section
12.2
Gastrointestinal Hormones
205
TABLE 12-3
P rim a ry S tru ctu re o f S ecretin F am ily
*
Hormone
Molecular Weight
Structure
Secretin
3055
(27 amino acids)
His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Arg-Leu-Arg-Asp-
Ser-Ala-Arg-Leu-Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val-NH
2
Glucagon
3484
(29 amino acids)
His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-
Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asp-Thr
VIP
3326
(28 amino acids)
His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-
Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH
2
GIP
5104
(43 amino acids)
Tyr-Ala-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Met-Asp-
Lys-Ile-Arg-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-
Gln-Gln-Lys-Gly-Lys-Lys-Ser-Asp-Trp-Lys-His-Asn-Ile-Thr-Gln
*Reproduced, with permission, from J. C. Thompson and M. Marx: Gastrointestinal hormones.
C urr. P ro b l. S u rg .,
21(6),
19 (1984). © 1984 by Year
Book Medical Publishers.
îHuman.
tPyr, glutamine in pyriform.
^Porcine.
systems and ion pathways is shown in Figure 12-3. The
mediators that stimulate acid secretion are acetylcholine,
gastrin, and histamine. Bombesin, a gastrin-releasing pep-
tide, is also released from enteric neurons by vagal stim-
ulation. The action of acetylcholine can be inhibited by
anticholinergic agents (e.g., atropine). The action of his-
tamine (the decarboxylated product of histidine, Chapter
17) is mediated by H
2
receptors. Hi receptors medi-
ate the action of histamine on smooth muscle, causing
bronchoconstriction, as in acute anaphylaxis and allergic
asthma. The actions of histamine can be selectively in-
hibited by specific Hi- and H
2
-receptor antagonists. The
introduction of H2-receptor antagonists (e.g., cimetidine
and ranitidine; see Figure 12-4) helps to heal duodenal and
gastric ulcers. Secretion of gastric acid can also be sup-
pressed by prostaglandin E derivatives (Chapter 18) and
substituted benzimidazoles that inhibit H+, K+-ATPase
(e.g., omeprazole, pantoprazole). Omeprazole consists of
a sulfinyl group which bridges two ring systems con-
sisting of benzimidazole and pyridine. The active drug
is formed by protonation in the stomach and rearranges
to form sulfenic acid and sulfenamide. H+, K+-ATPase
contains critical sulfhydryl groups located on the lumi-
nal side. Sulfenamide is covalently attached to H+, K+-
ATPase, causing an irreversible inhibition (Figure 12-5).
Complete inhibition occurs when two molecules of sulfe-
namide bind to the enzyme. The degree of proton pump
inhibition is dose-dependent and the drug is particularly
useful in patients with peptic ulcer disease not well con-
trolled by H2-receptor antagonists.
Although most of the action of gastrin is mediated via
the H
2
receptor, residual stimulation due to gastrin alone
suggests the presence of specific receptors for gastrin.
The precise intracellular events that lead to acid secre-
tion are not clear, but the second messengers in this process
appear to be cAMP and Ca2+. The H
2
receptor is coupled
to the adenylate cyclase system (Chapter 30), and its acti-
vation results in the intracellular elevation of cAMP con-
centration. Stimulation of cholinergic receptor systems is
coupled to increased Ca2+ permeability.
The H+ ions in the stimulated parietal cell are produced
by the action of carbonic anhydrase:
carbonic anhydrase
H20 + C 0
2
<
-> H
2
C 0
3
— H~ + HCO
3
and the H+ ions formed are secreted with the aid of
H+, K+-ATPase, which secretes H+ in exchange for K+
through the free-energy hydrolysis of ATP. K+ is trans-
ported into the lumen via a specific ion channel. In
the lumen, the accompanying anion for H+ is Cl- se-
creted from the parietal cell. The chloride ions are de-
rived from the plasma and transported into the parietal
cell via the electroneutral Cl- / HC0
3
exchange. Thus,
for every H+ secreted into the gastric lumen, there is a
