Primary Gastrointestinal Tract

The structural organization of the primary GI tract consists of a luminally oriented mucosa, submucosa, muscularis externa, and serosa (Fig. 1-2).¹ The mucosa consists of a superficial epithelium, lamina propria, and muscularis mucosae. Epithelial cells carry out digestive, secretory, and absorptive functions, as well as immune surveillance. The lamina propria consists of connective tissue, blood, and lymphatic vasculature. The muscularis mucosae is made up of smooth muscle cells that function primarily to change the shape and surface area of the epithelial cell layer in response to luminal distention. The submucosa consists of collagen, elastin, secretory glands, and major blood vessels. Motility of the GI tract is provided by circular and longitudinal layers of smooth muscle, interposed between the submucosa and serosa. Two nerve plexuses, the submucosal plexus and myenteric plexus, contain the intrinsic nervous system of the GI tract. The submucosal plexus (Meissner’s plexus) lies between the submucosa and the circular smooth muscle, and regulates the overlying epithelium. The myenteric plexus lies between the circular and longitudinal muscle layers, and regulates their contraction. The serosa is a thin external membrane consisting of a layer of serous fluid-secreting cells. Serous secretions serve to reduce friction from the muscular motion of the GI tract. Each segment of the primary GI tract has unique features that promote one or more of the GI functions (Fig. 1-3A to 1-3D).

Figure 1-2 General organizational structure of the primary gastrointestinal tract.

Figure 1-3 A, Microscopic structure of the esophagus (×400). B, Microscopic structure of the stomach (×400). C, Microscopic structure of the intestine (×400). D, Microscopic structure of the colon (×400). E, Microscopic structure of the pancreas (×400). F, Microscopic structure of the liver (×400).

(Courtesy of Dr. Arno Wuenschmann of the University of Minnesota.)

Pancreas

The pancreas contains exocrine and endocrine elements, which serve to regulate digestion and metabolism, respectively. The exocrine pancreas is a mixed tubuloalveolar or tubuloacinar gland. Acinar cells synthesize and secrete digestive enzyme into a ductal system for transport to the small intestine (Fig. 1-3E).^2,3 Islet cells of the endocrine pancreas are interspersed between the acinar and duct cells. The exocrine pancreas has four major physiologic functions: (a) acinar cell secretion of digestive zymogens, which initiate protein, carbohydrate, and lipid digestion; (b) acinar cell secretion of antibacterial proteins, which serve to regulate the small intestinal bacterial flora; (c) ductal cell secretion of bicarbonate and water, which serves to hydrate and neutralize the duodenal pH; and (d) ductal cell secretion of pancreatic intrinsic factor, which facilitates cobalamin (vitamin B₁₂) binding and absorption in the distal ileum.^2,3 The exocrine pancreas does not have a direct arterial blood supply. Acinar cells are instead perfused by venous blood emanating from islet vasa efferentia via an islet–acinar portal system.⁴ Arterial blood first perfuses the islets, which secrete their hormones (e.g., insulin, glucagon) into the postcapillary venules and veins that then perfuse the acinar cells. The endocrine pancreas thereby autoregulates exocrine secretions and pancreatic growth. The efferent nerve supply to the pancreas includes both sympathetic and parasympathetic fibers. Sympathetic postganglionic fibers arise from the celiac and cranial mesenteric plexuses and accompany the arteries to the exocrine pancreas. Parasympathetic preganglionic fibers are distributed by branches of the vagi traversing the stomach and duodenum and terminate at the acini, islets, or intrinsic cholinergic nerves of the pancreas. In general, parasympathetic nerve fibers stimulate exocrine pancreatic secretion, and sympathetic nerve fibers inhibit exocrine pancreatic secretion.⁵

Liver

The hepatic lobule is the anatomic unit of the liver. In the anatomic model, liver lobules are organized into irregular polygons demarcated by connective tissue and composed of plates of hepatocytes radiating outward from the central vein to the portal triads (Fig. 1-3F). The hepatic acinus is the functional unit of the liver. In the functional model, hepatocytes are instead oriented around the afferent vascular system (portal veins and hepatic arteries) just as they anastomose into sinusoids (Fig. 1-3F), and the central vein is at the periphery of the acinus instead of centrally located as in the anatomic model. The acinus is divided into three contiguous zones (1-3) that correspond to distance from the arterial blood supply. Hepatocytes closest to the arterioles (zone 1) receive the greatest oxygen content, but are also the first to be affected by toxins transported from the gut to the portal vein. Zone 3 hepatocytes reside at the periphery of the acinus near the central vein, and zone 2 hepatocytes are interspersed between zones 1 and 3. The anatomic model is perhaps easier to understand, but the functional model serves as a better foundation for understanding liver pathology.^6,7

