DESCRIPTION (provided by applicant): Sleep apnea (SA) affects up to 15% of the US population. Many who suffer from SA develop hypertension, which depends in large part on elevated sympathetic nerve activity (SNA). Although central neural mechanisms underlying SA-induced sympathetic activation are largely unknown, efforts to investigate these processes benefit from the fact that the hypertension can be modeled experimentally by exposing rats to chronic intermittent hypoxia (CIH). Studies using the CIH model have implicated two main factors in the development of hypertension - activation of the renin-angiotensin system and the arterial chemoreceptor reflex. Because pre-sympathetic PVN neurons are key mediators of increased SNA evoked by circulating angiotensin II (ANG II) and arterial chemoreceptor activation, co-activation of these inputs by CIH could induce cellular adaptations that increase PVN neuronal activity and excitability, thereby causing a persistent rise in SNA. Preliminary studies indicate that these actions can be modified by local tissue hypoxia, which is postulated to also contribute to the CIH-induced increase in PVN neuronal activity. Specific Aims are to: (1) Establish the contributions of arterial chemoreceptor and ANG II inputs to the PVN in CIH-induced sympathoexcitation and hypertension. (2) Record from pre-sympathetic PVN neurons in vivo and determine how CIH affects the rate and patterning of tonic discharge, basal and hypoxia-induced reductions of PVN pO2 as well as neuronal response to acute activation and silencing of chemoreceptor- and ANG II-sensitive inputs. (3) Perform whole-cell patch clamp recordings from pre-sympathetic PVN neurons in brain slices and determine effects of CIH on cell activity and excitability as well as membrane potential and current responses to glutamate and ANG II. Determine how tissue hypoxia modulates glutamatergic and persistent sodium currents in pre-sympathetic PVN neurons and how these are modulated by prior exposure to CIH. Record and manipulated pO2 in the PVN to mimic values observed in conscious rats during exposure to CIH and determine how tissue hypoxia modulates glutamatergic and ANG II-stimulated PVN neuronal activity. By determining how CIH modifies PVN neuronal responses to specific afferent inputs and how tissue hypoxia further modulates these effects, the proposed studies should provide new and potentially important insight into the neurogenic mechanisms of SA-induced hypertension. Project Narrative: Sleep apnea is a form of sleep disordered breathing that affects a large percentage of the adult population in the US. Sleep apnea is associated with many cardiovascular complications including high blood pressure. This project seeks to uncover fundamental cellular adaptations that occur among sympathetic- regulatory neurons in the hypothalamus upon exposure to episodes of hypoxia. Our goal is to identify new molecular targets for treatment of elevated sympathetic activity and high blood pressure that accompany sleep apnea.
|Effective start/end date||4/1/08 → 8/31/08|
- National Institutes of Health: $362,704.00