Muscarinic M1- and M2-receptors mediating opposite effects on neuromuscular transmission in rabbit vas deferens

Eltze, Manfrid

doi:10.1016/0014-2999(88)90801-1

Cited by 176 publications

(109 citation statements)

References 44 publications

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“…The affinities obtained at uterine muscarinic receptors of immature guinea-pigs were compared to those determined at M 1 (rabbit vas deferens), M 2 (guinea-pig atria) and M 3 receptors (guinea-pig ileum). The antimuscarinic potencies of the antagonists at Mb M2 and M 3 receptors (pArvalues, Table 1) werein good agreement with their affinity estimates determined in radioligand binding studies (Lazareno and Roberts 1989;Waelbroeck et al 1989) and previous functional studies (Barlow et al 1976;Gilani and Cobbin 1986;Micheletti et al 1987;Eltze 1988;Eltze et al 1988;Waelbroeck et al 1989;. A comparison of these affinity values with those determined at uterine muscarinic receptors suggests that the muscarinic receptor mediating contractions of the guinea-pig uterus is pharmacologically unique ( Table 1 ).…”

Section: Discussionsupporting

confidence: 80%

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Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus

Dörje

Friebe

Tacke

et al. 1990

Naunyn-Schmiedeberg's Arch Pharmacol

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Summary. The present study was designed to further characterize the muscarinic receptors mediating contraction of the guinea-pig uterus. The affinities of various selective muscarinic antagonists were determined and compared with those obtained at M 1 (rabbit vas deferens), M 2 (guinea-pig atria) and M 3 receptors (guinea-pig ileum).The contractile responses of uterine smooth muscle from immature guinea-pigs to carbachol (pD 2 = 5.73)were competitively antagonized by pirenzepine (pA 2 = 7.04), AF-DX 116diazepin-6-one) (pA 2 = 6.96), himbacine (pA 2 = 7.92), methoctramine (pA 2 = 7.52), 4-DAMP (4-diphenylacetoxy-N-methylpiperidine methiodide) (pA 2 = 8.87) and sila-hexocyclium (pA 2 = 8.81). A comparison of affinity values indicates that the muscarinic receptors present in guinea-pig uterus display a novel pharmacological profile which is not consistent with the presence of either an M 1 , M 2 or M 3 receptor. The affinities determined for the different antagonists rather showed a close similarity to those obtained at muscarinic receptors present in rat striatum and NG108-15 cells which are considered pharmacological equivalents (M 4 receptors) of the m4 gene product. We thus hypothesize that the guinea-pig isolated uterus preparation may serve as a simple functional assay system to study the pharmacology of M 4 receptors.

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Section: Discussionsupporting

confidence: 80%

“…Experiments on rabbit isolated vas deferens were performed according to Eltze (1988). Male New Zealand white rabbits (2.5-3.0 kg) were killed by i. v. injection of 120 mg/kg pentobarbitone sodium.…”

Section: Methodsmentioning

confidence: 99%

Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus

Dörje

Friebe

Tacke

et al. 1990

Naunyn-Schmiedeberg's Arch Pharmacol

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“…There is evidence for the presence of both facilitatory and inhibitory prejunctional muscarinic receptors of the M 1 subtype on both sympathetic and/or parasympathetic neurones supplying other genito-urinary organs (Eltze, 1988;Somogyi & de Groat, 1990;Somogyi et al, 1994;. In our study the putatively M 1 receptor-selective agonist McN-A-343 was without eect on neurotransmission to the guinea-pig prostate smooth muscle.…”

Section: Discussionsupporting

confidence: 41%

Cholinergic facilitation of neurotransmission to the smooth muscle of the guinea‐pig prostate gland

