Lai F M, Cobuzzi A, Spinelli W
Cardiovascular/Metabolic Diseases, Wyeth-Ayerst Research, Princeton, NJ 08543-8000, USA.
Life Sci. 1998;62(13):1179-86. doi: 10.1016/s0024-3205(98)00044-7.
We have characterized in vitro the muscarinic receptors mediating the contraction of the detrusor muscle in Cynomolgus monkeys and guinea pigs using carbachol as the agonist and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, M3-selective), methoctramine (M2-selective) and pirenzepine (M1-selective) as the antagonists. Carbachol induced a concentration-dependent contraction of the detrusor muscle of monkey and guinea pig yielding similar pD2 values of 6.67+/-0.03 (n=50) and 6.77+/-0.06 (n=36), respectively. In the detrusor muscle of Cynomolgus monkey, all antagonists produced a concentration-dependent inhibition of carbachol-induced contractions, without decreasing the maximal response. Schild plot analysis yielded slopes not different from unity for all antagonists. The order of antagonist potency was: 4-DAMP (pA2=8.96)>pirenzepine (pA2=6.66)>methoctramine (pA2=6.03), suggesting that M3 receptors have a dominant role in mediating detrusor contraction. In the detrusor muscle of the guinea pig, 4-DAMP and pirenzepine, but not methoctramine, produced a concentration-dependent inhibition of the carbachol-induced contractions, without decreasing the maximal response. Schild plot analysis yielded a slope not different from unity for 4-DAMP and pirenzepine. 4-DAMP (pA2=9.07) had a higher potency than pirenzepine (pA2=6.66), a finding consistent with previously published data. The present study shows that in Cynomolgus monkey stimulation of the M3 subtype is dominant in mediating detrusor contraction upon carbachol stimulation.
我们使用卡巴胆碱作为激动剂，4-二苯基乙酰氧基-N-甲基哌啶甲基碘化物（4-DAMP，M3选择性）、甲氧基氨（M2选择性）和哌仑西平（M1选择性）作为拮抗剂，在体外对食蟹猴和豚鼠逼尿肌收缩所介导的毒蕈碱受体进行了特性分析。卡巴胆碱引起猴和豚鼠逼尿肌浓度依赖性收缩，其pD2值分别为6.67±0.03（n = 50）和6.77±0.06（n = 36），二者相似。在食蟹猴的逼尿肌中，所有拮抗剂均产生浓度依赖性抑制卡巴胆碱诱导的收缩作用，且不降低最大反应。Schild图分析显示，所有拮抗剂的斜率均与1无差异。拮抗剂效力顺序为：4-DAMP（pA2 = 8.96）>哌仑西平（pA2 = 6.66）>甲氧基氨（pA2 = 6.03），提示M3受体在介导逼尿肌收缩中起主要作用。在豚鼠的逼尿肌中，4-DAMP和哌仑西平可产生浓度依赖性抑制卡巴胆碱诱导的收缩作用，且不降低最大反应，而甲氧基氨则无此作用。Schild图分析显示，4-DAMP和哌仑西平的斜率与1无差异。4-DAMP（pA2 = 9.07）的效力高于哌仑西平（pA2 = 6.66）这一结果与先前发表的数据一致。本研究表明，在食蟹猴中，卡巴胆碱刺激时，M3亚型的刺激在介导逼尿肌收缩中占主导地位。
