Effects of muscarinic M2 and M3 receptor stimulation and antagonism on responses to isoprenaline of guinea-pig trachea in vitro.

1. In guinea-pig and canine airway smooth muscle, there is reduced beta-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 beta-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 microM, approximately EC80), the relaxant potency of isoprenaline was significantly (P < 0.05) increased by 0.3 microM 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).(ABSTRACT TRUNCATED AT 250 WORDS)