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

Year 2002, Volume: 15 Issue: 4, 248 - 252, 03.12.2016

Abstract

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.

References

  • 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.
Year 2002, Volume: 15 Issue: 4, 248 - 252, 03.12.2016

Abstract

References

  • 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.
There are 33 citations in total.

Details

Journal Section Original Research
Authors

Ahmet Akıcı This is me

Muradiye Nacak This is me

Arthur Christopoulos This is me

Şule Oktay This is me

Publication Date December 3, 2016
Published in Issue Year 2002 Volume: 15 Issue: 4

Cite

APA Akıcı, A., Nacak, M., Christopoulos, A., Oktay, Ş. (2016). DARIFENACIN REVEALS A FUNCTIONAL ROLE FOR M4 MUSCARINIC ACETYLCHOLINE RECEPTORS IN GUINEA PIG GALLBLADDER. Marmara Medical Journal, 15(4), 248-252.
AMA Akıcı A, Nacak M, Christopoulos A, Oktay Ş. DARIFENACIN REVEALS A FUNCTIONAL ROLE FOR M4 MUSCARINIC ACETYLCHOLINE RECEPTORS IN GUINEA PIG GALLBLADDER. Marmara Med J. March 2016;15(4):248-252.
Chicago Akıcı, Ahmet, Muradiye Nacak, Arthur Christopoulos, and Şule Oktay. “DARIFENACIN REVEALS A FUNCTIONAL ROLE FOR M4 MUSCARINIC ACETYLCHOLINE RECEPTORS IN GUINEA PIG GALLBLADDER”. Marmara Medical Journal 15, no. 4 (March 2016): 248-52.
EndNote Akıcı A, Nacak M, Christopoulos A, Oktay Ş (March 1, 2016) DARIFENACIN REVEALS A FUNCTIONAL ROLE FOR M4 MUSCARINIC ACETYLCHOLINE RECEPTORS IN GUINEA PIG GALLBLADDER. Marmara Medical Journal 15 4 248–252.
IEEE A. Akıcı, M. Nacak, A. Christopoulos, and Ş. Oktay, “DARIFENACIN REVEALS A FUNCTIONAL ROLE FOR M4 MUSCARINIC ACETYLCHOLINE RECEPTORS IN GUINEA PIG GALLBLADDER”, Marmara Med J, vol. 15, no. 4, pp. 248–252, 2016.
ISNAD Akıcı, Ahmet et al. “DARIFENACIN REVEALS A FUNCTIONAL ROLE FOR M4 MUSCARINIC ACETYLCHOLINE RECEPTORS IN GUINEA PIG GALLBLADDER”. Marmara Medical Journal 15/4 (March 2016), 248-252.
JAMA Akıcı A, Nacak M, Christopoulos A, Oktay Ş. DARIFENACIN REVEALS A FUNCTIONAL ROLE FOR M4 MUSCARINIC ACETYLCHOLINE RECEPTORS IN GUINEA PIG GALLBLADDER. Marmara Med J. 2016;15:248–252.
MLA Akıcı, Ahmet et al. “DARIFENACIN REVEALS A FUNCTIONAL ROLE FOR M4 MUSCARINIC ACETYLCHOLINE RECEPTORS IN GUINEA PIG GALLBLADDER”. Marmara Medical Journal, vol. 15, no. 4, 2016, pp. 248-52.
Vancouver Akıcı A, Nacak M, Christopoulos A, Oktay Ş. DARIFENACIN REVEALS A FUNCTIONAL ROLE FOR M4 MUSCARINIC ACETYLCHOLINE RECEPTORS IN GUINEA PIG GALLBLADDER. Marmara Med J. 2016;15(4):248-52.