Cardiac Muscle Resembles Skeletal Muscle In Many Respects

The general picture of muscle contraction in the heart resembles that of skeletal muscle. Cardiac muscle, like skeletal muscle, is striated and uses the actin-myosin-tropomyosin-troponin system described above. Unlike skeletal muscle, cardiac muscle exhibits intrinsic rhyth-micity, and individual myocytes communicate with each other because of its syncytial nature. The T tubular system is more developed in cardiac muscle, whereas the sarcoplasmic reticulum is less extensive and consequently the intracellular supply of Ca2+ for contraction is less. Cardiac muscle thus relies on extracellular Ca2+ for contraction; if isolated cardiac muscle is deprived of Ca2+, it ceases to beat within approximately 1 minute, whereas skeletal muscle can continue to contract without an extracellular source of Ca2+. Cyclic AMP plays a more prominent role in cardiac than in skeletal muscle. It modulates intracellular levels of Ca2+ through the activation of protein kinases; these enzymes phosphorylate various transport proteins in the sarcolemma and sarcoplasmic reticulum and also in the troponin-tropomyosin regulatory complex, affecting intracellular levels of Ca2+ or responses to it. There is a rough correlation between the phosphorylation of Tpl and the increased contraction of cardiac muscle induced by catecholamines. This may account for the in-otropic effects (increased contractility) of P-adrenergic compounds on the heart. Some differences among skeletal, cardiac, and smooth muscle are summarized in

Table 49-3.

Ca2+ Enters Myocytes via Ca2+ Channels & Leaves via the Na -Ca2' Exchanger & the Ca2+ ATPase

As stated above, extracellular Ca2+ plays an important role in contraction of cardiac muscle but not in skeletal muscle. This means that Ca2+ both enters and leaves myocytes in a regulated manner. We shall briefly consider three transmembrane proteins that play roles in this process.

A. Ca2+ Channels_

Ca2+ enters myocytes via these channels, which allow entry only of Ca2+ ions. The major portal of entry is the

Figure 49-12. Organization of dystrophin and other proteins in relation to the plasma membrane of muscle cells. Dystrophin is part of a large oligomeric complex associated with several other protein complexes. The dystroglycan complex consists of a-dystroglycan, which associates with the basal lamina protein merosin, and p-dystroglycan, which binds a-dystroglycan and dystrophin. Syntrophin binds to the carboxyl terminal of dystrophin. The sarcogly-can complex consists of four transmembrane proteins: a-, p-, y-, and 8-sarcoglycan. The function of the sarcoglycan complex and the nature of the interactions within the complex and between it and the other complexes are not clear. The sarcoglycan complex is formed only in striated muscle, and its subunits preferentially associate with each other, suggesting that the complex may function as a single unit. Mutations in the gene encoding dystrophin cause Duchenne and Becker muscular dystrophy; mutations in the genes encoding the various sarcoglycans have been shown to be responsible for limb-girdle dystrophies (eg, MIM 601173). (Reproduced, with permission, from Duggan DJ et al: Mutations in the sarcoglycan genes in patients with myopathy. N Engl J Med 1997;336:618.)

Figure 49-12. Organization of dystrophin and other proteins in relation to the plasma membrane of muscle cells. Dystrophin is part of a large oligomeric complex associated with several other protein complexes. The dystroglycan complex consists of a-dystroglycan, which associates with the basal lamina protein merosin, and p-dystroglycan, which binds a-dystroglycan and dystrophin. Syntrophin binds to the carboxyl terminal of dystrophin. The sarcogly-can complex consists of four transmembrane proteins: a-, p-, y-, and 8-sarcoglycan. The function of the sarcoglycan complex and the nature of the interactions within the complex and between it and the other complexes are not clear. The sarcoglycan complex is formed only in striated muscle, and its subunits preferentially associate with each other, suggesting that the complex may function as a single unit. Mutations in the gene encoding dystrophin cause Duchenne and Becker muscular dystrophy; mutations in the genes encoding the various sarcoglycans have been shown to be responsible for limb-girdle dystrophies (eg, MIM 601173). (Reproduced, with permission, from Duggan DJ et al: Mutations in the sarcoglycan genes in patients with myopathy. N Engl J Med 1997;336:618.)

