Study of the participation of CRF neurotransmission in the bed nucleus of the stria terminalis in cardiovascular changes evoked by stress: interaction with the NMDA receptor/nitric oxide / guanilil cycles / protein kinase g signaling pathway?
Clinical and preclinical studies have demonstrated a role of stress in the pathogenesis of several cardiovascular diseases. However, the neurobiological mechanisms involved in cardiovascular complications related to stress is poorly understood. The bed nucleus of the stria terminalis (BNST) is a limbic structure localized in the rostral prosencephalon, which has been implicated in stress-evoked neuroendocrine, behavioral and cardiovascular responses. It has been reported an involvement of corticotropin-releasing factor (CRF) neurotransmission within the BNST in cardiovascular responses observed during acute stress sessions. However, although reports of neuroplasticity in BNST CRF neurotransmission following exposure to chronic stress protocols, a possible involvement of this neurochemical mechanism in cardiovascular changes evoked by chronic stressors has never been evaluated. Chronic stress exposure evokes several cardiovascular changes, which seem to play an important role in etiology of stress-evoked cardiovascular diseases. Therefore, one of the hypotheses to be tested in the present study is that BNST CRF neurotransmission is involved in cardiovascular changes evoked by chronic stress.Recent studies have demonstrated that activation of CRF1 receptors within the BNST facilitates local glutamatergic neurotransmission. An important mechanism of nitric oxide (NO) formation in the central nervous system is mediated by activation of the NMDA glutamatergic receptor, which in turn activates the neuronal isoform of the NO synthases enzyme (nNOS). The NO has several signaling mechanisms, but the main is mediated by stimulation of cyclic guanosine monophosphate (cGMP) formation that in turn activates protein kinase G. Although above evidence, a possible involvement of local glutamatergic and nitrergic signaling in regulation of cardiovascular function by BNST CRF neurotransmission has never been investigated. Therefore, a second hypothesis to be tested in the present study is that the control of cardiovascular responses during an acute stress session by BNST CRF1 receptor is mediated by local glutamatergic neurotransmission, acting via NMDA receptors and dependent of NO formation and activation of the soluble guanylate ciclase and protein kinase G.Therefore, the aims of the present study are: 1) to evaluate the involvement of BNST CRF neurotransmission in changes of baroreflex activity evoked by the chronic variable stress (CVS); 2) to study the involvement of BNST CRF neurotransmission in cardiovascular hiperesponsivity to an acute stressor evoked by the CVS; 3) to investigate the role of the NMDA receptor/NO/guanylate cyclase/protein kinase G signaling pathway in control of cardiovascular responses to acute restraint stress by the CRF1 receptor within the BNST. (AU)
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