Gallbladder

Expression and functional pharmacology of the bradykinin B1 receptor in the normal and inflamed human gallbladder

E Andre¹, D Gazzieri¹, E Bardella², J Ferreira³, M A Mori⁴, V V Saul⁴, M Bader⁴, J B Calixto⁵, R De Giorgio⁶, R Corinaldesi⁶, P Geppetti¹, M Trevisani¹

¹ Department of Experimental and Clinical Medicine, Pharmacology Unit, University of Ferrara, Ferrara, Italy
² Department of Surgery, University of Ferrara, Ferrara, Italy
³ Department of Chemistry, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
⁴ Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany
⁵ Department of Pharmacology, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil
⁶ Department of Internal Medicine and Gastroenterology, University of Bologna, Italy

Ms E Andre, Department of Experimental & Clinical Medicine, Pharmacology Unit, University of Ferrara, Via Fossato di Mortara 19, 44100 Ferrara, Italy; andre.eunice{at}unife.it

Background and aims: It has recently been described that bradykinin B₂ receptors are expressed in the human gallbladder and that their activation induces a powerful contraction, especially in acute cholecystitis tissues. Here the role of the B₁ receptor in the contractility of control and inflamed human gallbladder was investigated.

Methods: Strips of human gallbladder from either acute gallstone cholecystitis or elective gastro-entero-pancreatic surgery (control) were assessed in vitro and processed for reverse transcription-PCR analysis. Cumulative concentration–response curves with the selective B₁ receptor agonist, Lys-Des-Arg⁹-bradykinin, cholecystokinin and carbachol were performed in control and cholecystitis specimens.

Results: Lys-Des-Arg⁹-bradykinin concentration-dependently contracted strips of control gallbladders and its motor effect was higher in inflamed gallbladders. Lys-Des-Arg⁹-bradykinin-induced contraction was not altered by pretreatment with the selective bradykinin B₂ receptor antagonist, HOE140 (1 µM), the NK₁ (SR140333), NK₂ (SR48968) and NK₃ (SR142801) tachykinin receptor antagonists (all 1 µM), the muscarinic acetylcholine receptor antagonist, atropine (1 µM), and the cyclo-oxygenase inhibitor, indomethacin (5 µM). In contrast, the Lys-Des-Arg⁹-bradykinin-induced motor response was significantly reduced by the selective B₁ receptor antagonist, R-715. Finally, quantitative real-time PCR analysis indicated that B₁ receptor mRNA levels were significantly higher in cholecystitis smooth muscle specimens, when compared with that observed in control tissues.

Conclusions: Bradykinin B₁ receptor has an important role as a spasmogen of human gallbladder, and selective antagonists of the B₁ receptor may represent a valid therapeutic option to control pain in patients with acute cholecystitis.

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