L-type (long-duration current, large conductance) or slow Ca2+ channel, which is voltage-gated, opening during depolarization induced by spread of the cardiac action potential and closing when the action potential declines. These channels are equivalent to the dihy-dropyridine receptors of skeletal muscle (Figure 49-8). Slow Ca2+ channels are regulated by cAMP-dependent protein kinases (stimulatory) and cGMP-protein ki-nases (inhibitory) and are blocked by so-called calcium channel blockers (eg, verapamil). Fast (or T, transient) Ca2+ channels are also present in the plasmalemma, though in much lower numbers; they probably contribute to the early phase of increase of myoplasmic Ca2+.

The resultant increase of Ca2+ in the myoplasm acts on the Ca2+ release channel of the sarcoplasmic reticulum to open it. This is called Ca2+-induced Ca2+ release

(CICR). It is estimated that approximately 10% of the Ca2+ involved in contraction enters the cytosol from the extracellular fluid and 90% from the sarcoplasmic reticulum. However, the former 10% is important, as the rate of increase of Ca2+ in the myoplasm is important, and entry via the Ca2+ channels contributes appreciably to this.

This is the principal route of exit of Ca2+ from myo-cytes. In resting myocytes, it helps to maintain a low level of free intracellular Ca2+ by exchanging one Ca2+ for three Na+. The energy for the uphill movement of Ca2+ out of the cell comes from the downhill movement of Na+ into the cell from the plasma. This exchange contributes to relaxation but may run in the re

Table49-3. Some differences between skeletal, cardiac, and smooth muscle.

Skeletal Muscle

Cardiac Muscle

Smooth Muscle

1. Striated.

1. Striated.

1. Nonstriated.

2. No syncytium.

2. Syncytial.

2. Syncytial.

3. Small T tubules.

3. Large T tubules.

3. Generally rudimentary T tubules.

4. Sarcoplasmic reticulum well-developed and Ca2+ pump acts rapidly.

4. Sarcoplasmic reticulum present and Ca2+ pump acts relatively rapidly.

4. Sarcoplasmic reticulum often rudimentary and Ca2+ pump acts slowly.

5. Plasmalemma lacks many hormone receptors.

5. Plasmalemma contains a variety of receptors (eg, a- and ß-adrenergic).

5. Plasmalemma contains a variety of receptors (eg, a- and p-adrenergic).

6. Nerve impulse initiates contraction.

6. Has intrinsic rhythmicity.

6. Contraction initiated by nerve impulses, hormones, etc.

7. Extracellular fluid Ca2+ not important for contraction.

7. Extracellular fluid Ca2+ important for contraction.

7. Extracellular fluid Ca2+important for contraction.

8. Troponin system present.

8. Troponin system present.

8. Lacks troponin system; uses regulatory head of myosin.

9. Caldesmon not involved.

9. Caldesmon not involved.

9. Caldesmon is important regulatory protein.

10. Very rapid cycling of the cross-bridges.

10. Relatively rapid cycling of the cross-bridges.

10. Slow cycling of the cross-bridges permits slow prolonged contraction and less utilization of ATP.

verse direction during excitation. Because of the Ca2+-Na+ exchanger, anything that causes intracellular Na+ (Na+j) to rise will secondarily cause ing more forceful contraction. This is referred to as a positive inotropic effect. One example is when the drug digitalis is used to treat heart failure. Digitalis inhibits the sarcolemmal Na+-K+ ATPase, diminishing exit of Na+ and thus increasing Na+;. This in turn causes Ca2+ to increase, via the Ca2+-Na+ exchanger. The increased Ca2+; results in increased force of cardiac contraction, of benefit in heart failure.

