Functional characterization of muscarinic receptors in rat duodenum

Pfaff, Otmar; Gross, J.; Waelbroeck, Magalì; Mutschler, E.; Lambrecht, Günter

doi:10.1016/0024-3205(95)93789-h

Cited by 8 publications

(2 citation statements)

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“…In addition, the stereoselectivity ratio for HHD in RAM [(R)/(S) = 288] is in very good agreement with that obtained in functional experiments at M 3 receptors in guinea-pig ileum longitudinal smooth muscle (= 191;Feifel et al 1990) and submucosal arterioles (= 229-275; Bungardt et al 1992) as well as in rat duodenum longitudinal smooth muscle (= 186;Pfaff et al 1995a). These findings provide additional evidence that stereoselectivity ratios of chiral antagonists may be used to characterize muscarinic receptor subtypes (Feifel et al 1990;Dörje et al 1991;Waelbroeck et al 1992Waelbroeck et al , 1996Pfaff et al 1995b).…”

Section: Discussionsupporting

confidence: 71%

Characterization of postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle

Weiser

Mutschler

Lambrecht

1997

Naunyn-Schmiedeberg's Arch Pharmacol

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The present study was designed to characterize the postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle by means of a series of muscarinic agonists and subtype-preferring key muscarinic antagonists. Cumulative addition of muscarinic agonists elicited concentration-dependent contractions with the following rank order of potency (pD2 values): (+)-muscarine (6.36) > or = oxotremorine M (6.21) > or = arecaidine propargyl ester (APE) (6.18) > carbachol (5.68) = (+/-)-methacholine (5.65) > 4-(4-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium chloride (4-Cl-McN-A-343) (4.28) > 4-(3-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride (McN-A-343) (3.89). (+)-Muscarine, oxotremorine M, carbachol and (+/-)-methacholine behaved as full agonists, whereas APE, 4-Cl-McN-A-343 and McN-A-343 displayed partial agonism. The contractile responses of the rat anococcygeus muscle to (+/-)-methacholine were competitively antagonized by pirenzepine (pA2 = 6.92), 11-[[4-[4-(diethylamino)butyl]-1-piperidinyl]acetyl] 5,11-dihydro-6H-pyrido(2,3-b) (1,4)-benzodiazepine-6-one (AQ-RA 741; pA2 = 6.75), himbacine (pA2 = 7.11), (+/-)-p-fluoro-hexahydro-sila-difenidol (p-F-HHSiD; pA2 = 7.68) and the (R)- and (S)-enantiomers of hexahydro-difenidol [(R)-HHD: pA2 = 8.52; (S)-HHD: pA2 = 6.06]. A comparison of the pA2 values derived from studies of contraction in rat anococcygeus muscle with literature binding (pKi values) and functional affinities (pA2 values) obtained at native M1-M4 receptors strongly suggests that the postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle are of the M3 subtype.

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Section: Discussionsupporting

confidence: 71%

Characterization of postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle

Weiser

Mutschler

Lambrecht

1997

Naunyn-Schmiedeberg's Arch Pharmacol

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“…In addition, there is a body of evidence that somadendritic muscarinic receptors located on intramural nonadrenergic noncholinergic (NANC) nerves, may mediate tetrodotoxin-sensitive relaxation. Functional investigations showed that these neuronal inhibitory receptors are present in rat duodenum (Micheletti et al 1988;Pfaff et al 1995), lower esophageal sphincter of the opossum (Gilbert et al 1984) as well as in rabbit (Creed et al 1977) and cat (Gillespie and McGrath 1974) anococcygeus muscle. While the somadendritic muscarinic receptors mediating relaxation in rat duodenum and opossum esophageal sphincter are most probably of the M 1 subtype, those found in rabbit and cat anococcygeus, however, have not been characterized so far.…”

Section: Introductionmentioning

confidence: 99%

Evidence for muscarinic M4 receptors mediating nonadrenergic noncholinergic relaxations in rabbit anococcygeus muscle

Gross

Mutschler

Lambrecht

1997

Naunyn-Schmiedeberg's Arch Pharmacol

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The aim of the present study was to characterize the muscarinic receptor subtype mediating nonadrenergic noncholinergic (NANC) relaxations in the rabbit anococcygeus muscle (RAM) by the use of muscarinic receptor agonists and a battery of key muscarinic antagonists. In addition, experiments were carried out to identify the NANC neurotransmitter(s) involved in the inhibitory NANC neurotransmission. In preparations with histamine-raised tone, the nonselective muscarinic agonists (pD2 values) (+)-muscarine (5.23), cis-dioxolane (5.16), oxotremorine M (4.95) and carbachol (4.06) produced concentration-dependent relaxations corresponding to 72.6-85.0% of the histamine-induced precontraction. In contrast, the subtype-preferring (M1/M4 over M2 and M3 receptors) agonists 4-(3-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride (McN-A-343), (S)-4-(dimethylamino)-1-methyl-2-butynyl-N-(3-chlorophenyl)carbamate methobromide [(S)-BN 228], (R)- and (S)-N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide [(R)- and (S)-BM 5] showed no or rather low [(S)-BN 228] muscarinic activity. The low potencies, together with the ineffectiveness of some agonists, indicated a low effective receptor reserve associated with the relaxant response. No contractile responses to (+)-muscarine were observed neither in unstimulated nor in precontracted preparations suggesting that the existence of an excitatory postjunctional muscarinic receptor may be excluded. The nicotinic antagonist hexamethonium had no influence on relaxant responses to (+)-muscarine, but abolished relaxations elicited by (-)-nicotine. This demonstrates that the RAM contains also nicotinic acetylcholine receptors (AchRs) mediating inhibitory NANC responses. Relaxations induced by the stimulation of muscarinic and nicotinic AchRs as well as by electrical field stimulation (EFS) were completely abolished by tetrodotoxin and were also sensitive to the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine (L-NOARG), indicating that NO plays an important role as an inhibitory NANC transmitter in RAM. All muscarinic antagonists investigated did not influence the histamine-induced precontraction, but shifted the concentration-response curve of (+)-muscarine to the right in a parallel fashion. Schild analysis yielded regression lines of unit slope, indicating competitive antagonism. The following rank order of antagonist potencies (pA2 values) was found: 11-([4-[4-(diethylamino)-butyl]-1-piperidinyl]-acetyl-5,11-dihydro-6H-py rido (2,3-b) (1,4)-benzodiazepine-6-one hydrochloride (AQ-RA 741; 8.08) = himbacine (8.03) > or = tripitramine (7.69) > or = p-fluorohexahydro-sila-difenidol (p-F-HHSiD; 7.48) > or = methoctramine (7.30) > or = pirenzepine (7.18) > or = guanylpirenzepine (6.24). A comparison of the pA2 values determined in the RAM with published data from binding studies at muscarinic M1-M4 and m5 receptors suggests that the functional muscarinic receptor mediating NANC relaxation in the RAM is of the M4 subtype. Taken together, the results obtained in the present...

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The (S)-(+)-enantiomer of dimethindene: a novel M2-selective muscarinic receptor antagonist

Pfaff

Hildebrandt

Waelbroeck³

et al. 1995

European Journal of Pharmacology

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Functional characterization of muscarinic receptors in rat duodenum

Cited by 8 publications

References 0 publications

Characterization of postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle

Characterization of postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle

Evidence for muscarinic M4 receptors mediating nonadrenergic noncholinergic relaxations in rabbit anococcygeus muscle

The (S)-(+)-enantiomer of dimethindene: a novel M2-selective muscarinic receptor antagonist

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