In either model, portal venous and arterial blood flows centripetally, that is, toward the central vein, whereas bile flows centrifugally, that is, away from the central vein. Hepatocytes extract nutrients and oxygen from portal and arterial perfusion, respectively, and produce bile acids and other bile constituents that are transported from hepatocytes into bile canaliculi, ductules, and ducts.⁸ Hepatocytes account for 60% of the liver cell mass and contribute to the wide range of metabolic activities described in the preceding section. Hepatocytes are supported by other cell types, which account for 40% of the liver cell mass.

Parasympathetic Innervation

Parasympathetic innervation is supplied by the vagus and pelvic nerves. The vagus innervates the upper GI tract, and the pelvic nerve innervates the lower GI tract. Parasympathetic neurons have long preganglionic fibers that synapse in ganglia in or near the target organs. Postganglionic neurons of the parasympathetic nervous system are classified as either cholinergic or peptidergic. Cholinergic neurons release acetylcholine (ACh) as the neurotransmitter, whereas peptidergic neurons release one or more enteric neuropeptides, including substance P (SP), vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), and gastrin-releasing peptide (GRP). The vagus nerve is a mixed nerve in which 75% of the fibers are afferent and 25% are efferent. Afferent fibers transmit sensory information from mechanoreceptors and chemoreceptors in the wall of the GI tract to the central nervous system (CNS). Efferent fibers deliver motor information from the CNS back to cells in the periphery, for example, smooth muscle, secretory, and endocrine cells. Thus, mechanoreceptors and chemoreceptors in the GI mucosa relay afferent information to the CNS via the vagus nerve, which triggers reflexes whose efferent limb is also in the vagus nerve.

Sympathetic Innervation

Sympathetic innervation is supplied by spinal segments T1 to L3 of the thoracolumbar spinal cord. As part of the “fight-versus-flight” response, the sympathetic nerves innervate the heart, blood vessels, bronchi, and GI tract. Sympathetic neurons have short preganglionic fibers that synapse at ganglia (celiac, superior mesenteric, inferior mesenteric, and hypogastric) outside the GI tract. Postganglionic neurons of the sympathetic nervous system are adrenergic and release norepinephrine as the neurotransmitter. Approximately 50% of the sympathetic nerve fibers are afferent and 50% are efferent. As with parasympathetic innervation, sensory and motor information is relayed between the GI tract and the CNS, and is coordinated by the submucosal and myenteric plexuses.

Intrinsic Innervation

The ganglia of the enteric nervous system are located in the submucosal and myenteric plexuses, and control the contractile, secretory, and endocrine functions of the gut.^15,16 Enteric ganglia receive inputs from the parasympathetic and sympathetic nervous systems, which serve to modulate their activity. Enteric neurons are cholinergic, adrenergic, and/or peptidergic, and may secrete one or more neurotransmitters (Fig. 1-5).

Innervation and Gap Junctions

Skeletal muscle contraction is voluntary and under the regulation of the somatic nervous system. Each skeletal muscle cell is innervated by a motoneuron, and each muscle fiber behaves as a single unit. Smooth muscle, on the other hand, is involuntary and under the regulation of the autonomic nervous system. GI smooth muscles are only sparsely innervated (referred to as unitary smooth muscle), and it is instead the gap junctions that permit the rapid spread of electrical activity from cell to cell followed by coordinated contraction. The multiunit smooth muscles of the iris and vas deferens have fewer gap junctions and little or no coupling between cells, and therefore are more dependent upon neural activation.

Sarcomeric Organization

Smooth muscle lacks striations because the thick and thin filaments are not organized into sarcomeres as they are in skeletal or cardiac muscle.

Nuclear Density

During embryonic development, skeletal muscle fibers develop through the fusion of myoblasts into multinucleated skeletal muscle cells. Nuclei are usually found at the periphery of the muscle fiber and the contractile proteins (e.g., myosin, active, troponin) are located more centrally in the fiber. Smooth muscle cells typically are uninucleate.