This Ca2+ pump, situated in the sarcolemma, also contributes to Ca2+ exit but is believed to play a relatively minor role as compared with the Ca2+-Na+ exchanger.

It should be noted that there are a variety of ion channels (Chapter 41) in most cells, for Na+, K+, Ca2+, etc. Many of them have been cloned in recent years and their dispositions in their respective membranes worked out (number of times each one crosses its membrane, location of the actual ion transport site in the protein, etc). They can be classified as indicated in Table 49-4. Cardiac muscle is rich in ion channels, and they are also important in skeletal muscle. Mutations in genes encoding ion channels have been shown to be responsible for a number of relatively rare conditions affecting muscle. These and other diseases due to mutations of ion channels have been termed channelopathies; some are listed in Table 49-5.

Table 49-4. Major types of ion channels found in cells.

Type

Comment

External ligand-gated

Open in response to a specific extracellular molecule, eg, acetylcholine.

Internal ligand-gated

Open or close in response to a specific intracellular molecule, eg, a cyclic nucleotide.

Voltage-gated

Open in response to a change in membrane potential, eg, Na+, K+, and Ca2+ channels in heart.

Mechanically gated

Open in response to change in mechanical pressure.

Table 49-5. Some disorders (channelopathies) due to mutations in genes encoding polypeptide constituents of ion channels.1

Disorder2

Ion Channel and Major Organs Involved

Central core disease (MIM 117000)

Ca2+ release channel (RYR1) Skeletal muscle

Cystic fibrosis (MIM 219700)

CFTR (Cl- channel) Lungs, pancreas

Hyperkalemic periodic paralysis (MIM 170500)

Sodium channel Skeletal muscle

Hypokalemic periodic paralysis (MIM 114208)

Slow Ca2+ voltage channel (DHPR) Skeletal muscle

Malignant hyperthermia (MIM 180901)

Ca2+ release channel (RYR1) Skeletal muscle

Myotonia congenita (MIM 160800)

Chloride channel Skeletal muscle

1Data in part from Ackerman NJ, Clapham DE: Ion channelsbasic science and clinical disease. N Engl J Med 1997;336:1575. 2Other channelopathies include the long QT syndrome (MIM 192500); pseudoaldosteronism (Liddle syndrome, MIM 177200); persistent hyperinsulinemic hypoglycemia of infancy (MIM 601820); hereditary X-linked recessive type II nephrolithiasis of infancy (Dent syndrome, MIM 300009); and generalized myotonia, recessive (Becker disease, MIM 255700). The term "myotonia" signifies any condition in which muscles do not relax after contraction.

Inherited Cardiomyopathies Are Due to Disorders of Cardiac Energy Metabolism or to Abnormal Myocardial Proteins

An inherited cardiomyopathy is any structural or functional abnormality of the ventricular myocardium due to an inherited cause. There are nonheritable types of cardiomyopathy, but these will not be described here. As shown in Table 49-6, the causes of inherited cardiomyopathies fall into two broad classes: (1) disorders of cardiac energy metabolism, mainly reflecting mutations in genes encoding enzymes or proteins involved in fatty acid oxidation (a major source of energy for the myocardium) and oxidative phosphorylation; and (2) mutations in genes encoding proteins involved in or affecting myocardial contraction, such as myosin, tropomyosin, the troponins, and cardiac myosin-binding protein C. Mutations in the genes encoding these latter proteins cause familial hypertrophic car-diomyopathy, which will now be discussed.

Table 49-6. Biochemical causes of inherited cardiomyopathies.1,2

Cause

Proteins or Process Affected

Inborn errors of fatty acid oxidation

Carnitine entry into cells and mitochondria Certain enzymes of fatty acid oxidation

Disorders of mitochondrial oxidative phosphorylation

Proteins encoded by mito-

chondrial genes Proteins encoded by nuclear genes

Abnormalities of myocardial contractile and structural proteins

ß-Myosin heavy chains, troponin, tropomyosin, dys-trophin

1Based on Kelly DP, Strauss AW: Inherited cardiomyopathies. N Engl J Med 1994;330:913.

