Warhurst G, Higgs N B, Fakhoury H, Warhurst A C, Garde J, Coy D H
Department of Medicine, University of Manchester, Hope Hospital, Salford, England.
Gastroenterology. 1996 Aug;111(2):325-33. doi: 10.1053/gast.1996.v111.pm8690197.
BACKGROUND & AIMS: Somatostatin peptides are potent inhibitors of intestinal ion secretion, providing the rationale for their use in treating secretory diarrhea. However, the nature of the receptors that mediate these effects is unclear. The aims of this study were to investigate expression of somatostatin receptor subtypes (SSTRs) 1-5 in rat colonic epithelium and to identify which subtype(s) mediate inhibition of adenosine 3', 5'-cyclic monophosphate (cAMP)-activated secretion using SSTR-selective analogues.
SSTR expression was determined by reverse-transcription polymerase chain reaction and immunoblotting. Effects of somatostatin analogues on electrogenic ion secretion were studied in isolated colonic mucosa mounted in Ussing chambers.
Crypt epithelium expressed messenger RNA for SSTR1 and SSTR2 and low levels of SSTR5. A splice variant of SSTR2 (SSTR2B) was also detected. The SSTR2 selective analogue NC-812 was a potent inhibitor of forskolin-activated secretion and cAMP accumulation. In contrast, peptides selective for SSTR3 (DC-25/12) and SSTR5 (DC-23/99) were weak inhibitors of secretion. NC-812 also inhibited dibutyryl cAMP-activated secretion, indicating a site of action distal to cAMP production. Immunoblot analysis confirmed expression of a 93-kilodalton SSTR2 protein in crypt cell membranes.
SSTR2 receptors expressed by colonocytes mediate somatostatin's antisecretory actions in rat colon. Somatostatin analogues directed to specific SSTRs may provide the basis for more selective antidiarrheal drugs.
生长抑素肽是肠道离子分泌的强效抑制剂，这为其用于治疗分泌性腹泻提供了理论依据。然而，介导这些作用的受体的性质尚不清楚。本研究的目的是调查生长抑素受体亚型（SSTRs）1 - 5在大鼠结肠上皮中的表达，并使用SSTR选择性类似物确定哪种亚型介导对腺苷3',5'-环磷酸（cAMP）激活的分泌的抑制作用。
通过逆转录聚合酶链反应和免疫印迹法测定SSTR的表达。在安装于尤斯灌流小室的分离结肠黏膜中研究生长抑素类似物对电生性离子分泌的影响。
隐窝上皮表达SSTR1和SSTR2的信使核糖核酸以及低水平的SSTR5。还检测到SSTR2的一种剪接变体（SSTR2B）。SSTR2选择性类似物NC - 812是福斯可林激活的分泌和cAMP积累的强效抑制剂。相比之下，对SSTR3（DC - 25/12）和SSTR5（DC - 23/99）有选择性的肽是分泌的弱抑制剂。NC - 812也抑制二丁酰cAMP激活的分泌，表明其作用位点在cAMP产生的下游。免疫印迹分析证实隐窝细胞膜中存在93千道尔顿的SSTR2蛋白。
结肠细胞表达的SSTR2受体介导生长抑素在大鼠结肠中的抗分泌作用。针对特定SSTRs的生长抑素类似物可能为更具选择性的止泻药物提供基础。
