PROJECT SUMMARY/ABSTRACTSleep apnea is the most common form of sleep disordered breathing and patients with sleep apnea exhibitpersistent activation of the sympathetic nervous system ? which has known negative consequences, includingthe development of chronic hypertension. Intermittent hypoxia (IH) has been implicated as the primarystimulus for evoking increases in sympathetic activity and resultant hypertension with recurrent apneas.Evidence from animals suggests the persistent rise in sympathetic nervous system activity with IH occursthrough changes in both chemoreflex and baroreflex function; however, little is known regarding thecontribution of these reflexes to sympathetic discharge patterns in humans. Along these lines, research inanimals supports a contribution of endothelin-1 to autonomic changes with IH, however these findings have yetto be translated to humans. Thus, the overall goal of this K99/R00 application is to better understand theeffect of IH on sympathetic neuronal discharge patterns in humans, as well as mechanisms thatmediate persistent sympathoexcitation with IH. We will use measures of sympathetic nervous systemactivity and a novel action potential analysis approach to test ideas about reflex-mediated sympatheticdischarge patterns and contributing mechanisms in IH. In Aim 1, we will characterize sympathetic neuronaldischarge patterns in response to acute IH in healthy humans. In Aim 2, we will use acute hyperoxia toidentify the contribution of the carotid chemoreflex to sympathetic nervous system activation with IH. In Aim 3,we will use intravenous phenylephrine to identify the contribution of the baroreflex to sympathetic nervoussystem activation with IH. In Aim 4, we will identify the contribution of endothelin-1 to sympathetic dischargepatterns with IH and its role in chemoreflex- and baroreflex-mediated changes in sympathetic nervous systemactivity. The proposed novel human studies are designed to provide a major step forward in understanding thelink between IH and persistent sympathoexcitation ? and by extension, hypertension and associatedcardiovascular disease risk in humans with sleep apnea. To our knowledge, this is the first effort to understandsympathetic discharge patterns in response to IH in humans from both a descriptive (Aim 1) and mechanistic(Aims 2-4) standpoint. Importantly, we will collect basic physiological data under tightly-controlled conditionsin healthy humans to systematically examine the effect of IH and identify key contributing mechanisms onsympathetic control that will be critical to our understanding prior to targeted work in patients with sleep apnea.By better understanding the effect of acute IH on sympathetic activity, therapeutic approaches can bedesigned to systematically normalize sympathetic control of the cardiovascular system in conditionsof IH (e.g. sleep apnea) to prevent the development of hypertension and other complications related tosympathetic over-activity. Furthermore, these projects will serve as a vehicle to build upon the Applicant'straining in neurovascular control and her recently completed F32-funded work by providing opportunities forher to gain additional knowledge and learn new experimental techniques and approaches. Importantly, this willalso generate an investigative niche for the Applicant's intellectual and technical skill sets that will launch herindependent career.
|Effective start/end date||8/1/16 → 7/31/21|
- National Institutes of Health: $143,778.00