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Gastrointestinal Exocrine (Lumencrine) Secretions. The Reception Theory as the Basis for Developing the First Antisecretory Pharmacotherapy Drugs

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Abstract

Secretions of the gastrointestinal (GI) tract were identified since antiquity. However, the role of these secretions in the process of digestion was not recognized after a couple of centuries. Modern knowledge about the secretory activity and regulation of the gut began with the work of Camillo Golgi (1843–1926), Jan Evangelista Purkyně (1787–1869), William Beaumont (1785–1853), Rudolph Heidenhain (1834–1897), Ivan Petrovich Pavlov (1849–1936). GI secretions include oral secretions (saliva), gastric juice, pancreatic juice, intestinal juice, bile, and other co-released components produced by the glandular cells of the digestive tract. Enzymes and their cofactors represent major components of these digestive juices that help to break down proteins, fats, and carbohydrates into simple absorbable substances. The GI juices also contain water, ions, mineral salts, and other endogenous proteins. In its broader sense, however, GI secretions include neuromediators and hormones. Of special attention is the secretion of the cells of the stomach (known as gastric juice), which has immense clinical implications in gastric pathology. Though it was widely accepted that hydrochloric acid is a major component of stomach juice, the clinical importance of gastric acid was not appreciated until the cellular and molecular mechanisms of gastric secretion were unraveled. It was known that gut secretions are controlled by a complex network involving the nervous and humoral systems as well as components of ingested food. However, nothing was known about the molecular processes regulating the secretory activity of the stomach. Compelling evidences on the mechanisms of regulation of gastric secretion came in the second half of the twentieth century following the groundbreaking investigations led by Sir James Whyte Black (1924–2010), which was rooted on chemical reception theory proposed around the beginning of the twentieth century by John Newport Langley (1852–1925) and Paul Ehrlich (1854–1915). The theory of chemical reception posits that chemical receptive substances (receptors), which are plasma membrane proteins, are required for receiving incoming chemical messengers (hormones and neurotransmitters) that initiate cellular response. The discovery of the hormone gastrin by John Sydney Edkins (1863–1940) in 1906 and of the GI source and functions of the hormone histamine by a student of Pavlov, Popielski Leon Bernardovich (Popielski Lev Bernardovich) (1866–1920) in 1916, coupled with the discovery of proton pumps in 1973 by Allen L. Ganser (1942–), and John Gaetano Forte (1934–2012), made it possible for the pioneer investigator Dr. George Sachs to extensively study proton pump inhibitors (PPI) and histamine (H) type 2 receptor blockers, which provided a good and superior alternative to gastric surgery that was initially the mainstay of treatment of gastric ulcer. This chapter not only gives a historic account on discoveries and the clinical importance of gastric secretions, but also discusses the mechanisms and secretory functions of the various regions of the GI tract.

Keywords

  • Reception theory
  • Chemical reception
  • Chemical signaling
  • Ion transport
  • Gastrointestinal secretions
  • Saliva
  • Exocrine glands
  • Duacrine glands
  • Gastric juice
  • Pancreatic juice
  • Intestinal juice
  • Bile
  • Proton pumps
  • Proton pump inhibitors
  • Histamine type 2 receptor blockers
  • Gastric pharmacology
  • Gastric history
  • John Newport Langley
  • Paul Ehrlich
  • Sir James Whyte Black
  • John Sydney Edkins
  • Popielski Leon Bernardovich (Popielski Lev Bernardovich)
  • Allen L. Ganser
  • John Gaetano Forte
  • George Sachs

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  • DOI: 10.1007/978-3-319-91056-7_11
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Fig. 11.1
Fig. 11.2
Fig. 11.3
Fig. 11.4
Fig. 11.5
Fig. 11.6
Fig. 11.7
Fig. 11.8
Fig. 11.9
Fig. 11.10
Fig. 11.11
Fig. 11.12
Fig. 11.13
Fig. 11.14

Note The lumen of the canaliculus pH is about 1.5–1.9 units, which is increased by almost five times in the mucus coat. The pH in the cytosol of the parietal cell is 7.4 (7.0–7.4) [347, 348]

Fig. 11.15
Fig. 11.16
Fig. 11.17
Fig. 11.18
Fig. 11.19
Fig. 11.20
Fig. 11.21
Fig. 11.22
Fig. 11.23
Fig. 11.24
Fig. 11.25
Fig. 11.26
Fig. 11.27

Abbreviations

HCl:

Hydrochloric acid

M1, M2, M3, M4, and M5:

Muscarinic acetylcholine receptor types

µg/kg:

Microgram per kilogram

µg/kg/h:

Microgram per kilogram per hour

PPIs:

Proton pump inhibitors

GABA:

Gamma-aminobutyric acid

NO:

Nitric oxide

CCK:

Cholecystokinin

CNS:

Central nervous system

5-HT(2A):

Serotonin 2A (5-HT(2A)) receptor

LD50 or LC50:

Lethal dose or concentration 50%

nmol/kg:

Nanomole per kilogram

microM:

Micromole

4-DAMP:

4-Diphenyl-acetoxy-N-methyl-piperidine

ATP4A:

Adenosine triphosphate type 4A

TM4, TM5, TM6, and TM8:

Transmembrane segments

Kir4.1:

ATP-dependent inwardly rectifying potassium

KCNQ1:

Voltage-gated potassium channel, KQT-like subfamily Q, member 1

KCNE2:

Member 2 of the potassium voltage-gated channel subfamily E also known as MinK-related peptide 1 (MiRP1)

CFTR:

Cystic fibrosis transmembrane conductance regulator

CLIC-6:

Chloride intracellular channel protein 6

Cl:

Chloride ion

K+:

Potassium ion

KCC4:

K+-Cl cotransporter type 4

Å:

Armstrong

GERD:

Gastroesophageal reflux disease

SLC26A9:

Solute carrier family 26 (anion exchanger), member 9

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Welcome, M.O. (2018). Gastrointestinal Exocrine (Lumencrine) Secretions. The Reception Theory as the Basis for Developing the First Antisecretory Pharmacotherapy Drugs. In: Gastrointestinal Physiology. Springer, Cham. https://doi.org/10.1007/978-3-319-91056-7_11

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