derivatives stimulate pepsinogen secretion by a mechanism that can be antagonized by atropine,

indicating a muscarinic receptor. The receptor is an M1

type. Endogenous cholinergic stimulation

through the vagal nerve results in the formation of a gastric secretion that is rich in pepsin. Although

both exogenous histamine and gastrin can stimulate pepsin secretion, their actions appear to be

indirectly due to the concomitant secretion of gastric acid rather than to direct stimulation of chief cells.

Chief cells have also been shown to possess cholecystokinin receptors, and cholecystokinin-like peptides

appear to have a direct stimulatory action on chief cells. The oxyntic mucosa contains somatostatin cells

near chief cells. Pepsinogen secretion in response to a variety of stimuli has been demonstrated to be

inhibited by somatostatin.

The major physiologic function of pepsin is to initiate protein digestion. Pepsin is highly active

against collagen and may be important in the digestion of animal protein. Intragastric protein hydrolysis

by pepsin is incomplete, and relatively large peptides enter the intestine, although amino acids and

small peptide fragments are released. These products of partial hydrolysis are important signals for

gastrin and cholecystokinin release, which in turn regulate digestive processes. In this way, pepsin also

contributes to the overall coordination of the digestive process.

INTRINSIC FACTOR

6 The gastric mucosa is the site of production of intrinsic factor, which is necessary for the absorption of

cobalamin from the ileal mucosa. Total gastrectomy is regularly followed by cobalamin malabsorption,

as is resection of the proximal stomach or atrophic gastritis that involves the oxyntic mucosa.

Autoradiographic and immunocytochemical techniques have confirmed the parietal cell as the site of

intrinsic factor synthesis and storage in humans. Intrinsic factor secretion, like acid secretion, is

stimulated by histamine, acetylcholine, and gastrin. Unlike acid production, intrinsic factor secretion

peaks rapidly after stimulation and then returns to baseline. The amount of intrinsic factor secreted

usually greatly exceeds the amount needed to bind and absorb available dietary cobalamin.

GASTRIC BICARBONATE PRODUCTION

It is generally agreed that the gastric mucosa secretes HCO3− in addition to acid. The cells responsible

for HCO3− production are presumed to be the surface mucous cells facing the gastric lumen, and

HCO3− transport has been postulated to protect against damage from luminal acid. In theory, H+ ions

diffusing from luminal bulk fluids toward the gastric mucosa could be neutralized by secreted HCO3−

near the surface (Fig. 44-15). In this way, nearly neutral pH can be maintained at the mucosal surface,

even if the total amount of hydrochloride secreted greatly exceeds gastric HCO3− production. The

occurrence of pH gradients at the surface of the gastric mucosa have been demonstrated in humans

using microelectrodes. Drugs or chemicals that inhibit bicarbonate secretion result in acidification of the

mucosal surface.

The degree of luminal acidity, reflected by pH, required to stimulate bicarbonate secretion is greater

in the stomach than in the duodenum. Direct exposure of the gastric mucosa to pH levels of 2.0 or more

increases bicarbonate secretion. In the duodenum, exposure of the mucosa to pH 5.0 doubles

bicarbonate secretion, whereas exposure to pH 2.0 increases alkaline secretion 10-fold.

Cholinergic agonists, vagal nerve stimulation, and sham feeding have all been shown to increase

gastric HCO3− production. The effects of cholinergic stimulation can be blocked by atropine. In the

human stomach, exposure to luminal perfusates at pH 2.0 has been associated with increased release of

prostaglandin E2

. Prostaglandin E2 and its synthetic derivatives are also potent stimulants of gastric

bicarbonate secretion. Because mucosal bicarbonate production can be decreased in experimental

models by indomethacin, endogenous prostaglandins are thought to be important in the mucosal

alkaline response.

GASTRIC BLOOD FLOW

Because the gastric mucosa is metabolically highly active, control of mucosal blood flow is of great

physiologic importance. In addition, studies have implicated perfusion abnormalities in the development

of mucosal lesions during periods of stress. Mucosal blood flow is regulated by neural, hormonal, and

1159

locally active influences.

Postganglionic sympathetic nerve fibers reach the stomach in association with its blood supply and

richly innervate small mucosal arteries. Mucosal capillaries do not receive adrenergic innervation.

Electrical stimulation of sympathetic nerves supplying the stomach is followed by decreased total

gastric blood flow, decreased flow in celiac and gastroepiploic vessels, and diminished blood flow to the

mucosa. Studies in animals demonstrate that vasoconstriction of the gastric vascular bed is mediated by

α-adrenergic receptors and that vasodilation is mediated by β-adrenergic receptors.

Figure 44-15. Schematic representation of mucosal bicarbonate secretion showing neutralization of luminal hydrogen ions

immediately above the mucosal surface.

Stimulation of the vagus nerve is followed by a prompt increase in blood flow, suggesting a dilatory

effect of parasympathetic nerves. The effects of vagal stimulation on mucosal blood flow are

complicated by accompanying increases in acid secretion. Almost all stimuli that increase acid

production also increase blood flow secondarily.

A number of gastrointestinal peptide hormones affect gastric blood flow, most because of their ability

to increase or decrease acid secretion. Thus, gastrin, because it is a potent stimulant of acid secretion,

also increases mucosal blood flow. Cholecystokinin appears to have direct vasodilatory effects on the

gastric vasculature. Vasopressin has been well demonstrated to have direct vasoconstrictor activity.

Nitric oxide modulates basal gastric vascular tone and controls gastric vasodilation and hyperemia.

Nitric oxide mediates the hyperemic response that accompanies increases in acid secretion, although the

molecule has no direct stimulatory role in acid production.