2Mutations (eg, point mutations, or in some cases deletions) in the genes (nuclear or mitochondrial) encoding various proteins, enzymes, or tRNA molecules are the fundamental causes of the inherited cardiomyopathies. Some conditions are mild, whereas others are severe and may be part of a syndrome affecting other tissues.

Mutations in the Cardiac ^-Myosin Heavy Chain Gene Are One Cause of Familial Hypertrophic Cardiomyopathy

Familial hypertrophic cardiomyopathy is one of the most frequent hereditary cardiac diseases. Patients exhibit hypertrophy—often massive—of one or both ventricles, starting early in life, and not related to any extrinsic cause such as hypertension. Most cases are transmitted in an autosomal dominant manner; the rest are sporadic. Until recently, its cause was obscure. However, this situation changed when studies of one affected family showed that a missense mutation (ie, substitution of one amino acid by another) in the P-myosin heavy chain gene was responsible for the condition. Subsequent studies have shown a number of missense mutations in this gene, all coding for highly conserved residues. Some individuals have shown other mutations, such as formation of an a/P-myosin heavy chain hybrid gene. Patients with familial hypertrophic cardiomyopa-thy can show great variation in clinical picture. This in part reflects genetic heterogeneity; ie, mutation in a number of other genes (eg, those encoding cardiac actin, tropomyosin, cardiac troponins I and T, essential and regulatory myosin light chains, and cardiac myosin-binding protein C) may also cause familial hypertrophic cardiomyopathy. In addition, mutations at different sites in the gene for P-myosin heavy chain may affect the function of the protein to a greater or lesser extent. The missense mutations are clustered in the head and head-rod regions of myosin heavy chain. One hypothesis is that the mutant polypeptides ("poison polypeptides") cause formation of abnormal myofibrils, eventually resulting in compensatory hypertrophy. Some mutations alter the charge of the amino acid (eg, substitution of arginine for glutamine), presumably affecting the conformation of the protein more markedly and thus affecting its function. Patients with these mutations have a significantly shorter life expectancy than patients in whom the mutation produced no alteration in charge. Thus, definition of the precise mutations involved in the genesis of FHC may prove to be of important prognostic value; it can be accomplished by appropriate use of the polymerase chain reaction on genomic DNA obtained from one sample of blood lymphocytes. Figure 49-13 is a simplified scheme of the events causing familial hypertrophic cardiomyopathy.

Another type of cardiomyopathy is termed dilated cardiomyopathy. Mutations in the genes encoding dys-trophin, muscle LIM protein (so called because it was found to contain a cysteine-rich domain originally detected in three proteins: Lin-II, Isl-1, and Mec-3), and the cyclic response-element binding protein (CREB) have been implicated in the causation of this condition. The first two proteins help organize the contractile apparatus of cardiac muscle cells, and CREB is involved

Figure 49-13. Simplified scheme of the causation of familial hypertrophic cardiomyopathy (MIM 192600) due to mutations in the gene encoding P-myosin heavy chain. Mutations in genes encoding other proteins, such as the troponins, tropomyosin, and cardiac myosin-binding protein C can also cause this condition. Mutations in genes encoding yet other proteins (eg, dystrophin) are involved in the causation of dilated cardiomyopathy.

Figure 49-13. Simplified scheme of the causation of familial hypertrophic cardiomyopathy (MIM 192600) due to mutations in the gene encoding P-myosin heavy chain. Mutations in genes encoding other proteins, such as the troponins, tropomyosin, and cardiac myosin-binding protein C can also cause this condition. Mutations in genes encoding yet other proteins (eg, dystrophin) are involved in the causation of dilated cardiomyopathy.

in the regulation of a number of genes in these cells. Current research is not only elucidating the molecular causes of the cardiomyopathies but is also disclosing mutations that cause cardiac developmental disorders (eg, septal defects) and arrhythmias (eg, due to mutations affecting ion channels).