Lau

Pennefather

Mitchelson

2000

British J Pharmacology

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1 Functional experiments have been conducted to assess the eects of acetylcholine and carbachol, and the receptors on which they act to facilitate neurotransmission to the stromal smooth muscle of the prostate gland of the guinea-pig. 2 Acetylcholine and carbachol (0.1 mM ± 0.1 mM) enhanced contractions evoked by trains of electrical ®eld stimulation (20 pulses of 0.5 ms at 10 Hz every 50 s with a dial setting of 60 V) of nerve terminals within the guinea-pig isolated prostate. In these concentrations they had negligible eects on prostatic smooth muscle tone. The facilitatory eects of acetylcholine, but not those of carbachol, were further enhanced in the presence of physostigmine (10 mM). 3 The facilitatory eects of carbachol were unaected by the neuropeptide Y Y 1 receptor antagonist BIBP 3226 ((R)-N 2 -(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-argininamide) (0.3 mM, n=3) or suramin (100 mM, n=5). Prazosin (0.1 mM, n=5) and guanethidine (10 mM, n=5) alone and in combination (n=4), reduced responses to ®eld stimulation and produced rightward shifts of the log concentration-response curves to carbachol. 4 The rank orders of potency of subtype-preferring muscarinic receptor antagonists in inhibiting the facilitatory actions of acetylcholine and carbachol were: pirenzepine 4 HHSiD (hexahydrosiladifenidol) 4 pF-HHSiD (para-¯uoro-hexahydrosiladifenidol) 5 himbacine, and pirenzepine 4 HHSiD 4 himbacine 5 pF-HHSiD, respectively. These pro®les suggest that muscarinic receptors of the M 1 -subtype mediate the facilitatory eects of acetylcholine and carbachol on neurotransmission to the smooth muscle of the guinea-pig prostate.

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“…and the reference drugs pirenzepine and methoctramine. The receptors studied were M 1 -receptors in rabbit vas deferens (Eltze, 1988;, cardiac M 2 -receptors in guinea-pig atria and smooth muscle M 3 -receptors in guinea-pig ileum. Furthermore, we report on in vitro experiments with hexahydro-sila-difenidol and its p-fluoro derivative 7b in ganglionic (M 1 ), atrial (M 2 ) and ileal (M 3 fpreparations of the rat.…”

Section: Lntroductionmentioning

confidence: 99%

“…The presynaptic musearlnie receptors in rabbit vas deferens and the postsynaptic receptors in guinea-pig atria and ileum have been weil established tobelang to different subclasses: ganglionic M 1 -, cardiac M 2 -and smooth musclejglandular M 3 -receptors (Eltze, 1988;Eltze and Figala, 1988;Lambrecht et al, 1988a-c;). This heterogeneity is based mainly on the different affinities of selective antagonists such as…”

Section: General Considerationsmentioning

confidence: 99%

Affinity profiles of hexahydro-sila-difenidol analogues at muscarinic receptor subtypes

Lambrecht

Feifel

Wagner-Röder

et al. 1989

European Journal of Pharmacology

103

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In an attempt to assess the structural requirements of hexahydro-sila-difenidol for potency and selectivity, a series of analogues modified in the amino group and the phenyl ring were investigated for their affinity to muscarinic M 1 -(rabbit vas deferens), Mr (guinea-pig atria) and Mr (guinea-pig ileum) receptors. All compounds were competitive antagonists in the three tissues. Their affinities to the three muscarinic receptor subtypes differed by more than two orders of magnitude and the observed receptor selectivities were not associated with high affinity. The pyrrolidino and hexamethyleneimino analogues, compounds substituted in the phenylring with a methoxy group or a chlorine atom as weil as p-fluoro-hexahydro-difenidol displayed the same affinity profile as the parent compound, hexahydro-sila-difenidol: M 1 = M 3 > M 2 • A different selectivity patternwas observed for p-fluoro-hexahydro-sila-difenidol: M 3 > M 1 > M 2 • This compound exhibited its highest affinity for M 3 -receptors in guinea-pig ileum (pA 2 = 7.84), intermediate affinity for M 1 -receptors in rabbit vas deferens (pA 2 = 6.68) and lowest affinity for the Mrreceptors in guinea-pig atria (pA 2 = 6.01). This receptor selectivity profile of p-fluoro-hexahydro-sila-difenidol was confirmed in ganglia (M 1 ), atria (M 2 ) and ileum (M 3 ) of the rat. Furthermore, dose ratios obtained with either pirenzepine (Mt) or hexahydrosila-difenidol (M 2 and M 3 ) and the p-fluoro analogue used in combination suggested that the antagonism was additive, implying mutual competition with a single population of muscarinic receptor subtypes. These results indicate that p-fluoro-hexahydro-sila-difenidol represents a valuable tool for characterization of muscarinic receptor subtypes.

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Muscarinic M1- and M2-receptors mediating opposite effects on neuromuscular transmission in rabbit vas deferens

Cited by 176 publications

References 44 publications

Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus

Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus

Cholinergic facilitation of neurotransmission to the smooth muscle of the guinea‐pig prostate gland

Affinity profiles of hexahydro-sila-difenidol analogues at muscarinic receptor subtypes

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