Bases of gastrointestinal pharmacology

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Regulation of proton secretion

The gastric parietal cell, located in the oxyntic glands of the gastric body and fundus, is the common effector of hydrochloric acid (HCl) secretion. The active production of H⁺ is mediated by the H⁺/K⁺-ATPase proton pump, which secretes a hydrogen ion in exchange for a potassium ion with expenditure of metabolic energy (ATP). This process is stimulated by three main synergistic pathways:

• Histaminergic (Paracrine) Pathway: Enterochromaffin-like cells (ECL) release histamine, which binds to the G_s protein-coupled H₂ receptor, activating adenylate cyclase and raising intracellular levels of cyclic AMP (cAMP).
• Cholinergic (Neurocrine) Pathway: Vagal stimulation releases acetylcholine that acts on muscarinic M₃ receptors coupled to G_q protein, increasing free intracellular calcium ([Ca²⁺]_i).
• Gastrinic (Endocrine) Pathway: The G cells of the antrum secrete gastrin, which via the type B cholecystokinin receptor (CCK₂), also coupled to G_q protein, increases [Ca²⁺]_i.

Synergistic Mechanism of the Parietal Cell

The synergistic activation of cAMP and [Ca²⁺]_i induces the phosphorylation of cytoskeletal proteins via Protein Kinase A (PKA) and Calmodulin Kinase. This causes the translocation and fusion of the intracellular tubulovesicles (rich in inactive H⁺/K⁺-ATPase pumps) with the canalicular apical membrane, multiplying the active secretory surface by a hundred. Blocking the final common pathway (the proton pump) is clinically more effective than blocking just one of the higher activating pathways (such as histamine or acetylcholine).

Dynamics of intestinal motility

The enteric nervous system (ENS) controls motility intrinsically through the myenteric plexus of Auerbach (located between the circular and longitudinal muscle layers) and the submucosal plexus of Meissner. The key neurotransmitters are:

• ACETYLCHOLINE Main excitatory neurotransmitter, it induces smooth muscle contraction and fluid secretion via M₃ receptors.
• SEROTONIN (5-HT) Coordinator of the peristaltic reflex. Stimulation of 5-HT₄ receptors on intrinsic primary afferent neurons facilitates the release of acetylcholine, promoting anterograde propulsion. On the contrary, stimulation of 5-HT₃ receptors mediates the sensory transmission of pain and nausea.
• DOPAMINE It exerts an inhibitory tone on the upper gastrointestinal tract through D₂ receptors, reducing the secretion of myenteric acetylcholine.