Hypertension is an important risk factor for the development of cardiovascular disease. Despite major therapeutic advances, hypertension is often treatment resistant and still causes countless deaths from stroke and heart disease. Hypertension may be neurogenic i.e. it is associated with and probably caused by a chronic elevation of sympathetic nerve activity (SNA). This SNA elevation has many suspected causes such as an increase in carotid body activity, brainstem hypoxemia and CNS oxidative stress but the CNS network that ultimately mediates the SNA elevation is not well understood. One reason is our limited understanding of the connections and function of most brainstem pathways implicated in the generation of SNA. This proposal focuses on the contribution of the A5 group of hindbrain noradrenergic neurons to the regulation of SNA and blood pressure (BP). This choice is motivated by four considerations. First, A5 neurons are the main source of noradrenergic input to sympathetic preganglionic neurons. Second, noradrenaline exerts powerful excitatory effects on sympathetic preganglionic neurons. Third, A5 neurons are strongly activated by hypoxia and therefore could mediate some of the effects of hypoxia on SNA and contribute to the adaptive changes elicited by hypoxia. Lastly, the efflux of noradrenaline metabolites from the brain of hypertensive humans (MHPG) is elevated, which suggests that CNS NA-release may be abnormally high. These four considerations suggest that A5 neurons hyperactivity could contribute to neurogenic hypertension. I will test the hypothesis that A5 noradrenergic cells activate the sympathetic nervous system by exciting sympathetic preganglionic neurons via NA-release. Second, I propose to determine the transcriptome and connectome of A5 neurons, and compare them with that of neighboring neurons that control BP in the rostral ventrolateral medulla. And finally, I will test whether A5-dependent NA-release causes sympathetic hyperactivity in a model of sleep apnea (acute intermittent hypoxia). Understanding the hindbrain networks controlling the sympathetic system may benefit the treatment of any condition associated with sympathetic dysfunction, like neurogenic hypertension, heart failure and multiple systems atrophy. Page 6 Project Summary/Abstract
Project summary This proposal focuses on the contribution of the A5 group of hindbrain noradrenergic neurons to the regulation of sympathetic nerve activity and blood pressure. Understanding the function of these neurons may benefit the treatment of any condition associated with sympathetic dysfunction, like neurogenic hypertension, heart failure and multiple systems atrophy.
