PLASTICITY AT SYNAPSES IN THE LOWER URINARY TRACT

下尿路突触的可塑性

• 批准号: 2144974
• 负责人: GEORGE T SOMOGYI
• 金额: $ 14.27万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2144974
• 关键词: acetylcholine; adenosine triphosphate; alpha adrenergic receptor; biological signal transduction; electrostimulus; high performance liquid chromatography; laboratory rat; muscarinic receptor; neural plasticity; neurophysiology; neurotransmitter transport; norepinephrine; parasympathetic nervous system; protein kinase C; receptor expression; second messengers; synapses; urinary bladder; urination

We are using an in vitro model to study the release of acetylcholine (Ach) and norepinephrine (NE) from isolated strips of the rat urinary bladder. In preliminary experiments, Ach release evoked by electrical stimulation of the parasympathetic postganglionic nerve terminals in the urinary bladder was modulated in an entirely different way that in terminals in other organs such as the heart or gut. We found that presynaptic facilitatory M1 and inhibitory M2 muscarinic receptors operate in the rat bladder and subsequent reproduced this finding in the human bladder. We propose that the inhibitory M2 receptors operate when there are low levels of Ach as during urine storage, whereas during micturition high endogenous levels of Ach activate the facilitatory M1 mechanism and induce facilitation of Ach release. Thus, these presynaptic sites could be the primary target for drugs used to control bladder hyperactivity. The facilitated release is inhibited by muscarinic antagonists, drugs frequently used in the treatment of bladder dysfunction. In addition, we have found facilitatory alpha1 adrenoceptors on the parasympathetic nerve endings in the bladder. Both groups of receptors may exhibit plasticity in response to pathophysiologic changes in the bladder. This may explain for example, the observation that the selective alpha1 antagonist, terazosin significantly diminishes bladder pressure in patients with neuropathic but not normal bladders. Our aim is to examine plasticity of these modulatory receptors in rat models of obstructed micturition and neuropathic bladder function following spinal cord injury. Our hypotheses are a) that the facilitatory M1 and inhibitory M2 receptors will downregulate due to higher levels of Ach (bladder hyperactivity) thereby reducing both facilitation and inhibition, b) NE release will be increased due to down-regulation of inhibitory presynaptic M2 receptors on adrenergic nerve terminals, c) the increased release of NE will enhance ACh release through an effect at presynaptic alpha1 adrenoceptors. Presynaptic modulation of ACh release in the hyperactive bladder offers an alternative mechanism of action for drugs used in the treatment of these disorders and opens new avenues for development of drugs acting selectively on cholinergic nerve terminals.

我们正在使用体外模型研究乙酰胆碱的释放 （ACH）和去甲肾上腺素（NE）来自大鼠尿的分离条 膀胱。 在初步实验中，ACH释放由电气引起 刺激副交感神经后神经末端 膀胱以完全不同的方式调节 其他器官（例如心脏或肠道）中的终端。 我们发现 突触前促进性M1和抑制性M2毒蕈碱受体 在大鼠膀胱中运行，随后再现了这一发现 人膀​​胱。 我们建议抑制性M2受体在 尿液储存过程中的ACH水平较低，而在 排尿高度内源性ACH激活了促进性M1 机理和促进ACH释放的促进。 因此，这些 突触前部位可能是用于控制药物的主要目标 膀胱多动症。 促进的释放受到 毒蕈碱拮抗剂，经常用于膀胱治疗的药物 功能障碍。 此外，我们发现了促进性alpha1 膀胱副交感神经末端的肾上腺受体。 两个都 一组受体可能会表现出可塑性 膀胱的病理生理变化。 例如，这可能解释 选择性alpha1拮抗剂Terazosin的观察结果 明显降低神经性患者的膀胱压力 但不是正常的膀胱。 我们的目的是检查这些的可塑性 障碍物的大鼠模型中的调节受体和 脊髓损伤后的神经性膀胱功能。 我们的 假设是a）促进性M1和抑制性M2受体 由于较高的ACH（膀胱多动症），将下调 从而减少促进和抑制作用，b）释放将是 由于抑制性突触前M2受体的下调而增加 在肾上腺能神经末端，c）NE WILL的释放增加 通过突触前α1的效果增强ACH释放 adrenoceptors。 ACH释放的突触前调节过度活跃 膀胱为使用的药物提供了另一种作用机制 这些疾病的治疗并为发展开发了新的途径 在胆碱能神经末端有选择性作用的药物。