Prostaglandins are important mucosally produced compounds that have clear effects on the gastric

vasculature. Prostaglandins of the E class have been shown in animals and humans to increase gastric

blood flow at doses that decrease acid secretion. Indomethacin, in doses sufficient to inhibit

prostaglandin formation, decreases the diameter of submucosal blood vessels and reduces basal blood

flow. Complete inhibition of cyclooxygenase activity causes an approximate 50% reduction in resting

blood flow. These studies suggest that endogenous, locally produced prostaglandins are crucial to

maintaining basal gastric blood flow in humans and probably act in concert with endogenous nitric

oxide.

GASTRIC MOTILITY

Gastric Smooth Muscle

Consideration of gastric motility requires that the stomach be viewed in functional terms as two

different regions, the proximal one-third and the distal two-thirds. These areas are distinct in terms of

smooth muscle anatomy, electrical activity, and contractile function. The regions do not correspond to

the traditional anatomic divisions of fundus, corpus, and antrum.

In the proximal stomach, three layers of gastric smooth muscle can be distinguished: an outer

longitudinal layer, a middle circular layer, and an inner oblique layer. In the distal two-thirds of the

stomach, the longitudinal layer is most clearly defined, and the inner oblique layer is usually not

distinct. The gastric smooth muscle ends at the pylorus.

The smooth muscle of the proximal stomach is electrically stable, whereas the smooth muscle of the

distal stomach demonstrates spontaneous, repeated electrical discharges. Gastric smooth muscle exhibits

myoelectric activity that is based on a highly regular pattern called the slow wave.10 In the stomach,

1160

slow waves occur with a frequency of three cycles per minute. Slow waves do not, by themselves, lead

to gastric contractions, but they do set the maximum rate of contractions at three per minute. Gastric

contractions occur when action potentials are phase locked with the crest of the slow wave.

Extracellular electrical recording from the serosal surface of the stomach also demonstrates the

intrinsic electrical activity of the distal stomach in the form of pacesetter potentials. Pacesetter

potentials reflect partial depolarization of the gastric smooth muscle cell and are recorded during

relatively long periods (2 or 3 seconds). Pacesetters originate along the greater curvature at a point in

the proximal third of the stomach. Pacesetter potentials, discharging at a rate of three times per minute

in humans, drive cells located distally. Spread of the pacesetter potentials is faster along the greater

curvature, so that a ring of electrical activity reaches the pylorus simultaneously along both curvatures.

The pacesetter potentials do not result in smooth muscle contraction unless an additional depolarization

is superimposed in the form of an action potential. When action potentials occur, a ring of smooth

muscle contraction moves peristaltically along the distal stomach toward the pylorus.

Duodenal slow-wave frequency and maximum rate of phasic contractions are higher than those

observed in the stomach. The duodenal rate is approximately 12 cycles per minute; the contraction rate

declines progressively to nine cycles per minute in the distal ileum.

The smooth muscle activity of the proximal stomach is fundamentally different from that of the distal

stomach. There are no pacesetters or action potentials in the proximal stomach. As a result, peristalsis

does not occur. Proximal gastric contraction is tonic and prolonged, and increases in luminal pressure

are often sustained for several minutes.

Coordination of Contraction

Important vagally mediated reflexes influence intragastric pressure, presumably by affecting contractile

activity of smooth muscle in the proximal stomach. The most important reflex is termed receptive

relaxation and occurs with ingestion of a meal. Increasing gastric volumes are accommodated with little

increase in intragastric pressure by relaxation of the proximal stomach. This receptive relaxation allows

the proximal stomach to act as a storage site for ingested food in the immediate postprandial period.

Afferent impulses, presumed to originate from stretch receptors in the gastric wall, are carried along

vagal fibers; efferent vagal discharges are inhibitory. Receptive gastric accommodation is lost after

either truncal or proximal gastric vagotomy. After the meal has been ingested, proximal contractile

activity increases; alterations in proximal gastric tone cause the compressive movement of gastric

content from the fundus to the antrum.

Food that enters the antrum from the proximal stomach is propelled peristaltically toward the

pylorus. A number of observations indicate that the pylorus closes 2 or 3 seconds before the arrival of

the antral contraction ring. This coordinate closing of the pylorus allows a small bolus of liquid and

suspended food particles to pass while retropulsing the main mass of gastric contents back into the

proximal antrum. The churning action that results, mixes ingested food particles, gastric acid, and

pepsin, and contributes to the grinding function of the stomach. Solid food particles do not ordinarily

pass the pylorus unless they are no larger than 1 mm.

A consistent finding in humans ingesting a mixed solid–liquid meal is that liquids empty more quickly

than solids. Characteristically, solid food empties only after a lag period, whereas liquid emptying

begins almost immediately. A traditional interpretation of these human observations has been that the

proximal stomach is the dominant force in determining how quickly a liquid meal empties by the

gastroduodenal pressure gradient generated by proximal gastric contractions. The actions of the

proximal stomach in liquid emptying are also regulated by the sieving actions of the antropyloric

segment and are modified by the nutrient composition of the ingested meal. The distal gastric segment

has been postulated to control solid emptying through its grinding and peristaltic actions. This

traditional concept of the two-component stomach is useful in considering observations in patients who

have undergone gastric operative procedures. Patients who have undergone proximal gastric vagotomy

exhibit accelerated emptying of liquids but have normal solid emptying. Because of loss of receptive

relaxation, the denervation of the proximal stomach is presumed to increase intragastric pressure and

accelerate liquid emptying while leaving the distal gastric segment unaffected. Conversely, vagal

denervation of the antrum interrupts gastric emptying of solids to a greater degree than liquids.

Although this model of gastric emptying oversimplifies the many mechanisms (gastric, pyloric, and

intestinal) that work in concert to control gastric emptying, it provides a useful framework for

considering the effects of gastric surgical procedures.

1161