Synergy between 5-HT4 receptor stimulation and phosphodiesterase 4 inhibition in facilitating acetylcholine release in human large intestinal circular muscle

被引：7

作者：

Pauwelyn, V. ^{[1
]}

Ceelen, W. ^{[2
]}

Lefebvre, R. A. ^{[1
]}

机构：

[1] Univ Ghent, Heymans Inst, Dept Pharmacol, Ghent, Belgium

[2] Ghent Univ Hosp, Dept Gastrointestinal Surg, Ghent, Belgium

来源：

NEUROGASTROENTEROLOGY AND MOTILITY | 2018年 / 30卷 / 02期

关键词：

5-HT4; receptor; acetylcholine release; human large intestine; phosphodiesterase; prucalopride; OBSTRUCTIVE PULMONARY-DISEASE; PIG DESCENDING COLON; SMOOTH-MUSCLE; IN-VITRO; NUCLEOTIDE PHOSPHODIESTERASES; CHOLINERGIC NEUROTRANSMISSION; NEUROMUSCULAR FUNCTIONS; SELECTIVE INHIBITORS; CHRONIC CONSTIPATION; INOTROPIC RESPONSE;

D O I：

10.1111/nmo.13162

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background: Gastroprokinetic properties of 5-HT4 receptor agonists, such as prucalopride, are attributed to activation of 5-HT4 receptors on cholinergic nerves innervating smooth muscle in the gastrointestinal smooth muscle layer, increasing acetylcholine release and muscle contraction. In porcine stomach and colon, phosphodiesterase (PDE) 4 has been shown to control the signaling pathway of these 5-HT4 receptors. The aim of this study was to investigate the PDE-mediated control of these 5-HT4 receptors in human large intestine. Methods: Circular smooth muscle strips were prepared from human large intestine; after incubation with [H-3]-choline, electrically induced tritium outflow was determined as a measure for acetylcholine release. The influence of PDE inhibition on the facilitating effect of prucalopride on electrically induced acetylcholine release was studied. Key Results: The non-selective PDE inhibitor IBMX enhanced the facilitating effect of prucalopride on electrically induced acetylcholine release. The selective inhibitors vinpocetine (PDE1), EHNA (PDE2) and cilostamide (PDE3) did not influence, while rolipram and roflumilast (PDE4) enhanced the prucalopride-induced facilitation to the same extent as IBMX. Conclusions & Inferences: In human large intestinal circular muscle, the intracellular pathway of 5-HT4 receptors facilitating cholinergic neurotransmission to large intestinal circular smooth muscle is controlled by PDE4. If the synergy between 5-HT4 receptor agonism and PDE4 inhibition is confirmed in a functional assay with electrically induced cholinergic contractions of human large intestinal circular smooth muscle strips, combination of a selective 5-HT4 receptor agonist with a selective PDE4 inhibitor might enhance the in vivo prokinetic effect of the 5-HT4 receptor agonist in the large intestine.

引用

页数：10

共 55 条

[1] 5-HT4-elicited positive inotropic response is mediated by cAMP and regulated by PDE3 in failing rat and human cardiac ventricles [J].

Afzal, F. ;

Andressen, K. W. ;

Mork, H. K. ;

Aronsen, J. M. ;

Sjaastad, I. ;

Dahl, C. P. ;

Skomedal, T. ;

Levy, F. O. ;

Osnes, J-B ;

Qvigstad, E. .

BRITISH JOURNAL OF PHARMACOLOGY, 2008, 155 (07) :1005-1014

[2] THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: Enzymes [J].

