No evidence for a role of muscarinic M2 receptors in functional antagonism in XXXX @entity825 .

@entity825 @entity37421 @entity9563 @entity4140 @entity112 @entity3044 @entity2710 @entity291 @entity2472
1. The functional antagonism between @entity2710 - or @entity112 -induced @entity2472 and beta-adrenoceptor-mediated relaxation was evaluated in @entity291 tracheal smooth muscle in vitro. In addition, the putative contribution of muscarinic M2 receptors mediating inhibition of beta-adrenoceptor-induced biochemical responses to this functional antagonism was investigated with the selective muscarinic antagonists, @entity4140 (M1 over M2), AF-DX 116 and @entity9563 (M2 over M3), and @entity37421 (M3 over M2). 2. By use of isotonic tension measurement, contractions were induced with various concentrations of @entity2710 or @entity112 , and @entity3044 concentration-relaxation curves were obtained in the absence or presence of the muscarinic antagonists. Antagonist concentrations were chosen so as to produce selective blockade of M2 receptors (AF-DX 116 0.1 microM, @entity9563 30 microM), or half-maximal blockade of M3 receptors ( @entity4140 0.1 microM, AF-DX 116 0.5 microM, @entity37421 0.03 microM). Since these latter antagonist concentrations mimicked KB values towards @entity291 tracheal smooth muscle M3 receptors, antagonist-induced decreases in contractile tone were compensated for by doubling the agonist concentration. 3. It was found that @entity3044 -induced relaxation of @entity291 tracheal smooth muscle preparations was dependent on the nature and the concentration of the contractile agonist used. Thus, @entity3044 pD2 (-log EC50) values were decreased 3.7 log units as a result of increasing cholinergic tone from 22 to 106%, and 2.4 log units by increasing @entity112 tone over a similar range. Furthermore, maximal relaxability of cholinergic tone decreased gradually from 100% at low to only 1.3% at supramaximal @entity2472 levels, whereas with @entity112 almost complete relaxation was maintained at all concentrations applied. As a result, @entity3044 relaxation was clearly hampered with @entity2710 compared to @entity112 at equal levels of contractile tone.4. In the presence of @entity9563 , @entity3044 relaxation was facilitated for most concentrations of @entity2710 , and for all concentrations of @entity112 . These changes could be explained by the decreased @entity2472 levels for both contractile agonists in the presence of @entity9563 .5. @entity3044 -induced relaxation of cholinergic @entity2472 was also facilitated by AF-DX 116 as well as by @entity4140 and @entity37421 , and these (small) changes were again related to the(small) decreases in cholinergic @entity2472 levels that were present in these experiments despite the additional administration of the agonist to readjust contractile tone. Similarly, changes in @entity3044 relaxation of @entity112 -induced tone could be explained by different @entity2472 levels.6. These results can be explained by the sole involvement of muscarinic M3 receptors, and provide no evidence for a role of muscarinic M2 receptors in functional antagonism in @entity291 @entity825 . Furthermore,they stress the importance of taking into account non-cholinergic controls as well as @entity2472 levels in these experiments.
