title: Tetramethylpyrazine stimulates cystic fibrosis transmembrane conductance regulator-mediated anion secretion in distal colon of rodents.
abstract: OBJECTIVE
  To investigate the effect of tetramethylpyrazine (TMP), an active compound from Ligustium Wollichii Franchat, on electrolyte transport across the distal colon of rodents and the mechanism involved.
  
  
  METHODS
  The short-circuit current (I(SC)) technique in conjunction with pharmacological agents and specific inhibitors were used in analyzing the electrolyte transport across the distal colon of rodents. The underlying cellular signaling mechanism was investigated by radioimmunoassay analysis (RIA) and a special mouse model of cystic fibrosis.
  
  
  RESULTS
  TMP stimulated a concentration-dependent rise in I(SC), which was dependent on both Cl(-) and HCO(3)(-), and inhibited by apical application of diphenylamine-2,2'-dicarboxylic acid (DPC) and glibenclamide, but resistant to 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid disodium salt hydrate (DIDS). Removal of Na(+) from basolateral solution almost completely abolished the I(SC) response to TMP, but it was insensitive to apical Na(+) replacement or apical Na(+) channel blocker, amiloride. Pretreatment of colonic mucosa with BAPTA-AM, a membrane-permeable selective Ca(2+) chelator, did not significantly alter the TMP-induced I(SC). No additive effect of forskolin and 3-isobutyl-1-methylxanthine (IBMX) was observed on the TMP-induced I(SC), but it was significantly reduced by a protein kinase A inhibitor, H(89). RIA results showed that TMP (1 mmol/L) elicited a significant increase in cellular cAMP production, which was similar to that elicited by the adenylate cyclase activator, forskolin (10 micromol/L). The TMP-elicited I(SC) as well as forskolin- or IBMX-induced I(SC) were abolished in mice with homozygous mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) presenting defective CFTR functions and secretions.
  
  
  CONCLUSIONS
  TMP may stimulate cAMP-dependent and CFTR-mediated Cl(-) and HCO(3)(-) secretion. This may have implications in the future development of alternative treatment for constipation.
authors: Department of Physiology, Zhengzhou University, Henan Province, China.
authors: Qiong
authors: Q
authors: He
authors: Jin-Xia
authors: JX
authors: Zhu
authors: Ying
authors: Y
authors: Xing
authors: Lai-Ling
authors: LL
authors: Tsang
authors: Ning
authors: N
authors: Yang
authors: Dewi Kenneth
authors: DK
authors: Rowlands
authors: Yiu-Wa
authors: YW
authors: Chung
authors: Hsiao-Chang
authors: HC
authors: Chan
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D000838:Anions / Q000378:metabolism; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D003248:Constipation / Q000188:drug therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D008297:Male; D051379:Mice; D018181:Mice, Inbred CFTR; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000318:Adrenergic beta-Agonists; D000838:Anions; D011719:Pyrazines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C017953:tetramethylpyrazine