Metabotropic glutamate receptor regulation of cardiovascular activity in conscious rats

有证据表明第1组谷氨酸代谢型受体（mGluR）在心血管调节中，包括外周和中枢神经系统（CNS）的影响。第1组mGluR包括存在于海马、皮质、丘脑、小脑、脑干和脊髓中的mGlu 1和mGlu 5亚型。它们涉及多种病症，包括癫痫、局部缺血、疼痛、焦虑、精神分裂症和神经变性疾病（Bordi和Ugolini，1999; Dalfo等人，2004，2005; Albasanz等人，2005; Vidnyanszky等人，1994; Valerio等人，1997; Gasparini等人，2008; Conn等人，2009年）。mGluR在外周组织中的作用很少被研究（Gill和Pulido，2001，2005），尽管第1组mGluR已经在神经末梢、壁内神经节、心肌及其传导系统中显现（Gill等人，1999年，Iglesias等人，2007年）。这些受体被认为与动脉压和心率的维持有关（Foley等人，1999; Matsumura等人，1999年）。此外，mGluR参与主动脉弓水平压力感受器活性的转导（Paton et al. 2010）。已经描述了由mGlu受体的激动剂和拮抗剂介导的心血管作用在大鼠的延髓中，包括孤束核（NTS）和延髓头端腹外侧（RVLM）（Simms等人，2006; Tsuchihashi等人，2000年; Viard和Sapru，2002年）。这些结构形成调节心血管系统的核心神经回路：NTS是压力感受器和外周化学感受器传入的终止部位，RVLM容纳驱动脊髓中的节前心血管神经元的运动前交感神经元。NTS中的mGluR 2已显示可调节压力感受器心脏迷走神经反射的增益（Simms等人，2006），但尚无关于第1组mGluR的数据。在临床前研究（例如Conn et al，2009）中，第1组配体显示的治疗前景可能会或可能不会受到不良心血管事件的影响。在RVLM和脊髓组水平，1 mGluR增加动脉压和心率，表明对交感神经系统的直接影响（Celuch & García Mdel，2002; Tsuchihashi et al. 2000）。最近已经描述了mGlu 5受体的正构和变构激动剂和拮抗剂（Gasparini等人，2008年，Conn等人，2009），但这些化合物影响心血管系统的潜力尚未用真正的亚型选择性配体进行研究。目的：研究工业合作伙伴提供的一些mGluR 5受体配体对心血管活性的影响。假设：mGluR 5刺激增加动脉压。我们将描绘周边与中央行动的mGluR 5和评估的机制，通过改变自主神经系统的活动，他们影响动脉血压和心率。在清醒大鼠中使用无线电遥测技术，我们将在iPRECIO装置递送mGluR激动剂和拮抗剂期间长期监测血压和交感神经活动（参见McBryde等人，2010）;这种新型装置允许程控输注速率、储液器再填充和化合物的变化（Abe等人，2009）。将构建剂量反应曲线。为了描述外周效应与中枢效应，将通过脑室内输注药物。我们还将比较脱水大鼠（2-3天）的作用，以确定mGluR 5在高渗期间心血管控制中的任何综合作用。将使用功率谱分析（Waki等人，2006）分析收缩压和脉搏间期。所有技术都可在宿主的实验室中获得（例如Sales等人，2010年; Waki等人，2007年）。作为临床应用的一步，工业合作伙伴将在较大物种中进行比较研究。工业公司和学术部门合作的好处在其他地方。

Evidence exists for group 1 glutamate metabotropic receptors (mGluR) in cardiovascular regulation that include both peripheral and central nervous system (CNS) effects. Group 1 mGluR comprise mGlu1 and mGLu5 subtypes that are present in the hippocampus, cortex, thalamus, cerebellum, brainstem and spinal cord. They have been implicated in a variety of disorders including epilepsy, ischemia, pain, anxiety, schizophrenia and neurodegenerative diseases (Bordi and Ugolini, 1999; Dalfo et al., 2004, 2005; Albasanz et al., 2005; Vidnyanszky et al., 1994; Valerio et al., 1997; Gasparini et al., 2008; Conn et al., 2009). The role of mGluR in peripheral tissues has been little studied (Gill and Pulido, 2001, 2005) although group 1 mGluR have been visualized in nerve terminals, intramural ganglia, myocardium and its conducting system (Gill et al., 1999, Iglesias et al., 2007). These receptors are thought to be associated with the maintenance of arterial pressure and heart rate (Foley et al., 1999; Matsumura et al., 1999). Additionally, mGluR are involved in the transduction of baroreceptor activity at the level of the aortic arch (Paton et al. 2010). Cardiovascular effects mediated by agonists and antagonists of mGlu receptors have been described in the medulla oblongata including the nucleus tractus solitarii (NTS) and rostral ventrolateral medulla (RVLM) of rats (Simms et al. 2006; Tsuchihashi et al., 2000; Viard and Sapru, 2002). These structures form core neural circuitry regulating the cardiovascular system: the NTS is the site of termination of baroreceptor and peripheral chemoreceptor afferents and the RVLM houses pre-motor sympathetic neurones that drive pre-ganglionic cardiovascular neurones in the spinal cord. mGluR 2 in NTS have been shown to modulate the gain of the baroreceptor cardiac vagal reflex (Simms et al. 2006) but no data are available concerning group 1 mGluR. The therapeutic promise shown by group 1 ligands in preclinical studies (e.g. Conn et al, 2009) may or may not be compromised by adverse cardiovascular events. At the level of both the RVLM and spinal cord group 1 mGluR increased arterial pressure and heart rate indicating a direct effect on the sympathetic nervous system (Celuch & García Mdel, 2002; Tsuchihashi et al. 2000). Orthosteric and allosteric agonists and antagonists of mGlu5 receptors have been described recently (Gasparini et al., 2008, Conn et al., 2009) but the potential of these compounds to influence the cardiovascular system has not been studied with truly subtype-selective ligands. AIM: To examine a number of mGluR5 receptor ligands supplied by the industrial partner on cardiovascular activity. HYPOTHESIS: mGluR 5 stimulation increases arterial pressure. We will delineate peripheral versus central actions of mGluR5 and assess the mechanisms by which they affect arterial pressure and heart rate through alterations of autonomic nervous system activity. Using radio-telemetry in conscious rats we will monitor blood pressure and sympathetic nerve activity chronically (see McBryde et al. 2010) during iPRECIO device delivered mGluR agonists and antagonists sub-cutaneously; this novel device allows programmed infusion rates, reservoir re-filling and change of compound (Abe et al. 2009). Dose response curves will be constructed. To delineate peripheral vs central effects, drugs will be infused intra-cerebroventricularly. We will also compare effects in dehydrated rats (2-3 days) to determine any integrative role of mGluR 5 have in cardiovascular control during hyperosmolality. Systolic pressure and pulse interval will be analysed using power spectral analysis (Waki et al. 2006). All techniques are available in the host's lab (e.g. Sales et al. 2010; Waki et al. 2007). As a step towards clinical application, comparative studies will be performed in larger species by the industrial partner. Benefits of the collaboration for the industrial company and academic department are given elsewhere.