SELECTIVE INHIBITION OF RESPONSES TO CARBACHOL AND McN‐A‐343 IN THE RABBIT VAS DEFERENS

Choo, L. K.; Mitchelson, F.

doi:10.1111/j.1440-1681.1990.tb01361.x

Cited by 11 publications

(4 citation statements)

References 19 publications

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“…McN-A-343 produces inhibition of the twitch responses of the rabbit vas deferens produced by field stimulation (Eltze 1988 ;Choo & Mitchelson 1990 ;Shannon et al 1993). This response has therefore been attributed to presynaptic muscarinic receptors of the M 1 subtype located on noradrenergic nerve terminals, stimulation of which causes inhibition of transmitter release and inhibition of contractile function (Grimm et al 1994).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of field stimulation-induced contractions of rabbit vas deferens by muscarinic receptor agonists: selectivity of McN-A-343 for M1 receptors

Davies

Scholes

Virdi

et al. 2001

Journal of Pharmacy and Pharmacology

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Inhibition of the field stimulation-induced twitch responses of the rabbit vas deferens by the muscarinic receptor agonist, McN-A-343, has been attributed to presynaptic muscarinic receptors of the M1 subtype located on noradrenergic nerve terminals. Stimulation of these receptors causes inhibition of transmitter release and inhibition of the contractile response. However, the selectivity of McN-A-343 for M1 receptors has been questioned and this throws doubt on whether the prejunctional receptors of the rabbit vas deferens are of the M1 subtype. In this study we have undertaken a comprehensive re-evaluation of the inhibition of prostatic and epididymal portions of the rabbit isolated field-stimulated vas deferens by several agonists, including McN-A-343, and quantified the antagonism by M1-selective antagonists, pirenzepine and telenzepine. Prostatic and epididymal portions of vasa deferentia from New Zealand White rabbits were immersed in a low Ca2+ Krebs solution at 32+/-0.5 degrees C gassed with 5% CO2 in oxygen. Yohimbine (1.0mM) was present throughout to block prejunctional alpha2-adrenoceptors. Field stimulation was applied by repeated application of single pulses (30 V, 0.05 Hz, 0.5 ms) and isometric contractions recorded. Carbachol and oxotremorine initially potentiated the epididymal contractions but at higher concentrations there was inhibition. In the prostatic portion, oxotremorine only inhibited. McN-A-343 produced inhibitory responses only in both epididymal and prostatic portions. Pirenzepine shifted the concentration-response curves forthe inhibitory responses to oxotremorine to the right. However, the potentiation of the twitches also became more apparent with the lower concentrations of oxotremorine. Schild plots for the antagonism by pirenzepine yielded pA2 values of 7.96+/-0.004 and 7.7+/-0.02 for the epididymal and prostatic portions, respectively. The concentration-response curves for the inhibition of twitches by McN-A-343 were displaced to the right in a parallel manner by pirenzepine in both prostatic and epididymal portions with no potentiation of the twitches. The Schild plot for this antagonism generated pA2 values of 7.68+/-0.01 and 8.07+/-0.01, respectively. Telenzepine caused parallel shifts of the McN-A-343 concentration-response curves to the right in prostatic portions, the pA2 value being 8.70+/-0.13. Telenzepine (10(-7) M) abolished the inhibitory effect of carbachol to reveal only concentration-dependent potentiation of the contractions. The Schild plot for antagonism of this contractile effect yielded a pA2 value (7.07+/-0.09) that was significantly less by almost two orders of magnitude (1.70) than the value for the antagonism by telenzepine of the McN-A-343-induced inhibitory response. The pA2 values of pirenzepine and telenzepine against the inhibitory responses of the rabbit vas deferens are consistent with the involvement of M1 receptors. This leads to the conclusion that McN-A-343 causes inhibition through this receptor type. The doubts concerning the selectivity of Mc...

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Section: Introductionmentioning

confidence: 99%

Inhibition of field stimulation-induced contractions of rabbit vas deferens by muscarinic receptor agonists: selectivity of McN-A-343 for M1 receptors

Davies

Scholes

Virdi

et al. 2001

Journal of Pharmacy and Pharmacology

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“…Where the slope of the plot did not differ significantly from unity, a line with unit slope was fitted to deter mine the dissociation constant [20], Rabbit Vas deferens. Vasa deferentia from male rabbits were set up as described by Eltze [21 ] and as previously modified [22]. Briefly, segments of the tis sue were set up under a tension of 0.75 g in a 20-ml organ bath containing Eltze's solution [21] at 31 °C, continuously gassed with 95% O2, 5% CO2.…”

