Hirschowitz B I, Keeling D, Lewin M, Okabe S, Parsons M, Sewing K, Wallmark B, Sachs G
UCLA VA.
Dig Dis Sci. 1995 Feb;40(2 Suppl):3S-23S. doi: 10.1007/BF02214869.
The secretion of gastric acid is regulated both centrally and peripherally. The finding that H2-receptor antagonists are able to reduce or abolish acid secretion due to vagal, gastrinergic, and histaminergic stimulation shows that histamine plays a pivotal role in stimulation of the parietal cell. In the rat, the fundic histamine is released from the ECL cell, in response to gastrin, acetylcholine, or epinephrine, and histamine release is inhibited by somatostatin or by the H3-receptor ligand, R-alpha-methyl histamine. The parietal cell has a muscarinic, M3, receptor responsible for [Ca]i regulation. Blockade of muscarinic receptors by atropine can be as effective as H2-receptor blockade in controlling acid secretion. However, general effects on muscarinic receptors elsewhere produce significant side effects. The different receptor pathways converge to stimulate the gastric H+,K(+)-ATPase, the pump responsible for acid secretion by the stomach. This enzyme is an alpha,beta heterodimer, present in cytoplasmic membrane vesicles of the resting cell and in the canaliculus of the stimulated cell. It has been shown that acid secretion by the pump depends on provision of K+Cl- efflux pathway becoming associated with the pump. As secretion occurs only in the canaliculus, this K+Cl- pathway is activated only when the pump inserts into the canalicular membrane. Transport by the enzyme involves reciprocal conformational changes in the cytoplasmic and extracytoplasmic domain. These result in changes in sidedness and affinity for H3O+ and K+, enabling active H+ for K+ exchange. The acid pump inhibitors of the substituted benzimidazole class, such as omeprazole, are concentrated in the canaliculus of the secreting parietal cell and are activated there to form sulfenamides. The omeprazole sulfenamide, for example, reacts covalently with two cysteines in the extracytoplasmic loops between the fifth and sixth transmembrane and the seventh and eighth transmembrane segments of the alpha subunit of the H+,K(+)-ATPase, forming disulfide derivatives. This inhibits ATP hydrolysis and H+ transport, resulting in effective, long-lasting regulation of acid secretion. Therefore, this class of acid pump inhibitor is significantly more effective and faster acting than the H2 receptor antagonists. K+ competitive antagonists bind to the M1 and M2 transmembrane segments of the alpha subunit of the acid pump and also abolish ATPase activity. These drugs should also be able to reduce acid secretion more effectively than receptor antagonists and provide shorter acting but complete inhibition of acid secretion.
胃酸分泌受中枢和外周调节。H2受体拮抗剂能够减少或消除由迷走神经、胃泌素能和组胺能刺激引起的胃酸分泌，这一发现表明组胺在壁细胞刺激中起关键作用。在大鼠中，胃底组胺由肠嗜铬样（ECL）细胞释放，以响应胃泌素、乙酰胆碱或肾上腺素，而组胺释放受生长抑素或H3受体配体R-α-甲基组胺抑制。壁细胞有一个负责调节细胞内钙离子浓度（[Ca]i）的毒蕈碱型M3受体。阿托品阻断毒蕈碱受体在控制胃酸分泌方面与H2受体阻断一样有效。然而，对其他部位毒蕈碱受体的普遍作用会产生显著的副作用。不同的受体途径汇聚以刺激胃H⁺，K⁺-ATP酶，该泵负责胃的胃酸分泌。这种酶是一种α，β异二聚体，存在于静息细胞的细胞质膜囊泡和受刺激细胞的小管中。已表明该泵的胃酸分泌取决于与泵相关的K⁺Cl⁻外流途径的提供。由于分泌仅发生在小管中，这种K⁺Cl⁻途径仅在泵插入小管膜时才被激活。该酶的转运涉及细胞质和细胞外结构域的相互构象变化。这些变化导致对H₃O⁺和K⁺的取向和亲和力改变，从而实现H⁺与K⁺的主动交换。取代苯并咪唑类的胃酸泵抑制剂，如奥美拉唑，集中在分泌壁细胞的小管中并在那里被激活形成亚磺酰胺。例如，奥美拉唑亚磺酰胺与H⁺，K⁺-ATP酶α亚基的第五和第六跨膜以及第七和第八跨膜段之间的细胞外环中的两个半胱氨酸共价反应，形成二硫衍生物。这抑制了ATP水解和H⁺转运，从而有效、持久地调节胃酸分泌。因此，这类胃酸泵抑制剂比H2受体拮抗剂显著更有效且起效更快。K⁺竞争性拮抗剂与胃酸泵α亚基的M1和M2跨膜段结合，也消除ATP酶活性。这些药物应该也能够比受体拮抗剂更有效地减少胃酸分泌，并提供作用时间较短但完全的胃酸分泌抑制。
