MECHANISMS UNDERLYING THE CIRCADIAN RHYTHM OF IOP

IOP 昼夜节律的机制

• 批准号: 2710864
• 负责人: DOUGLAS S GREGORY
• 金额: $ 28.21万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-08-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2710864
• 关键词: adenylate cyclase; alpha adrenergic receptor; atrial natriuretic peptide; circadian rhythms; cyclic AMP; cyclic GMP; dark adaptation; enzyme activity; forskolin; intraocular aqueous flow; intraocular fluid; intraocular pressure; laboratory rabbit; light adaptations; melatonin; nitric oxide synthase; protein kinase; radiotracer; second messengers; statistics /biometry; sympathetic nervous system; uvea ciliary body

The specific aims of this proposal are (1) to characterize the daily rhythms of ciliary process cAMP and cGMP in vivo, and (2) to determine the roles of a2-adrenergic receptor control of adenylate cyclase, (3) natriuretic peptide control of cGMP, and (4) soluble guanylate cyclase, nitric oxide synthase modulation of cGMP in control of the circadian rhythms of intraocular pressure and the aqueous flow rate in rabbits and to explore the possible interaction between the sympathetic system and cGMP. Rabbits have robust, reproducible daily rhythms of intraocular pressure and aqueous flow, and the latter makes a significant contribution to the daily change of intraocular pressure. The PI observations of decreased nocturnal intraocular pressure, aqueous flow and the concentration of cyclic AMP in the aqueous after (-adrenergic blockade support a role for (-adrenergic receptor/adenylate cyclase mediated mechanisms in the nocturnal increases of intraocular pressure and aqueous flow. Sympathetic input via the ocular sympathetic nerves plays an important role in control of both rhythms; surgical sympathectomy markedly blunts the nocturnal increases of intraocular pressure, aqueous flow and aqueous cyclic AMP. In spite of ample evidence that a2-adrenergic agonists potently decrease intraocular pressure and the aqueous flow rate, a role for a2-adrenergic receptors in control of the rhythm of intraocular pressure remains to be demonstrated - While considerable evidence has been developed implicating cyclic AMP in control of intraocular pressure and aqueous flow, the role of cyclic GMP has been largely overshadowed by cyclic AMP until recently. While investigating the role a2-adrenergic receptors, the PI has developed a technique to measure endogenous iris-ciliary body and ciliary process cyclic nucleotides levels in vivo. Preliminary studies have demonstrated nocturnal increase of cAMP and cGMP in iris-ciliary processes suggesting that both cyclic nucleotides may play roles in control of the circadian rhythms of IOP and aqueous flow. Measurement of tissue cyclic nucleotide levels in vivo provides a powerful tool for elucidating their role in control of the circadian rhythms of aqueous flow and IOP.

该提案的具体目的是（1）表征每日 睫状过程营地和体内CGMP的节奏，以及（2）至 确定腺苷酸A2-肾上腺素受体控制的作用 CGMP的循环酶，（3）NATRIARITE肽的控制，（4）可溶性 鸟烯基环化酶，一氧化氮合酶在CGMP中的调节 控制眼内压的昼夜节律和 兔子中的水流速并探索可能的相互作用 在交感神经系统和CGMP之间。兔子有强大的 眼内压和水流的每日节奏，可再现的节奏， 后者为每日变化做出了重大贡献 眼内压。 夜间降低的PI观察结果 眼内压，水流和环状浓度 在水中的AMP之后（ - 肾上腺素能阻断支持 （ - 肾上腺素能受体/腺苷酸环化酶介导的机制 眼内压和水流的夜间增加。 通过眼交感神经的交感神经输入扮演 在控制这两种节奏方面的重要作用；手术交感神经切除术 明显钝化了眼内压的夜间增加， 水流和水性环状AMP。尽管有充分的证据表明 A2-肾上腺素能激动剂有效降低眼内压力和 水流速，A2-肾上腺素受体在对照中的作用 眼内压的节奏仍有待证明 - 虽然已经开发了大量证据，暗示了循环 放大器控制眼内压和水流，角色 循环GMP的循环AMP在很大程度上掩盖了直到 最近。在研究A2-肾上腺素能受体的角色时， PI开发了一种测量内源性虹膜丝体的技术 和纤毛过程循环核苷酸在体内的水平。初步的 研究表明，CAMP和CGMP的夜间增加 虹膜 - 丝状过程表明两个环状核苷酸都可能 在控制IOP和水性的昼夜节律中发挥作用 流动。在体内的组织环核苷酸水平的测量 提供了一种强大的工具来阐明其在控制中的作用 水流和IOP的昼夜节律。