Spread of Depolarization

The rapid spread of depolarization of striated muscle is facilitated by an extensive transverse T-tubule system coupled to the sarcoplasmic reticulum. Smooth muscles are devoid of the T-tubule system and instead rely on a system of subplasmalemmal caveolae representing invaginations of the cell membrane. Caveolae link extracellular stimuli with intracellular effectors in smooth muscle cells. Caveolae, and their integral caveolin proteins, are believed to be the smooth muscle equivalent of the T-tubule system of striated muscle.

Regulatory Proteins

Contraction of striated muscle is a thin-filament regulated process. Ca²⁺ binds to troponin C, one of the thin filament proteins, producing a conformational change in the troponin–tropomyosin complex. The conformational change permits binding of actin to the myosin heads, activation of myosin adenosine triphosphatase (ATPase), and cross-bridge cycling. Contraction of smooth muscle is instead a thick-filament regulated process. Troponin C is not expressed in smooth muscle, and Ca²⁺ instead binds to the calcium-binding protein, calmodulin. In turn Ca²⁺–calmodulin activates myosin light-chain kinase, permitting phosphorylation of the 20-kDa myosin light chains, activation of myosin ATPase, and cross-bridge cycling (Fig. 1-6).¹⁸

Figure 1-6 Biochemical activation of smooth muscle contraction.

(From Costanzo L (ed): Physiology, 4^th ed. Philadelphia: Saunders, 2010.)

Sources of Calcium

Striated muscle cells derive calcium solely from internal stores, specifically the sarcoplasmic reticulum. Depolarization of the T-tubule system causes a conformational change in its voltage-sensitive dihydropyridine receptor, which, in turn, causes opening of the Ca²⁺-release channel in the adjacent sarcoplasmic reticulum. Many GI smooth muscles have a similar dependence on sarcoplasmic reticulum Ca²⁺ release, but most smooth muscles also have a major (or minor) dependence on influx of extracellular Ca²⁺ through voltage-gated, ligand-gated, and inositol triphosphate (IP₃)-gated Ca²⁺ channels (Fig. 1-7).

Figure 1-7 Dependence of gastrointestinal smooth muscle contraction upon extracellular and intracellular sources of Ca²⁺. ATP, adenosine triphosphate; Ca, calcium; G, G protein; IP₃, inositol tris-phosphate; PIP₂, phosphatidyl inositol bisphosphate; PLC, phospholipase C; R, receptor.

(From Costanzo L (ed): Physiology, 4^th ed. Philadelphia: Saunders, 2010.)

Contractile Patterns

Length–tension and force–velocity relationships are apparent in both striated and smooth muscles, although some differences have been noted. Tetanic or tonic contractions are physiologically possible in striated muscle, but most striated muscle contractions are of the twitch or phasic type. Contractions of GI smooth muscle can be either phasic or tonic. Phasic contractions are periodic contractions followed by relaxation. Phasic contractions are often propagating and are found in the esophageal body, gastric antrum, small intestine, and colon. Tonic contractions maintain a constant level of contraction or tone with only intermittent periods of relaxation. They are found in the gastric fundus and in the gastroesophageal, pyloric, ileocolic, and internal anal sphincters.

Slow Waves

Action potentials in smooth muscle are triggered by oscillating depolarization and repolarization waves referred to as “slow waves.”¹⁹ Slow waves are a unique feature of the electrical activity of GI smooth muscle. The origin of the slow waves is still unsettled,²⁰ but it has been proposed that slow waves originate in the interstitial cells of Cajal (ICC) in the myenteric plexus.¹⁹ Cyclic depolarizations and repolarizations of the ICC are postulated to rapidly spread to adjacent smooth muscle via low-resistance gap junctions. In this way the ICC could serve as “pacemakers” and set the slow wave frequency (from 3 to 12 slow waves per minute) along the GI tract. When slow waves depolarize the membrane potential to threshold, action potentials are superimposed on top of the slow waves giving rise to strong contractions.¹⁹

Bioenergetics

Smooth muscles contract much slower (P_max t_1/2 = 70 sec; shortening velocity = 0.12 L/sec) than striated muscle, but they nonetheless achieve the same overall force production (S = 223 mN/mm²; see Table 1-2). Smooth muscles can develop and maintain this force at surprisingly low adenosine triphosphate (ATP) consumption (J_ATP = 1.2 µmol/g/min). Consequently smooth muscle contraction is more economical from a bioenergetics standpoint. It is this property (high-force output at low ATP consumption) that permits some smooth muscles, notably the GI tract sphincters, to maintain tone for prolonged periods of time.

