DARIFENACIN REVEALS A FUNCTIONAL ROLE FOR M4 MUSCARINIC ACETYLCHOLINE RECEPTORS IN GUINEA PIG GALLBLADDER

Yıl 2002, Cilt: 15 Sayı: 4, 248 - 252, 03.12.2016

Ahmet Akıcı Muradiye Nacak Arthur Christopoulos Şule Oktay

Öz

Objective: Previous studies have revealed the presence of M1 to M4 muscarinic receptors in guinea pig gallbladder, with M3 and M4 receptors being claimed to mediate contractions.
Methods: In the present study, cumulative concentration-response curves to carbachol were constructed in the absence and presence of darifenacin, which has greater selectivity for M3 over M4 receptors, in guinea-pig gallbladder.
Results: Darifenacin caused concentration- dependent dextral shifts of the carbachol curve, however, at 1 pM, it also caused a degree of insurmountable antagonism. Using a novel analytical approach, we obtained a pKB estimate for darifenacin (7.51 ± 0.14) that is in excellent agreement with its affinity for M2/M4, but not M3 receptors.
Conclusion: Given our previous demonstration that M2 receptors are unlikely to contribute to muscarinic contractions in this tissue, our current
findings provide pharmacological evidence for a predominant role of M4 muscarinic receptors in guinea pig gallbladder contractions.
Key Words: Muscarinic receptor, Guinea-pig, Gallbladder, Contraction, Darifenacin.

Kaynakça

• Caufield Ml’, Birdsall HJM. International Union of Pharmacology. XVII: Classification of muscarinic acetylcholine receptors. Pharmacol Rev 1998:50:279-290.
• Eglen RM, Reddy fl, Watson hi, Challiss RAJ. Muscarinic acetylcholine receptor subtypes in smooth muscle. Trends Pharmacol Sci 1994,15:1 14-1 19.
• Eltze M, Ronig fl, Ullrich B, Grebe T. Contraction of guinea-pig gallbladder: muscarinic M3 or M4 receptors? Eur J Pharmacol 1997;332:77-87.
• Takahashi T, Kurosawa S, Owyang C. Regulation of PI hydrolysis and cAMP formation by muscarinic M3 receptor in guinea-pig gallbladder. Am J Physiol 1994; 267.G523-G528.
• Von Schrenck T, Sievers J, Mirau S, Raedler A. Greten fl. Characterization of muscarinic receptors on guinea-pig gallbladder smooth muscle. Gastroenterology 1993; 105:1341- 1349.
• Von Schrenck T, Mackensen B, Mende U, et at. Signal transduction pathway of the muscarinic receptors mediating gallbladder contraction. Haunyn-Schmied. Arch Pharmacol 1994.-349: 346-354.
• Özkutlu U, Alican İ, Karahan E, et al. Are m- cholinoceptors of guinea-pig gallbladder smooth muscle of m4 subtype? Pharmacology 1993;46:308-314.
• Oktay Ş, Cabadak fl, İskender E, et al. Evidence for the presence of muscarinic M2 and M4 receptors in guinea-pig gallbladder smooth muscle. J Auton Pharmacol 1998,18:195-204.
• Parkman HP, Pagano AP, Ryan JP. Subtypes of muscarinic receptors regulating gallbladder cholinergic contractions. Am J Physiol 1999;84:71-76.
• Karaalp A, Akıcı A, Akbulut tl, Ulusoy FIB, Oktay Ş. Distinct functional muscarinic receptors in guinea-pig gallbladder, ileum and atria. Pharmacol Res 1999:39:389-395.
• Akıcı A, Karaalp, A, İskender E, Christopoulus A, El-Eakahany EE, Oktay Ş. Further evidence for the heterogeneity of functional muscarinic receptors in guinea-pig gallbladder. Eur J Pharmacol 2000:388:1 15-123.
• Alabaster VA. Discovery and development of selective M3 antagonists for clinical use. Life Sci 1997:60:1053-1060.
• Wallis RM, Fiapier CM. Muscarinic antagonists in development for disorders of smoothe muscle function. Life Sci 1999:64:395-401.
• Christopoulos A, Parsons AM, Lew MJ, El- Fakahany EE. The assessment of antagonist potency under conditions of transient response kinetics. Eur J Pharmacol 1999; 382:217-227.
• Christopoulos A, Coles P, Lay L, Lew MJ, Angus JA. Pharmacological analysis of cannabinoid receptor activity in the rat vas deferens. Br J Pharmac 2001;132:1281-1291.
• Christopoulos A. From captive agonism to insurmountable antagonism: Demonstrating the power of analytical pharmacology. Clin Exp Pharmacol Physiol 2001,-28:223-229.
• Lew MJ, Angus. Analysis of competitive agonist-antagonist interactions by nonlinear regression. Trends Pharmacol Sci 1995,16:328-337.
• 5 1
• Ahmet Akıcı, et al
• Van Charldorp KJ, Van Zwieten PA. Comparison of the muscarinic receptors in the coronary artery, cerebral artery and atrium of the pig, riaunyn-Schmied. Arch Pharmacol 1989;339:403-408.
• Doods fin, Willim KD, Boddeke HWGM, Entzeroth M. Characterization of muscarinic receptors in guinea-pig uterus. Eur J Pharmacol 1993;250:223-230.
• Eglen RM, Michel AD, Whiting RL. Characterization of the muscarinic receptor subtype mediating contractions of the guinea- pig uterus. Br J Pharmacol 1989; 96:497-499.
• Eglen RM, Michel AD, Levine WB, Whiting RL. Analysis of muscarinic receptors in guinea-pig estrogen-dominated uterus, in vitro. Br J Pharmacol 1991 ; 104.-44P.
• Eglen RM, Whiting RL. Heterogeneity of vascular muscarinic receptors. J Auton Pharmacol 1990;10:233-245.
• Chen Q, Yu P, De Petris G, Biancani P, Behar
• J. Distinct muscarinic receptors and signal transduction pathways in gallbladder muscle. J Pharmacol Exp Ther 1995;273:650- 655.
• Heinig T, Von Schrenck T, De Weerth A, Kölsch K, Schultz M, Izbicki JR. Characterization of gallbladder muscarinic receptor subtypes: Signal transduction and
• RT-PCR studies. Gastroenterology 1997; 112:746.
• Choppin A, Eglen RM. Pharmacological characterization of muscarinic receptors in dog isolated ciliary and urinary bladder smooth muscle. Br J Pharmacol 2001;132:835-842.
• Choppin A, Eglen RM, Pharmacological characterization of muscarinic receptors in mouse isolated urinary bladder smooth muscle. Br J Pharmacol 2001 ; 133:1035- 1040.
• Choppin A, Eglen RM, Hedge SS. Pharmacological characterisation of muscarinic receptors in rabbit isolated iris sphincter muscle and urinary bladder smooth muscle. Br J Pharmacol 1998;124:883-888.
• Hedge SS, Choppin A, Bonhaus D, et al. Functional role of M2 and M3 muscarinic receptors in the urinary bladder of rats in vitro and in vivo. Br J Pharmacol 1997; 120:1409 1418.
• Yamanishi T, Chappie CR, Yasuda K, Chess- Williams R. The role of M2-muscarinic receptors in mediating contraction of the pig urinary bladder in vitro. Br J Pharmacol 2000;131:1482-1488.