Pharmacological Research, Vol. 39, No. 5, 1999 Article No. phrs.1999.0453, available online at http:www.idealibrary.com on DISTINCT FUNCTIONAL MUSCARINIC RECEPTORS IN GUINEA-PIG GALLBLADDER, ILEUM AND ATRIA a a ¨ a ATILA KARAALP , AHMET AKICI , HUSEYIN AKBULUT , NEFISE BARLAS ULUSOY b and SULE OKTAY a, a Department of Pharmacology and Clinical Pharmacology, Marmara Uni ersity School of ˙ b Medicine, Haydarpas ¸a, 81326 Istanbul, Turkey and Department of Gastroenterology, Marmara ˙ Uni ersity School of Medicine, Haydarpas ¸a, 81326 Istanbul, Turkey Accepted 4 January 1999 Objecti e: The contractile responses of guinea-pig gallbladder smooth muscle cells have been suggested to be mediated by M and M muscarinic receptors by different research 3 4 groups. Therefore, in the present study, several pharmacological properties of cholinergic Ž . functions in guinea-pig gallbladder, guinea-pig ileum mediated via M receptors , and 3 Ž . guinea-pig and rat atria mediated via M receptors were compared. Methods: The 2 isometric contractions of isolated guinea-pig ileum, guinea-pig gallbladder, guinea-pig and rat atrial strips in in itro organ bath were recorded on a polygraph and the effects of carbachol, oxotremorine, McN-A-343, and clozapine have been investigated. Results: Three muscarinic receptor agonists, carbachol, oxotremorine and McN-A-343 showed different order of potencies in their negative inotropic effects and contractile actions in guinea-pig gallbladder suggesting that functional muscarinic receptors in the gallbladder are distinct from those in the atria, and similar to M -subtypes. Clozapine which was shown to have 4 antagonistic affinity for muscarinic M , M , M and M , but partial agonistic affinity for 1 2 3 5 muscarinic M receptors, contracted gallbladder concentration-dependently. On the other 4 hand, clozapine antagonised carbachol-induced ileal and gallbladder contractions and negative inotropic effects indicating that it acts like a partial agonist in the gallbladder. Conclusion: It was concluded that the contractile muscarinic receptors of guinea-pig Ž . Ž . gallbladder are distinct from those of atria M and ileum M , but seem to be of M 2 3 4 subtype. 1999 Academic Press KEY WORDS: muscarinic, guinea-pig, gallbladder, ileum, atria, McN-A 343, oxotremorine, carbachol, clozapine. INTRODUCTION Cholinergic negative inotropic and chronotropic re- sponses in atria are known to be mediated via M 2 receptors 1 , and most of the smooth muscle prepa- rations have been demonstrated to have functional muscarinic M receptors 2 . The contractile respon- 3 ses have been reported to be mediated by mus- carinic M receptors in a few smooth muscle prepa- 2 rations such as porcine basilar artery 3 and guinea- pig uterus 4 6 , and by muscarinic M receptors in 1 canine saphenous and femoral veins 7 . Recently, the contractile responses of the guinea-pig gallblad- Corresponding author. der smooth muscle cells have been suggested to be mediated by M receptors 8, 9 . On the contrary, 4 other groups 10 13 have claimed the presence of functional M receptors in this tissue. 3 On the other hand, radioligand binding studies and Northern blot analysis have revealed the exis- tence of a mixed population of muscarinic binding sites in the majority of smooth muscles from many species 14 18 . Similarly, we have reported that guinea-pig gallbladder smooth muscle cells express both M and M receptor proteins by Western blot 2 4 analysis 9 . Therefore, it was planned to compare the effects of several muscarinic agonists in guinea- pig gallbladder, guinea-pig ileum and guinea-pig and rat atria to demonstrate the possible functional mus- carinic receptor subtype differences. 104366189905038907$30.000 1999 Academic Press