Nitric Oxide System 1 Introduction

A relatively surprising addition to the family of chemical messengers is nitric oxide (NO). NO is a free radical gas of limited solubility in water. Since NO is

Renal Kininogen

Renal Kallikrein -

Inactive Phospholipase

Renal Kinin

(Kallidin = Lys-Bradykinin)

Active Phospholipase (+)

Membrane Phospholipid -

-Arachidonic Acid

Inhibits Na* reabsorption < (Renal tubule)

Cyclo-oxygenase -Cyclic Endoperoxides -

Prostaglandin Aj-«-(Active in renal cells) Prostaglandin E2-«-

FIGURE 15-16 Pathway for the generation of renal prostaglandins. See also Figure 15-16 for additional details of the kallikrein-kinin system and Chapter 16 for a detailed discussion of prostaglandin synthesis.

noncharged, it can rapidly diffuse across cell membranes and into cells; it has been shown to act as both an intracellular and an intercellular (paracrine) messenger to elicit a wide spectrum of biological responses. A physiological function for NO was first established in the vascular system when the endothelin-derived relaxing factor (EDRF) could be quantitatively explained by the formation of NO. NO is now known to be an integral participant in the signal transduction processes associated with the vascular, immune, and neural systems.

2. Chemistry, Biosynthesis, and Secretion

The formation of NO is an enzyme-mediated reaction (see Figure 15-17); the nitrogen donor is the amino acid L-arginine and the oxygen donor is molecular oxygen. The reaction is catalyzed by an NADPH requiring nitric oxide synthase (NOS). NOS enzymes are structurally related to cytochrome P450 reductase (see Chapter 2) and range in size from 130 to 160 kDa.

NOS exists both as a constitutive enzyme, which is regulated by Ca2+ and the calcium-binding protein, calmodulin, and as an inducible enzyme, which is not regulated by calmodulin. The regulatable forms of NOS are induced by interferon-« (INF-a), tumor necrosis factor-a (TNF-a), and interleukin-1/3 (IL-1/3) and inhibited by glucocorticoids. The inducible forms of NOS are associated with components of the host defense immune system.

3. Biological Actions of NO

The wide spectrum of biological actions of NO in the cardiovascular, nervous, and host defense systems is summarized in Table 15-9. Only the actions of NO in the cardiovascular system will be discussed in this chapter.

After the generation of NO in the endothelial cell by the NOS enzyme, the NO diffuses to an adjacent smooth muscle where it acts as an agonist to initiate biological responses (see Figure 15-18). Virtually all of the known biological actions of NO on the cardiovascular system are mediated by the activation of a soluble guanylate cyclase. The guanylate cyclase has heme as a prosthetic group, and NO binds tightly to this moiety. The resulting activation of the guanylate cyclase results in the production of cGMP, which is then postulated to have actions on protein kinases, nucleotide-sensitive phosphodiesterases, ion channels, or other unknown cellular proteins that are linked to the generation of the smooth muscle response of vasodilation and also to the inhibition of platelet adhesion and aggregation.

NO is a short-lived agonist in the cellular environment. NO is inactivated either by its chemical linkage nh, nh, c = nh n-h

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