THE CONTROL OF TISSUE-SENSITIVITY TO AUTONOMIC AGENTS

本项目的长期目标是检验假设， 我们在前几年提出的，现在正在得到接受， 靶器官的敏感性是一种动态现象， 内在反馈机制;实验操作， 灵敏度为研究 像眼睛这样的复杂系统，其中几个目标器官具有相同的 药理学特征;这种靶器官的改变 敏感性可能会影响药物的疗效;一些原因 疾病包括这种控制机制的失败，一旦 可以通过药理学手段纠正。 我们的具体目标 未来五年将阐明的性质和特殊性 β-（DFP，毛果芸香碱，氧化震颤素）和 生理诱导（刺激剥夺或过度刺激） 敏感性的变化，使用眼内肌肉作为主要模型系统。 我们将开发技术来诱导虹膜括约肌的亚敏感性 而不影响睫状肌的敏感性， 毒蕈碱系统的每个子组分中的特异性亚敏感性，以及 将使用选择性敏感性改变技术作为一种手段， 分析毒蕈碱系统的复杂性。 我们将进一步测试 假设这种敏感性的变化与 在毒蕈碱（的不同亚群）的浓度中， 受体。 我们还将研究虹膜括约肌改变的影响， 睫状肌敏感性对这些器官的正常功能， 瞳孔描记术和超声技术。 阐明 靶器官敏感性的调控机制具有普遍性 几乎所有生物医学科学领域都具有重要意义， 特别是对于使用自主药物的眼睛 长期用于治疗青光眼和调节性内斜视。 实验旨在确定负责的内源性因素 恒河猴胆碱能不敏感眼的持续性瞳孔缩小 也将进行。 这样的研究可以解释持续的 胆碱酯酶抑制剂治疗患者的瞳孔缩小， 应该对乙酰胆碱不敏感，并揭示一些，迄今未知的，基本的， 胆碱能机制方面。

The long-term objective of this project is to test the hypotheses, which were proposed by us in previous years and are now gaining acceptance, that the sensitivity of target organs is a dynamic phenomenon controlled by inherent feedback mechanisms; that experimental manipulation of this sensitivity provides a new avenue for studying individual components of complex systems like the eye, in which several target organs have the same pharmacological characteristics; that such alterations in target organ sensitivity may affect the efficacy of drugs; and that the cause of some disorders involves the failure of such control mechanisms which, once identified, can be corrected by pharmacological means. Our specific aims for the next five-years will be to elucidate the nature and specificity of pharmacologically- (DFP, pilocarpine, oxotremorine) and physiologically-induced (stimulus deprivation or overstimulation) sensitivity changes, using intraocular muscles as primary model systems. We will develop techniques to induce subsensitivity in the iris sphincter without affecting the sensitivity of the ciliary muscles, to induce specific subsensitivity in each subcomponent of the muscarinic system, and will use the techniques of selective sensitivity alterations as one means of analyzing the complexity of the muscarinic system. We will further test the hypothesis that such changes in sensitivity are associated with changes in the concentration of (different subpopulations of) muscarinic receptors. We will also study the effects of altered iris sphincter and ciliary muscle sensitivity on the normal functions of these organs using pupillographic and ultrasonic techniques, respectively. Elucidation of the mechanism of the control of target organ sensitivity is of great general significance with regard to virtually all areas of biomedical science and especially with regard to the eye, where autonomic agents are used chronically for the treatment of glaucoma and accomodative esotropia. Experiments aimed at identifying the endogenous factors responsible for episodes of sustained miosis in cholinergically subsensitive rhesus eyes will also be undertaken. Such studies may explain the cause of sustained miosis in the eyes of cholinesterase inhibitor-treated patients, which should be subsensitive to ACh, and reveal some, as yet unknown, basic aspects of cholinergic mechanisms.