Takagi Ikuyo, Nejima Jun, Kiuchi Kaname, Takagi Gen, Takano Teruo
First Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
J Cardiovasc Pharmacol. 2006 Nov;48(5):223-30. doi: 10.1097/01.fjc.0000247801.98874.a6.
Chronic stimulation of beta-adrenergic receptors (betaARs) induces betaAR downregulation. However, it is not known whether continuous activation of adenylyl cyclase without direct stimulation of betaARs leads to receptor downregulation. This study investigated the effects of chronic stimulation of adenylyl cyclase with colforsin, on hemodynamic variables, and on myocardial betaAR density. In all, 55 rabbits received intravenous colforsin (1.6 microg/kg/min, n = 20), isoproterenol (ISO; 0.4 microg/kg/min, n = 16), or saline (n = 19) for two weeks. After chronic drug administration, responses of systolic (Delta% peak LV +dP/dt) and diastolic function (Delta% peak LV -dP/dt), and heart rate (Delta% heart rate), to acute administration of ISO (0.05 to 0.2 microg/kg/min) or colforsin (5 to 20 nmol/kg/min) were decreased compared to those before chronic administration. betaAR density in the colforsin group (69.8 +/- 13.8 fmol/ml protein) was less than that in the saline group (79.8 +/- 15.0 fmol/ml protein, P < 0.05), but was greater than that in the ISO group (56.3 +/- 8.4 fmol/ml protein, P < 0.05). Thus, chronic direct stimulation of adenylyl cyclase elicited systolic and diastolic functional desensitization to betaAR stimulation or adenylyl cyclase stimulation, and myocardial betaAR downregulation.
β-肾上腺素能受体（βARs）的慢性刺激会导致βAR下调。然而，腺苷酸环化酶持续激活而无βAR直接刺激是否会导致受体下调尚不清楚。本研究调查了用福司柯林慢性刺激腺苷酸环化酶对血流动力学变量以及心肌βAR密度的影响。总共55只兔子接受静脉注射福司柯林（1.6微克/千克/分钟，n = 20）、异丙肾上腺素（ISO；0.4微克/千克/分钟，n = 16）或生理盐水（n = 19），持续两周。慢性给药后，与慢性给药前相比，急性给予ISO（0.05至0.2微克/千克/分钟）或福司柯林（5至20纳摩尔/千克/分钟）时，收缩功能（左心室峰值+ dP/dt变化百分比）、舒张功能（左心室峰值 - dP/dt变化百分比）和心率（心率变化百分比）的反应均降低。福司柯林组的βAR密度（69.8±13.8飞摩尔/毫升蛋白质）低于生理盐水组（79.8±15.0飞摩尔/毫升蛋白质，P < 0.05），但高于ISO组（56.3±8.4飞摩尔/毫升蛋白质，P < 0.05）。因此，腺苷酸环化酶的慢性直接刺激引发了对βAR刺激或腺苷酸环化酶刺激的收缩和舒张功能脱敏以及心肌βAR下调。