Ca2+ Also Regulates Contraction of Smooth Muscle

While all muscles contain actin, myosin, and tropo-myosin, only vertebrate striated muscles contain the troponin system. Thus, the mechanisms that regulate contraction must differ in various contractile systems.

Smooth muscles have molecular structures similar to those in striated muscle, but the sarcomeres are not aligned so as to generate the striated appearance. Smooth muscles contain a-actinin and tropomyosin molecules, as do skeletal muscles. They do not have the troponin system, and the light chains of smooth muscle myosin molecules differ from those of striated muscle myosin. Regulation of smooth muscle contraction is myosin-based, unlike striated muscle, which is actin-based. However, like striated muscle, smooth muscle contraction is regulated by Ca2+.

Phosphorylation of Myosin Light Chains Initiates Contraction of Smooth Muscle

When smooth muscle myosin is bound to F-actin in the absence of other muscle proteins such as tropomyosin, there is no detectable ATPase activity. This absence of activity is quite unlike the situation described for striated muscle myosin and F-actin, which has abundant ATPase activity. Smooth muscle myosin contains light chains that prevent the binding of the myosin head to F-actin; they must be phosphorylated before they allow F-actin to activate myosin ATPase. The ATPase activity then attained hydrolyzes ATP about tenfold more slowly than the corresponding activity in skeletal muscle. The phosphate on the myosin light chains may form a chelate with the Ca2+ bound to the tropomyosin-TpC-actin complex, leading to an increased rate of formation of cross-bridges between the myosin heads and actin. The phosphorylation of light chains initiates the attachment-detachment contraction cycle of smooth muscle.

Myosin Light Chain Kinase Is Activated by Calmodulin-4Ca2+ & Then Phosphorylates the Light Chains

Smooth muscle sarcoplasm contains a myosin light chain kinase that is calcium-dependent. The Ca2+ activation of myosin light chain kinase requires binding of caImoduIin-4Ca2+ to its kinase subunit (Figure 49-14).

Calmodulin

Myosin kinase (inactive)

Ca • calmodulin

L-myosin (inhibits myosin-actin interaction)

L-myosin (inhibits myosin-actin interaction)

H2PO,

Figure 49-14. Regulation of smooth muscle contraction by Ca2+. pL-myosin is the phosphorylated light chain of myosin; L-myosin is the dephosphorylated light chain. (Adapted from Adelstein RS, Eisenberg R: Regulation and kinetics of actin-myosin ATP interaction. Annu Rev Biochem 1980;49:921.)

Ca2+ • CALMODULIN-MYOSIN KINASE (ACTIVE)

pL-myosin (does not inhibit myosin-actin interaction)

Ca2+ • CALMODULIN-MYOSIN KINASE (ACTIVE)

pL-myosin (does not inhibit myosin-actin interaction)

H2PO,

Figure 49-14. Regulation of smooth muscle contraction by Ca2+. pL-myosin is the phosphorylated light chain of myosin; L-myosin is the dephosphorylated light chain. (Adapted from Adelstein RS, Eisenberg R: Regulation and kinetics of actin-myosin ATP interaction. Annu Rev Biochem 1980;49:921.)

The calmodulin-4Ca2+-activated light chain kinase phosphorylates the light chains, which then ceases to inhibit the myosin-F-actin interaction. The contraction cycle then begins.

Smooth Muscle Relaxes When the Concentration of Ca2+ Falls Below 10-7 Molar

Relaxation of smooth muscle occurs when sarcoplasmic Ca2+ falls below 10-7 mol/L. The Ca2+ dissociates from calmodulin, which in turn dissociates from the myosin light chain kinase, inactivating the kinase. No new phosphates are attached to the p-light chain, and light chain protein phosphatase, which is continually active and calcium-independent, removes the existing phosphates from the light chains. Dephosphorylated myosin p-light chain then inhibits the binding of myosin heads to F-actin and the ATPase activity. The myosin head detaches from the F-actin in the presence of ATP, but it cannot reattach because of the presence of dephos-phorylated p-light chain; hence, relaxation occurs.

