Metabotropic glutamate receptor regulation of cardiovascular activity in conscious rats

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.