Effects of muscarinic M2 and M3 receptor stimulation and antagonism on responses to isoprenaline of guinea‐pig trachea in vitro
Open Access
- 1 May 1994
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 112 (1), 179-187
- https://doi.org/10.1111/j.1476-5381.1994.tb13049.x
Abstract
1 In guinea-pig and canine airway smooth muscle, there is reduced β-adrenoceptor agonist sensitivity in tissues pre-contracted with muscarinic agonists when compared to tissues pre-contracted with other spasmogens, such as histamine or leukotriene D4. This reduced sensitivity may be the result of an interaction between muscarinic receptors and β-adrenoceptors. In this study the effects of M2 receptor antagonism and stimulation have been investigated on the relaxant potency of isoprenaline in guinea-pig isolated tracheal smooth muscle. 2 (+)-cis-Dioxolane contracted isolated tracheal strips in a concentration-dependent manner (EC50 = 11.5 ± 0.9 nm). The rank order of antagonist apparent affinities (with pA2 values in parentheses) was atropine (9.4 ± 0.1) > zamifenacin (8.2 ± 0.1) >para-fluoro-hexahydro-siladiphenidol (p-F-HHSiD, 7.2 ± 0.1) > pirenzepine (6.5 ± 0.1) > methoctramine (5.5 ± 0.1). Schild slopes were not significantly different from unity. This was consistent with a role of muscarinic M3 receptors in mediating contraction. 3 In tissues pre-contracted to 3 g isometric tension using (+)-cis-dioxolane (0.2 μm, approximately EC80), the relaxant potency of isoprenaline was significantly (P < 0.05) increased by 0.3 μm methoctramine (control EC50 = 32.2 ± 4.3 nm, plus methoctramine EC50 = 19.1 ± 4.5 nm). This concentration of methoctramine had no effect on contractile responses to (+)-cis-dioxolane (control, EC50 = 17.6 ± 3.2 nm, plus methoctramine, EC50 = 21.0 ± 4.4 nm). 4 When acetylcholine (non-selective), (+)-cis-dioxolane (non-selective), L-660,863 ((±)-3-(3-amino-1,2,4-oxadiazole-5-yl)-quinuclidine, M2-selective) or SDZ ENS 163 (thiopilocarpine, mixed M2 antagonist, partial M3 agonist) were used to achieve isometric tensions of 3 g, the relaxant potency of isoprenaline ranged from 3.7 ± 0.3 nm (SDZ ENS 163) to 49.4 ± 3.2 nm ((+)-cis-dioxolane). Reducing the concentration of these agonists (and therefore the level of developed tension to 2 g), significantly (P < 0.05) increased the relaxant potency of isoprenaline. In contrast, when histamine was used to pre-contract tissues to either 2 or 3 g (EC50 = 4.2 ± 0.6 and 3.8 ± 1.1 nm, respectively), there was no significant effect on the relaxant potency of isoprenaline. 5 There was a slight but significant (P < 0.05) reduction in the relaxant potency of isoprenaline, in tissues pre-contracted to 3 g using histamine in combination with (+)-cis-dioxolane (30 nm). This effect was reversed by M2 receptor antagonism, using methoctramine (1 μm). 6 These data suggest that in guinea-pig isolated trachea, the relaxant potency of isoprenaline may depend not only on the level of developed tension but also, on the level of muscarinic M2 receptor stimulation/blockade of the spasmogen inducing the tension. However, the lack of selective M2 agonist and the low M2/M3 selectivity of antagonists in this tissue do not permit definitive conclusions to be made about the role of these receptors in modulating isoprenaline potency.Keywords
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