, in turn, facilitates the dephosphorylation and inactivation of myosin light chains, which results in relaxation of smooth muscle (see Figure 12-3). NO plays a physiologic role in erectile tissue function, in which smooth muscle relaxation is required to bring about the influx of blood that causes erection. NO appears to be a pathophysiologic contributor to hypotension in septic shock.
Cell Adhesion
NO has effects on cell adhesion that result in reduced platelet aggregation and reduced neutrophil adhesion to vascular endothelium. The latter effect is probably due to reduced expression of adhesion molecules, for example, integrins, by endothelial cells.
Inflammation
Tissue injury causes NO synthesis, and NO appears to facilitate inflammation both directly and through the stimulation of prostaglandin synthesis by cyclooxygenase 2.
Other Effects
Some evidence suggests that NO may act as a neurotransmitter. NO also appears to be involved in some types of apoptosis and cell death.
Clinical Applications of NO Inhibitors & Donors
Although inhibitors of NO synthesis are of great research interest, none are currently in clinical use. NO can be inactivated by heme and hemoglobin, but application of this approach is in preclinical research.
In contrast, drugs that activate endogenous NO synthesis and donors of the molecule were in use long before NO was discovered and continue to be very important in clinical medicine. The cardiovascular applications of nitroprusside (Chapter 11) and the nitrates and nitrites (Chapter 12) have been discussed. The treatment of preeclampsia, pulmonary hypertension, and acute respiratory distress syndrome are currently under clinical investigation. Early results from pulmonary disease studies appear promising, and one preparation of NO gas (INOmax) has been approved for use in neonates with hypoxic respiratory failure.
Preclinical studies suggest that chronic use of NO donor drugs or dietary supplementation with arginine may assist in slowing atherosclerosis, especially in grafted organs. In contrast, acute rejection of grafts may involve upregulation of NOS enzymes, and inhibition of these enzymes may prolong graft survival.
Skill Keeper Answer: Noninnervated Receptors
(See Chapter 6)
Endothelial cells lining blood vessels have noninnervated muscarinic receptors. These M 3 receptors use the G q -coupling protein to activate phospholipase C, which releases inositol 1,4,5-trisphosphate and diacylglycerol from membrane lipids. eNOS is activated and NO is released, causing vasodilation. Histamine H 1 receptors are also found in the vascular endothelium and similarly cause vasodilation through the synthesis and release of NO. Other noninnervated (or poorly innervated) receptors found in blood vessels include 
2 and 
2 receptors. The 2 receptors use G i to inhibit adenylyl cyclase, reducing cyclic adenosine monophosphate (cAMP) and causing contraction in the vessel. (Recall that the blood pressure-lowering action of 2 agonists is mediated by actions in the CNS, not in the vessels.) Conversely, 2receptors activate adenylyl cyclase via G s and increase cAMP, resulting in relaxation.
Checklist
When you complete this chapter, you should be able to:
Name the enzyme responsible for the synthesis of NO in tissues.
List the major beneficial and toxic effects of endogenous NO.
List 2 drugs that cause release of endogenous NO.
List 2 drugs that spontaneously or enzymatically break down in the body to release NO.
Drug Summary Table: Nitric Oxide, Donors, & Inhibitors
Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Interactions Nitric oxide (NO) Nitric oxide gas Activates guanylyl cyclase, increases cGMP synthesis, causes smooth muscle relaxation Pulmonary hypertension Inhaled gas administered continuously Methemoglobinemia, conversion to nitrogen dioxide (a pulmonary irritant) Nitric oxide synthase (NOS) activatorsAcetylcholine, histamine, others Increased intracellular Ca2+ activates NOS, resulting in conversion of arginine to citrulline plus NO
See Chapters 7 and 16 Nitric oxide donors Nitroglycerin, other nitrates, nitroprusside Release NO in smooth muscle (nitrates) or in blood (nitroprusside); increase cGMP synthesis and cause relaxation in smooth muscle See Chapters 11 and 12
cGMP, cyclic guanosine monophosphate.