Table 49-7 summarizes and compares the regulation of actin-myosin interactions (activation of myosin ATPase) in striated and smooth muscles.

The myosin light chain kinase is not directly affected or activated by cAMP. However, cAMP-activated protein kinase can phosphorylate the myosin light chain kinase (not the light chains themselves). The phosphorylated myosin light chain kinase exhibits a significantly lower affinity for calmodulin-Ca2+ and thus is less sensitive to activation. Accordingly, an increase in cAMP dampens the contraction response of smooth muscle to a given elevation of sarcoplasmic Ca2+. This molecular mechanism can explain the relaxing effect of P-adrenergic stimulation on smooth muscle.

Another protein that appears to play a Ca2+-depen-dent role in the regulation of smooth muscle contraction is caldesmon (87 kDa). This protein is ubiquitous in smooth muscle and is also found in nonmuscle tissue. At low concentrations of Ca2+, it binds to tro-pomyosin and actin. This prevents interaction of actin with myosin, keeping muscle in a relaxed state. At higher concentrations of Ca2+, Ca2+-calmodulin binds caldesmon, releasing it from actin. The latter is then free to bind to myosin, and contraction can occur. Caldesmon is also subject to phosphorylation-dephos-phorylation; when phosphorylated, it cannot bind actin, again freeing the latter to interact with myosin. Caldesmon may also participate in organizing the structure of the contractile apparatus in smooth muscle. Many of its effects have been demonstrated in vitro, and its physiologic significance is still under investigation.

As noted in Table 49-3, slow cycling of the cross-bridges permits slow prolonged contraction of smooth muscle (eg, in viscera and blood vessels) with less utilization of ATP compared with striated muscle. The ability of smooth muscle to maintain force at reduced velocities of contraction is referred to as the latch state; this is an important feature of smooth muscle, and its precise molecular bases are under study.

Nitric Oxide Relaxes the Smooth Muscle of Blood Vessels & Also Has Many Other Important Biologic Functions

Acetylcholine is a vasodilator that acts by causing relaxation of the smooth muscle of blood vessels. However, it does not act directly on smooth muscle. A key observation was that if endothelial cells were stripped away from underlying smooth muscle cells, acetylcholine no longer exerted its vasodilator effect. This finding indicated that vasodilators such as acetylcholine initially interact with the endothelial cells of small blood vessels via receptors. The receptors are coupled to the phos-phoinositide cycle, leading to the intracellular release of

Table 49-7. Actin-myosin interactions in striated and smooth muscle.

Striated Muscle

Smooth Muscle (and Nonmuscle Cells)

Proteins of muscle filaments

Actin Myosin Tropomyosin Troponin (Tpl, TpT, TpC)

Actin

Myosin1

Tropomyosin

Spontaneous interaction of F-actin and myosin alone (spontaneous activation of myosin ATPase by F-actin

Yes

No

Inhibitor of F-actin-myosin interaction (inhibitor of F-actin-dependent activation of ATPase)

Troponin system (Tpl)

Unphosphorylated myosin light chain

Contraction activated by

Ca2+

Ca2+

Direct effect of Ca2+

4Ca2+ bind to TpC

4Ca2+ bind to calmodulin

Effect of protein-bound Ca2+

TpC ■ 4Ca2+ antagonizes Tpl inhibition of F-actin-myosin interaction (allows F-actin activation of ATPase)

Calmodulin ■ 4Ca2+ activates myosin light chain kinase that phosphorylates myosin p-light chain. The phosphorylated p-light chain no longer inhibits F-actin-myosin interaction (allows F-actin activation of ATPase).

'Light chains of myosin are different in striated and smooth muscles.

'Light chains of myosin are different in striated and smooth muscles.

