Suzuki K, Sugiyama S, Takagi K, Satake T, Ozawa T
Biochem Med Metab Biol. 1987 Apr;37(2):157-66. doi: 10.1016/0885-4505(87)90022-3.
It has been observed that repeated and prolonged beta-agonist treatment causes the impairment of beta-adrenergic function, so-called "desensitization" or "down regulation". To clarify the mechanism of down regulation, the following experiment was performed using guinea pig lungs. Animals were divided into four groups: In the metaproterenol groups, guinea pigs were treated with metaproterenol (10 mg/kg/day) by intraperitoneal injection once a day for 1 day or for 7 successive days In the control groups, guinea pigs were treated with saline by the same procedure as in the metaproterenol groups. In the group treated with metaproterenol for 7 days, there was a 45% reduction in the number of beta-adrenoceptors and a 62% reduction in adenylate cyclase activity, compared with those of the control group. However, there were no significant changes in the dissociation constant (Kd) of the receptors. On the other hand, no reduction in the number of beta-adrenoceptors and adenylate cyclase activity was observed in the group treated with metaproterenol once a day for 1 day, compared with those of the control group. Phospholipase (PLase) activity in the lung microsomes of guinea pigs injected with metaproterenol for 1 day and for 7 days was elevated by 14.4 and 33.1%, respectively, compared with that of the control groups. Phospholipid contents of lung membranes prepared from the animals treated with metaproterenol for 7 days were significantly decreased compared with those of the control group, though in the group treated with metaproterenol once a day for 1 day, phospholipid contents did not differ from those of the control. Lung membranes treated with PLase A2 revealed decreases both in the number of beta-adrenoceptors and adenylate cyclase activity, dose dependently. These results and the fact that membrane phospholipids are involved in the beta-adrenoceptor system suggest that down regulation observed during beta-agonist administration is, at least in part, attributed to degradation of phospholipids of lung membranes by the persistent activation of PLase in the tissue.
据观察，反复且长时间的β-激动剂治疗会导致β-肾上腺素能功能受损，即所谓的“脱敏”或“下调”。为阐明下调机制，使用豚鼠肺进行了以下实验。动物分为四组：在间羟异丙肾上腺素组中，豚鼠每天腹腔注射间羟异丙肾上腺素（10mg/kg/天），持续1天或连续7天。在对照组中，豚鼠按与间羟异丙肾上腺素组相同的程序注射生理盐水。与对照组相比，间羟异丙肾上腺素治疗7天的组中，β-肾上腺素能受体数量减少了45%，腺苷酸环化酶活性降低了62%。然而，受体的解离常数（Kd）没有显著变化。另一方面，与对照组相比，间羟异丙肾上腺素每天注射1天的组中，未观察到β-肾上腺素能受体数量和腺苷酸环化酶活性的降低。与对照组相比，注射间羟异丙肾上腺素1天和7天的豚鼠肺微粒体中的磷脂酶（PLase）活性分别升高了14.4%和33.1%。与对照组相比，间羟异丙肾上腺素治疗7天的动物制备的肺膜磷脂含量显著降低，而间羟异丙肾上腺素每天注射1天的组中，磷脂含量与对照组无差异。用PLase A2处理的肺膜显示β-肾上腺素能受体数量和腺苷酸环化酶活性均呈剂量依赖性降低。这些结果以及膜磷脂参与β-肾上腺素能受体系统这一事实表明，β-激动剂给药期间观察到的下调至少部分归因于组织中PLase的持续激活导致肺膜磷脂的降解。