Section: Binding Studiesmentioning

confidence: 99%

Variation in the Affinity of Amitriptyline for Muscarine Receptor Subtypes

Choi

Mitchelson²

1994

Pharmacology

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The affinity of amitriptyline for muscarine M₁ receptors was studied in the rat cerebral cortex and rabbit vas deferens utilizing binding studies as well as inhibition of carbachol-induced phosphoinositide hydrolysis in the cerebral cortex and blockade of the muscarinic prejunctional inhibition of sympathetic nerve stimulation in the rabbit vas deferens. The inhibition constants (K₁) or dissociation constants (K_b) obtained were approximately 6- to 20-fold lower than those obtained at muscarine M₂ receptors in rat atria (binding and negative inotropic response) indicating that amitriptyline exhibits a degree of muscarine M₁ receptor selectivity.

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“…Several findings support the hypothesis that these inhibitory heteroreceptors belong to the Ml subtype. Indeed, they have a high affinity for the MI > M2, M3, M4-preferring drug, pirenzepine (pA2 values 8.08-8.52;Lambrecht et al, 1989b;Choo & Mitchelson, 1990;Micheletti et al, 1990;D6rje et al, Eltze et al, 1993;Sagrada et al, 1993) and a low affinity for the M2= M4-preferring drug, methoctramine (pA2 value 6.85;Lambrecht et al, 1989b). In contrast with Micheletti et al (1990), we observed a high affinity (pA2 value 7.0) for the M1>M4 selective compound, guanylpirenzepine (Lambrecht et al, unpublished results).…”

Section: Introductionmentioning

confidence: 99%

Stereoselective recognition of the enantiomers of phenglutarimide and of six related compounds by four muscarinic receptor subtypes

Waelbroeck¹,

Lazareno

Pfaff

et al. 1996

British J Pharmacology

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1 We have compared the binding properties of the enantiomers of phenglutarimide (1) and of six related compounds to M, receptors in NB-OK-1 cells, M2 receptors in rat heart, M3 receptors in rat pancreas and the M4 receptors of rat striatum, with their functional (antimuscarinic) properties in rabbit vas deferens (MI/M4-like), guinea-pig atria (M2) and guinea-pig ileum (M3) receptors. The binding properties of the enantiomers of three of the compounds were also measured on cloned human ml-m4 receptors expressed by CHO cells, using [3H] 3 The pA2 values at the inhibitory heteroreceptors in the rabbit vas deferens, and at the guinea-pig atria and ileum for the seven more potent enantiomers were compatible with the previous classification of these receptors as MI/M4-like, M2 and M3, respectively. 4 Replacement of the phenyl by a thienyl ring or of the diethylamino by a piperidino group in the phenglutarimide molecule did not affect markedly the potencies of the high affinity enantiomer. In contrast, replacement of the phenyl by a cyclohexyl ring decreased 20 fold the active enantiomers potency. Methylation of the piperidine-2,6-dione nitrogen also reduced markedly the eutomers' affinities, more on the M, than on the other subtypes. 5 The selectivity profiles (recognition of four receptor subtypes) of six of the seven less active enantiomers were different from the corresponding more active enantiomers selectivity profiles, suggesting that the preparations used in this study were pure. However, we cannot not exclude the hypothesis that the batch of (S)-thienglutarimide used in this study was contaminated by less than 0.02% of the eutomer. 6 In contrast with the eutomer binding site, replacement of the phenyl ring by a thienyl or cyclohexyl ring did not affect binding of the low affinity enantiomers to the muscarinic receptor or the [3H]-NMSreceptor complex. The replacement of the diethylamino group by a piperidine ring, and N-methylation of the piperidine-2,6 dione moiety increased slightly these enantiomers' potencies. 7 The muscarinic receptors were extremely stereoselective, and had up to 20 000 fold lower affinity for the less active enantiomers. However, the stereochemical requirements of the muscarinic receptor subtypes were different for the enantiomers of compounds 1-7, being most stringent at M, receptors. 8 The weaker enantiomers behaved as competitive antagonists in pharmacological studies, at least in the concentration-range investigated.

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SELECTIVE INHIBITION OF RESPONSES TO CARBACHOL AND McN‐A‐343 IN THE RABBIT VAS DEFERENS

Cited by 11 publications

References 19 publications

Inhibition of field stimulation-induced contractions of rabbit vas deferens by muscarinic receptor agonists: selectivity of McN-A-343 for M1 receptors

Inhibition of field stimulation-induced contractions of rabbit vas deferens by muscarinic receptor agonists: selectivity of McN-A-343 for M1 receptors

Variation in the Affinity of Amitriptyline for Muscarine Receptor Subtypes

Stereoselective recognition of the enantiomers of phenglutarimide and of six related compounds by four muscarinic receptor subtypes

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