Oropharynx and Esophagus

In the oropharyngeal phase of swallowing, the animal prehends food and water with teeth and tongue, masticates and mechanically reduces the size of the food particles, forms a bolus at the base of the tongue, and propels the bolus caudally to the cricoesophageal sphincter. The sphincter relaxes and the bolus passes into the cranial esophageal body. Oropharyngeal mechanoreceptors transmit mechanical forces through an afferent neural pathway to the brainstem and efferent neural pathway to induce cricopharyngeal relaxation, esophageal body contraction, and primary esophageal peristalsis. Following swallowing, the cricopharyngeus contracts, pharyngeal muscles relax, and the oropharyngeal phase is repeated until feeding is completed (Fig. 1-8).

Figure 1-8 Regulation of oropharyngeal and esophageal motility. CES, Cricoesophageal sphincter; GES, gastroesophageal sphincter.

Aside from fluid and electrolyte secretion, the major physiologic function of the esophagus is the transport of ingested liquids and solids from the oral cavity to the stomach. Anatomic structures that permit this function are the striated muscle of the cranial esophageal sphincter (cricopharyngeus), the striated and smooth muscle of the esophageal body, and the smooth muscle of the caudal esophageal (gastroesophageal) sphincter. An important species difference between the dog and cat is in the musculature of the esophageal body. The full length of the canine esophageal body is composed of striated muscle, whereas the distal one-third to one-half of the feline esophageal body is composed of smooth muscle. The striated muscle of the cranial esophageal sphincter and esophageal body are innervated by somatic branches (glossopharyngeal, pharyngeal, and recurrent laryngeal) of the vagus nerve arising from the brainstem nucleus ambiguus. The smooth muscle of the esophageal body and caudal esophageal sphincter are innervated by autonomic branches (esophageal) of the vagus nerve arising from the dorsal motor nucleus of the vagus.^21,22

Primary peristaltic contractions associated with swallowing are reinforced by a secondary wave of contraction (secondary peristalsis) mediated physiologically by esophageal intraluminal distention. The gastroesophageal sphincter relaxes in advance of the propagated pressure wave to permit food to empty into the stomach. Once the bolus of food has passed into the stomach, the gastroesophageal sphincter resumes its high resting pressure.^23,24

Stomach

Anatomically, the stomach is composed of five distinct components: cardia, fundus, corpus, antrum, and pylorus. Physiologically, the stomach behaves as a two-component structure: a proximal stomach (cardia, fundus, first one-third of the corpus) characterized by slow tonic contractions, and a distal stomach (distal two-thirds of the corpus and antrum) characterized by phasic propagating contractions (Fig. 1-9).²⁵ Slow waves without action potentials give rise to the sustained tonic contractions of the proximal stomach. During swallowing, gastroesophageal sphincter and intragastric pressure decrease to accommodate emptying of solids and liquids. This phenomenon, referred to as receptive relaxation, takes place with each swallow, and as a consequence, large volumes can be accommodated with minimal increases in intragastric pressure. The proximal stomach becomes much less compliant with fundic disease or fundectomy.

Figure 1-9 Tonic and phasic contractions in the regulation of gastric emptying.

A pacemaker site in the proximal fundus of the greater curvature generates action potentials and phasic contractions that propagate from the site of origin circumferentially and distally to the pylorus.²⁶ During feeding, phasic contractions of the distal stomach trigger a repetitive cycle of propulsion, trituration, and retropulsion that progressively reduces the size of the ingesta. Thus, the peristaltic qualities of the distal stomach regulate the emptying of solid particles into the duodenum. Antral disease or antrectomy abolishes this physiologic effect resulting in a “dumping syndrome” as a result of accelerated gastric emptying, nutrient overload in the small intestine, and osmotic diarrhea.

Gastric emptying is regulated by several physiologic parameters, including (a) pyloric resistance and pressure differential between the stomach and duodenum; (b) water content—liquids are emptied more rapidly than solids; (c) nutrient composition—carbohydrates are emptied more rapidly than proteins which, in turn, are emptied more rapidly than lipids; (d) nutrient acidity—delayed at acid or alkaline pH; (e) nutrient osmolality—delayed at high osmolality; and (f) hot or cold temperatures. Duodenal, jejunal, and ileal braking mechanisms also feedback inhibit gastric emptying through activation of mucosal sensory receptors for fatty acids, tryptophan, osmolality, and acid. Intestinal braking mechanisms serve to prolong transit time and nutrient contact time.²⁵

