Person: KARAALP, ATİLA
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KARAALP
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ATİLA
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Publication Metadata only Distinct functional muscarinic receptors in guinea-pig gallbladder, ileum and atria(ACADEMIC PRESS LTD, 1999) AKICI, AHMET; Karaalp, A; Akici, A; Akbulut, H; Ulusoy, NB; Oktay, SObjective. The contractile responses of guinea-pig gallbladder smooth muscle cells have been suggested to be mediated by M-3 and M-4 muscarinic receptors by different research groups. Therefore, in the present study, several pharmacological properties of cholinergic functions in guinea-pig gallbladder, guinea-pig ileum (mediated via M-3 receptors), and guinea-pig and rat atria (mediated via Mt receptors) were compared, Methods: The isometric contractions of isolated guinea-pig ileum, guinea-pig gallbladder, guinea-pig and rat atrial strips in in vitro 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-4-subtypes. Clozapine which was shown to have antagonistic affinity for muscarinic M-1, M-2, M-3 and M-5, but partial agonistic affinity for muscarinic M-4 receptors, contracted gallbladder concentration-dependently. On the other 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 gallbladder are distinct from those of atria (M-2) and ileum (M-3), but seem to be of M-4 subtype. (C) 1999 Academic Press.Publication Metadata only Evidence for the presence of muscarinic M-2 and M-4 receptors in guinea-pig gallbladder smooth muscle(WILEY, 1998) KARAALP, ATİLA; Oktay, S; Cabadak, H; Iskender, E; Goren, Z; Caliskan, E; Orun, O; Aslan, N; Karaalp, A; Tolun, A; Ulusoy, NB; Levey, AI; El-Fakahany, EE; Kan, B1 The affinities of 10 selective muscarinic receptor antagonists against [H-3]-quinuclidinyl benzilate (QNB) binding were determined to characterize the muscarinic receptors present in guinea-pig gallbladder smooth muscle. The highest correlation was obtained for the comparison between the pK(i) values for the gallbladder smooth muscle and M-2 sites. Pirenzepine revealed two binding sites with affinities indicating the presence of muscarinic M-2 receptors in abundance and a minor population of an additional site(s). 2 Carbachol produced gallbladder contractions, stimulated phosphoinositide (PI) hydrolysis and inhibited cAMP formation concentration-dependently with pD(2) values of 6.12 +/- 0.11, 5.18 +/- 0.33 and 7.19 +/- 0.15, respectively. 3 Pirenzepine, 4-DAMP, HHSiD, pF-HHSiD, AF-DX 116, methoctramine, AQ-RA 741, guanylpirenzepine and AF-DX 384 showed competitive antagonism against carbachol-induced gallbladder contractions. There was no correlation between the pA(2) values for the gallbladder and pK(i) values for the M-2 sites, whereas significant correlations were found for the M-1, M-3 and M-4 sites, the best correlation being between the pA(2) values for the gallbladder and M-4 subtypes. 4 Finally, the presence of both m(2) and m(4) receptor proteins were demonstrated by Western blot analysis. It is concluded that guinea-pig gallbladder smooth muscle has both muscarinic M-2 and M-4 receptors, which are coupled to adenylate cyclase inhibition and PI hydrolysis. 5 Although it seems likely that Mt receptors do not play a primary role in carbachol-induced guinea-pig gallbladder contraction, the characterization of the muscarinic subtypes which mediate these contractile responses needs further evidence.Publication Metadata only Muscarinic M-2 receptors are not primarily involved in the contraction of guinea-pig gallbladder smooth muscle(ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, 1999) AKICI, AHMET; Akici, A; Karaalp, A; Iskender, E; El-Fakahany, EE; Oktay, SThe presence of M-1-M-4 receptors in guinea-pig gallbladder smooth muscle cells has been reported recently. The majority of these receptors are said to be of M-2 subtype. However, there are controversial reports about the functional muscarinic receptors that mediate contraction in this tissue. Similar to gallbladder, it was claimed that M-4 receptors mediate guinea-pig uterine contractions, but these receptors have appeared to be of M-2 subtypes later. Therefore, the antagonistic affinities of three M-2-selective muscarinic antagonists were determined in contraction and radioligand binding experiments in guinea-pig gallbladder in the present study. The antagonistic affinity Values (pK(i)) of gallamine, tripitramine and imperialine were as follows, respectively: 6.28+/-0.15, 8.65+/-0.10 and 6.55+/-0.07 against 0.250 nM [H-3]QNB binding. All three antagonists displaced the concentration-response curves to carbachol to the right in parallel without affecting the maximum responses. The pA(2) values obtained from constrained Schild plots (-log K-B) were 4.14+/-0.18 for gallamine, 6.79+/-0.09 for tripitramine, and 7.02+/-0.09 for imperialine. The antagonistic affinity values of gallamine, tripitramine and imperialine for M-2 receptors are reported to be 6.3, 9.6, 7.7, respectively. The pA(2) values obtained in this study clearly indicate that the primary muscarinic receptors involved in carbachol-induced guinea-pig gallbladder contraction are not of M-2 subtype. The poor correlation between the antagonistic affinity values of these antagonists obtained at radioligand binding (pK(i)) and contraction (pA(2)) experiments also support the conclusion that the majority of muscarinic receptors which have been reported to be of M-2 do not mediate the contractile responses. (C) 1999 Academic Press.