Nakazato Y, Oleshansky M A, Chiang P K
Department of Applied Biochemistry, Walter Reed Army Institute of Research, Washington, D.C. 20307-5100.
Arch Int Pharmacodyn Ther. 1988 May-Jun;293:209-18.
The effects of the muscarinic antagonists, atropine, aprophen, azaprophen and pirenzepine, on catecholamine secretion stimulated by acetylcholine (ACh) and nicotine were studied using perfused and isolated guinea-pig adrenal glands. Sequential 2-min infusions of ACh (10(-5)M) at 15-min intervals evoked repetitive catecholamine secretory responses for at least 1 hr. This dose of ACh produced a predominantly muscarinic receptor-mediated catecholamine secretory response, which was inhibited by all muscarinic antagonists used. The order of potency was atropine greater than azaprophen greater than pirenzepine greater than aprophen, with IC50 values of 1.0 x 10(-9), 3.8 x 10(-9), 7.0 x 10(-8) and 1.3 x 10(-6) M, respectively. In comparison, repeated 1-min infusions of nicotine (2 x 10(-5) M) at 15-min intervals evoked progressively smaller catecholamine secretory responses over the course of 1 hr. At higher doses, atropine, azaprophen and aprophen also inhibited the nicotine-induced catecholamine secretion. In contrast, pirenzepine had no effect on the nicotinic response. The IC50 values for atropine, azaprophen and aprophen were 2.7 x 10(-6), 1.5 x 10(-6), and 3.2 x 10(-6) M, respectively. Because the antinicotinic effect of atropine and azaprophen was achieved at concentrations 2 to 3 orders of magnitude higher than those needed for the antimuscarinic effect, it was most likely not pharmacologically significant, but rather due to nonspecific inhibition of the nicotinic receptor.
使用灌注和分离的豚鼠肾上腺，研究了毒蕈碱拮抗剂阿托品、阿普罗芬、阿扎丙芬和哌仑西平对乙酰胆碱（ACh）和尼古丁刺激的儿茶酚胺分泌的影响。以15分钟的间隔连续2分钟输注ACh（10⁻⁵M），可诱发重复性儿茶酚胺分泌反应，至少持续1小时。该剂量的ACh产生了主要由毒蕈碱受体介导的儿茶酚胺分泌反应，所用的所有毒蕈碱拮抗剂均能抑制该反应。效力顺序为阿托品＞阿扎丙芬＞哌仑西平＞阿普罗芬，IC50值分别为1.0×10⁻⁹、3.8×10⁻⁹、7.0×10⁻⁸和1.3×10⁻⁶M。相比之下，以15分钟的间隔重复1分钟输注尼古丁（2×10⁻⁵M），在1小时内诱发的儿茶酚胺分泌反应逐渐减小。在较高剂量下，阿托品、阿扎丙芬和阿普罗芬也能抑制尼古丁诱导的儿茶酚胺分泌。相比之下，哌仑西平对烟碱反应无影响。阿托品、阿扎丙芬和阿普罗芬的IC50值分别为2.7×10⁻⁶、1.5×10⁻⁶和3.2×10⁻⁶M。由于阿托品和阿扎丙芬的抗烟碱作用是在比抗毒蕈碱作用所需浓度高2至3个数量级的浓度下实现的，因此很可能在药理学上无显著意义，而是由于对烟碱受体的非特异性抑制。