During the fasting state the stomach is ordinarily empty, aside from swallowed saliva, a small amount of mucus, and cellular debris that collects in the gastric lumen. In addition, there may be particles of indigestible solids left from the previous meal. A mechanism exists to empty this fasting content: the migrating motility complex (MMC). The ability of the MMC to completely empty the stomach of residue is so striking that it is sometimes referred to as the “interdigestive housekeeper” of the GI tract.²⁵ The GI hormone, motilin, is involved in the regulation of the MMC. Cats and rabbits do not have an MMC, but instead have a less vigorous emptying pattern known as the migrating spike complex (MSC).^27,28

Intestine

Contractions in the small intestine serve three general functions: mixing of the ingesta with digestive enzymes and other secretions; circulation of the intestinal contents to facilitate contact with the intestinal mucosa; and net caudal propulsion of the intestinal contents. Intestinal contractions are governed by four motility patterns: segmentation, peristalsis, intestinointestinal inhibition, and the MMC.²⁹

Segmentation

If a contraction is not coordinated with activity above and below, intestinal contents are displaced both proximally and distally during the contraction and may, in fact, move cranially during the period of relaxation. Such contractions appear to divide the bowel into segments, which accounts for the term segmentation given to the process. Segmentation serves to mix and locally circulate the intestinal contents. Segmentation primarily involves circular smooth muscle contraction (Fig. 1-10).

Figure 1-10 Segmentation and peristalsis patterns of the small intestine.

Colon

The colon serves two important functions: (a) extraction of water and electrolytes from the luminal contents in the ascending and transverse colon and (b) storage of feces and control of defecation in the descending colon.³¹ This specialization of function has been attributed to regional differences in colonic motility patterns. Electrical slow-wave frequency and rhythmic phasic contractions are slower in the proximal colon (cecum and ascending colon), thus facilitating extraction of water from the fecal mass by diffusion and active transport. Retrograde giant contractions and anti-peristalsis further facilitate mixing of contents in the proximal colon. In contrast, motility of the distal colon (transverse and descending colon) is characterized primarily by migrating spike bursts and powerful giant migrating contractions that propagate the fecal mass toward the rectum (Fig. 1-11).^31,32

Figure 1-11 Motility patterns of the proximal and distal colon.

Gallbladder

During fasting, the gallbladder is relaxed and stores bile. When feeding resumes, hormonal (cholecystokinin) and neural (acetylcholine) mechanisms stimulate simultaneous gallbladder contraction and sphincter of Oddi relaxation, thereby facilitating emptying of bile into the small intestine.³³

Salivary Gland

Dogs and cats both have four sets of salivary glands: parotid, mandibular, sublingual, and zygomatic, all under autonomic regulation. The structural unit of the salivary gland is the salivon, consisting of acinar cells, which secrete the initial fluid and mucin; intercalated ducts, which form a short connection to the striated ducts; striated ducts, which are composed of epithelial cells and which modify the final ionic composition; and myoepithelial cells, which contract and serve to expel salivary fluid into the oropharynx (Fig. 1-12).

Figure 1-12 The salivon—the anatomic unit of the salivary gland.

Salivary secretions have five major functions: (a) hydration for mastication and deglutition; (b) evaporative cooling; (c) secretion of immunoglobulin (Ig) A; (d) HCO₃⁻ (bicarbonate) buffering prior to the initiation of digestion; and (e) release of R factor binding proteins for vitamin B₁₂ transport.^34,35 Salivary amylase, which initiates starch digestion in man, is not found in dog or cat saliva.³⁴ Primary secretion from the acinus contains Na⁺, Cl⁻, and HCO₃⁻ actively transported from the blood to gland and duct. As saliva is transported down the collecting ducts, it is further modified by exchange of Na⁺ for H⁺ and K⁺ and active reabsorption of Na⁺ and Cl⁻. At high flow rates, the salivary composition will resemble the primary secretion because there is less time for modification along the ducts (Fig. 1-13).³⁴

Figure 1-13 Composition of salivary secretion at low and high secretory rates.

(From Costanzo L (ed): Physiology, 4^th ed. Philadelphia: Saunders, 2010.)

