Scarpace P J, Koller M M, Rajakumar G
Geriatric Research, Education and Clinical Center, Department of Veterans Affairs Medical Center, Gainesville, FL 32608-1197.
Eur J Pharmacol. 1993 Sep 15;247(1):65-72. doi: 10.1016/0922-4106(93)90138-y.
We previously reported that the tricyclic antidepressant, desipramine desensitizes beta-adrenergic signal transduction in parotid and submandibular salivary glands. To determine the consequences of repeated desipramine administration on beta-adrenergic signal transduction in salivary glands from aged rats and whether the recovery after drug withdrawal is impaired, we assessed the effects of 28-day desipramine administration and the reversibility of this treatment following a 15-day washout period on beta-adrenoceptors and adenylyl cyclase activity in parotid and submandibular glands from F-344 rats of 6, 12 and 24 months of age. beta-Adrenoceptors were also assessed in the cerebral cortex. Desipramine administration down-regulated receptor number and attenuated isoproterenol-stimulated adenylyl cyclase activity in all three ages of rats. However, the reduction in isoproterenol-stimulated adenylyl cyclase activity was greater than the loss of receptor number. Desipramine administration attenuated the efficacy of NaF-stimulated activity with no change in forskolin-stimulated adenylyl cyclase activity. These data suggest that in addition to desensitizing beta-adrenergic-mediated signal transduction, desipramine impaired G-protein-mediated adenylyl cyclase stimulation. The recovery from desipramine desensitization was age dependent. beta-Adrenoceptor density recovered more slowly in the cerebral cortex and the submandibular gland in 24-month-old rats than in 6-month-old rats. In contrast, in 12-month-old rats, there was a receptor up-regulation and adenylyl cyclase supersensitivity. These data indicate that the capacity for receptor modulation is age dependent and suggest that desipramine treatment may down-regulate stimulatory G protein.
我们之前报道过，三环类抗抑郁药地昔帕明可使腮腺和颌下唾液腺中的β-肾上腺素能信号转导脱敏。为了确定反复给予地昔帕明对老年大鼠唾液腺中β-肾上腺素能信号转导的影响，以及停药后恢复是否受损，我们评估了给予地昔帕明28天以及在15天洗脱期后该治疗对6、12和24月龄F-344大鼠腮腺和颌下腺中β-肾上腺素能受体及腺苷酸环化酶活性的可逆性影响。还评估了大脑皮质中的β-肾上腺素能受体。给予地昔帕明下调了所有三个年龄组大鼠的受体数量，并减弱了异丙肾上腺素刺激的腺苷酸环化酶活性。然而，异丙肾上腺素刺激的腺苷酸环化酶活性的降低大于受体数量的减少。给予地昔帕明减弱了氟化钠刺激活性的效力，而福斯高林刺激的腺苷酸环化酶活性没有变化。这些数据表明，除了使β-肾上腺素能介导的信号转导脱敏外，地昔帕明还损害了G蛋白介导的腺苷酸环化酶刺激作用。从地昔帕明脱敏状态的恢复具有年龄依赖性。24月龄大鼠大脑皮质和颌下腺中β-肾上腺素能受体密度的恢复比6月龄大鼠慢。相比之下，12月龄大鼠存在受体上调和腺苷酸环化酶超敏反应。这些数据表明受体调节能力具有年龄依赖性，并提示地昔帕明治疗可能会下调刺激性G蛋白。
