Influence of methoctramine on the acetylcholine-isoprenaline functional antagonism in the guinea pig isolated trachea.
It has been suggested that activation of muscarinic M2 receptors is one of the components of the functional antagonism between muscarinic and beta-adrenoceptor agonists in canine and guinea pig tracheal smooth muscle. The aim of the present study was to determine in the guinea pig trachea the importance of this component according to the magnitude of the acetylcholine-induced contraction. Cumulative concentration-response curves for isoprenaline were obtained in the absence or presence of the muscarinic M2 receptor antagonist methoctramine (3 x 10(-7) M) in tracheal rings under basal tension or precontracted by acetylcholine 2 x 10(-7), 3 x 10(-6) and 10(-4) M, giving contractions of 25, 50 Or 75%, respectively, of the maximal tension induced by acetylcholine 3 x 10(-3) M. In the absence of methoctramine, acetylcholine induced a concentration-dependent shift of the concentration-response curves of isoprenaline (-log EC50 of isoprenaline are 8.09 +/- 0.07, 7.85 +/- 0.08, 7.38 +/- 0.12 and 6.49 +/- 0.12, n = 6 for basal tension and for acetylcholine concentrations of 2 x 10(-7), 3 x 10(-6) and 10(-4) M, respectively). In the presence of methoctramine, the basal -log EC50 of isoprenaline was unmodified, whereas the acetylcholine induced shifts of concentration-response curves of isoprenaline were abolished for low levels of contraction (25%) and significantly reduced to 50 and 75% levels of contraction. Under similar conditions, acetylcholine-induced shifts of concentration-response curves of isoprenaline were unmodified by the muscarinic M1 receptor antagonist pirenzepine (10(-7) M). These results suggest that the inhibitory effect of M2 receptors on beta-adrenoceptor agonists effects is important for low contraction levels induced by acetylcholine, and that this effect becomes less important for higher concentrations of acetylcholine.
Zhang
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Y
Faculté de Médecine Paris-Ouest, Laboratoire de Pharmacologie, Paris, France.
Molimard
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M
Advenier
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C
D000109:Acetylcholine / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D003959:Diamines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010276:Parasympatholytics / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D003959:Diamines; D010276:Parasympatholytics; D011976:Receptors, Muscarinic; D007545:Isoproterenol; D000109:Acetylcholine; C054938:methoctramine