Ca2+ through the action of inositol trisphosphate. In turn, the elevation of Ca2+ leads to the liberation of en-dothelium-derived relaxing factor (EDRF), which diffuses into the adjacent smooth muscle. There, it reacts with the heme moiety of a soluble guanylyl cyclase, resulting in activation of the latter, with a consequent elevation of intracellular levels of cGMP (Figure 49-15). This in turn stimulates the activities of certain cGMP-dependent protein kinases, which probably phosphorylate specific muscle proteins, causing relaxation; however, the details are still being clarified. The important coronary artery vasodilator nitroglycerin, widely used to relieve angina pectoris, acts to increase intracellular release of EDRF and thus of cGMP.

Quite unexpectedly, EDRF was found to be the gas nitric oxide (NO). NO is formed by the action of the enzyme NO synthase, which is cytosolic. The endothelial and neuronal forms of NO synthase are activated by Ca2+ (Table 49-8). The substrate is arginine, and the products are citrulline and NO:

NO synthase catalyzes a five-electron oxidation of an amidine nitrogen of arginine. L-Hydroxyarginine is an intermediate that remains tightly bound to the en zyme. NO synthase is a very complex enzyme, employing five redox cofactors: NADPH, FAD, FMN, heme, and tetrahydrobiopterin. NO can also be formed from nitrite, derived from vasodilators such as glyceryl trinitrate during their metabolism. NO has a very short half-life (approximately 3-4 seconds) in tissues because it reacts with oxygen and superoxide. The product of the reaction with superoxide is peroxynitrite (ONOO-), which decomposes to form the highly reactive OH* radical. NO is inhibited by hemoglobin and other heme proteins, which bind it tightly. Chemical inhibitors of NO synthase are now available that can markedly decrease formation of NO. Administration of such inhibitors to animals and humans leads to vasoconstriction and a marked elevation of blood pressure, indicating that NO is of major importance in the maintenance of blood pressure in vivo. Another important cardiovascular effect is that by increasing synthesis of cGMP, it acts as an inhibitor of platelet aggregation (Chapter 51).

Since the discovery of the role of NO as a vasodilator, there has been intense experimental interest in this substance. It has turned out to have a variety of physiologic roles, involving virtually every tissue of the body (Table 49-9). Three major isoforms of NO synthase have been identified, each of which has been cloned, and the chromosomal locations of their genes in hu-

Glyceryl Acetylcholine

Glyceryl Acetylcholine

Figure 49-15. Diagram showing formation in an endothelial cell of nitric oxide (NO) from arginine in a reaction catalyzed by NO synthase. Interaction of an agonist (eg, acetylcholine) with a receptor (R) probably leads to intracellular release of Ca2+ via inositol trisphos-phate generated by the phosphoinositide pathway, resulting in activation of NO synthase. The NO subsequently diffuses into adjacent smooth muscle, where it leads to activation of guanylyl cyclase, formation of cGMP, stimulation of cGMP-protein kinases, and subsequent relaxation. The vasodilator nitroglycerin is shown entering the smooth muscle cell, where its metabolism also leads to formation of NO.

Figure 49-15. Diagram showing formation in an endothelial cell of nitric oxide (NO) from arginine in a reaction catalyzed by NO synthase. Interaction of an agonist (eg, acetylcholine) with a receptor (R) probably leads to intracellular release of Ca2+ via inositol trisphos-phate generated by the phosphoinositide pathway, resulting in activation of NO synthase. The NO subsequently diffuses into adjacent smooth muscle, where it leads to activation of guanylyl cyclase, formation of cGMP, stimulation of cGMP-protein kinases, and subsequent relaxation. The vasodilator nitroglycerin is shown entering the smooth muscle cell, where its metabolism also leads to formation of NO.

mans have been determined. Gene knockout experiments have been performed on each of the three iso-forms and have helped establish some of the postulated functions of NO.

To summarize, research in the past decade has shown that NO plays an important role in many physiologic and pathologic processes.

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