Stomach

As a secretory organ, the stomach has several major functions, including initiation of protein digestion; inactivation of ingested bacteria, viruses, and parasites; secretion and binding of intrinsic factor to vitamin B₁₂; absorption of ferric iron; hormonal regulation of gastric and pancreatic secretions; mucous lubrication of the gastric contents; and protection of the gastric mucosa from the caustic effects of protons and pepsins.³⁶ The stomach accomplishes these diverse functions through the secretions of the gastric pit, the structural unit of the gastric mucosa. Gastric pits are branched tubular invaginations bearing multiple cell types and having multiple secretory functions: (a) parietal or oxyntic cells secrete protons and intrinsic factor; (b) chief cells secrete pepsinogens; (c) endocrine cells secrete the hormones gastrin and ghrelin; (d) surface epithelial cells secrete HCO₃⁻ and prostanoids; (e) neck and surface mucous cells secrete mucus containing sulfated glycoproteins; and (f) enterochromaffin cells secrete histamine (Table 1-3, Fig. 1-14).³⁶

Table 1-3 Cell Types, Secretions, and Functions in the Gastric Mucosa

Figure 1-14 The gastric pit—the anatomic unit of gastric secretion.

Physiology of Gastric Acid Secretion

The basal, cephalic, gastric, and intestinal phases of gastric acid secretion³⁶ were first characterized by Pavlov in his now-classic work on conditioned reflexes in the dog at the turn of the last century. Basal phase secretion is that small amount of gastric acid secretion that takes place in the absence of anticipation or physiologic stimulus. Along with the MMC, basal acid secretion serves to moderate bacterial flora and to degrade indigestible solids in the interdigestive state. The cephalic phase of gastric acid secretion results from olfactory, visual, and auditory cues, as well as from the mastication and swallowing of food. The cephalic phase accounts for 20% to 30% of the total acid secretory load and is mediated by vagal postganglionic neurons that stimulate parietal secretion directly or indirectly via gastrin release. The gastric phase accounts for 50% to 60% of the total acid secretory load and is mediated by the direct and indirect effects of gastric distention and amino acids on parietal and antral G cells (Fig. 1-15). The intestinal phase accounts for up to 10% of gastric acid secretion and is mediated by the effects of intraduodenal amino acids.

Figure 1-15 Cephalic and gastric phase regulation of gastric acid secretion. ACh, acetylcholine; GRP, gastrin-releasing peptide; HCl, hydrochloric acid.

(From Costanzo L (ed): Physiology, 4^th ed. Philadelphia: Saunders, 2010.)

Pharmacology of Gastric Acid Secretion

Parietal cells are stimulated directly and indirectly by neural (acetylcholine), endocrine (gastrin), and paracrine (histamine) mechanisms.³⁶ In a neural mechanism, depolarization of vagal postganglionic nerve fibers releases ACh which then binds to the muscarinic M₃ receptor on parietal cells. Binding of ACh to the M₃ receptor activates the phospholipase C, IP₃, and diacylglycerol (DAG) signal transduction pathway whose final pathway is the apical H⁺,K⁺-ATPase (Fig. 1-16). In a concurrent paracrine mechanism, enterochromaffin cells release histamine into the extracellular space where it binds to a histamine H₂ receptor on parietal cells. Binding of histamine to the H₂ receptor activates the adenylate cyclase, cyclic adenosine monophosphate (cAMP), protein kinase A signal transduction pathway, leading to activation of the final common pathway—the apical H⁺,K⁺-ATPase. Coincident with the neural and paracrine effects, gastrin is released from antral G cells in response to ACh, gastrin-releasing peptide, and amino acids. Gastrin circulates as a GI hormone having a primary effect of binding gastrin (or CCK_B) receptors on gastric parietal cells. Like ACh, gastrin stimulates parietal cell H⁺ secretion through the IP₃/DAG/Ca²⁺ second messenger system. Inhibition of parietal cell H⁺ secretion is mediated primarily via the paracrine effects of somatostatin, prostaglandins, and adenosine. All three paracrines inhibit parietal cell adenylate cyclase and cAMP production. Somatostatin has the additional effect of both inhibiting histamine release from enterochromaffin cells and gastrin release from antral G cells.

Figure 1-16 Acetylcholine (neurocrine), gastrin (endocrine), and histamine (paracrine) stimulate gastric acid secretion. Prostaglandins (paracrine) and somatostatin (multiple mechanisms) inhibit gastric acid secretion. ACh, acetylcholine; cAMP, cyclic AMP; CCK, cholecystokinin; ECL cells, Enterochromaffin-like cells; G cells, gastrin-producing cells; H, histamine; IP₃, inositol triphosphate; M, muscarinic.

(From Costanzo L (ed): Physiology, 4^th ed. Philadelphia: Saunders, 2010.)