Alexander, Stephen P. H. ;

Fabbro, Doriano ;

Kelly, Eamonn ;

Marrion, Neil ;

Peters, John A. ;

Benson, Helen E. ;

Faccenda, Elena ;

Pawson, Adam J. ;

Sharman, Joanna L. ;

Southan, Christopher ;

Davies, Jamie A. ;

Aldrich, R. ;

Attali, B. ;

Back, M. ;

Barnes, N. M. ;

Bathgate, R. ;

Beart, P. M. ;

Becirovic, E. ;

Biel, M. ;

Birdsall, N. J. ;

Boison, D. ;

Brauner-Osborne, H. ;

Broeer, S. ;

Bryant, C. ;

Burnstock, G. ;

Burris, T. ;

Cain, D. ;

Calo, G. ;

Chan, S. L. ;

Chandy, K. G. ;

Chiang, N. ;

Christakos, S. ;

Christopoulos, A. ;

Chun, J. J. ;

Chung, J. -J. ;

Clapham, D. E. ;

Connor, M. A. ;

Coons, L. ;

Cox, H. M. ;

Dautzenberg, F. M. ;

Dent, G. ;

Douglas, S. D. ;

Dubocovich, M. L. ;

Edwards, D. P. ;

Farndale, R. ;

Fong, T. M. ;

Forrest, D. ;

Fowler, C. J. ;

Fuller, P. ;

Gainetdinov, R. R. .

BRITISH JOURNAL OF PHARMACOLOGY, 2015, 172 (24) :6024-6109

[3] PRIMARY SEQUENCE OF CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE ISOZYMES AND THE DESIGN OF SELECTIVE INHIBITORS [J].

BEAVO, JA ;

REIFSNYDER, DH .

TRENDS IN PHARMACOLOGICAL SCIENCES, 1990, 11 (04) :150-155

[4] Selective stimulation of colonic transit by the benzofuran 5HT4 agonist, prucalopride, in healthy humans [J].

Bouras, EP ;

Camilleri, M ;

Burton, DD ;

McKinzie, S .

GUT, 1999, 44 (05) :682-686

[5] Regionally dependent neuromuscular functions of motilin and 5-HT4 receptors in human isolated esophageal body and gastric fundus [J].

Broad, J. ;

Hughes, F. ;

Chin-Aleong, J. ;

Sifrim, D. ;

Sanger, G. J. .

NEUROGASTROENTEROLOGY AND MOTILITY, 2014, 26 (09) :1311-1322

[6] Drugs acting at 5-HT4, D2, motilin, and ghrelin receptors differ markedly in how they affect neuromuscular functions in human isolated stomach [J].

Broad, J. ;

Goralczyk, A. ;

Mannur, K. ;

Dukes, G. E. ;

Sanger, G. J. .

NEUROGASTROENTEROLOGY AND MOTILITY, 2014, 26 (06) :851-861

[7] Cholinergic interactions between donepezil and prucalopride in human colon: potential to treat severe intestinal dysmotility [J].

Broad, J. ;

Kung, V. W. S. ;

Boundouki, G. ;

Aziz, Q. ;

De Maeyer, J. H. ;

Knowles, C. H. ;

Sanger, G. J. .

BRITISH JOURNAL OF PHARMACOLOGY, 2013, 170 (06) :1253-1261

[8] Safety assessment of prucalopride in elderly patients with constipation: a double-blind, placebo-controlled study [J].

Camilleri, M. ;

Beyens, G. ;

Kerstens, R. ;

Robinson, P. ;

Vandeplassche, L. .

NEUROGASTROENTEROLOGY AND MOTILITY, 2009, 21 (12) :1256-1263+e117

[9] Increased colonic transit in rats produced by a combination of a cholinesterase inhibitor with a 5-HT4 receptor agonist [J].

Campbell-Dittmeyer, K. ;

Hicks, G. A. ;

Earnest, D. L. ;

Greenwood-Van Meerveld, B. .

NEUROGASTROENTEROLOGY AND MOTILITY, 2009, 21 (11) :1197-+

[10] Synergy between 5-HT4 receptor activation and acetylcholinesterase inhibition in human colon and rat forestomach [J].

Cellek, S. ;

Thangiah, R. ;

Jarvie, E. M. ;

Vivekanandan, S. ;

Lalude, O. ;

Sanger, G. J. .

NEUROGASTROENTEROLOGY AND MOTILITY, 2008, 20 (05) :539-545

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