Essential hypertension is a leading form of cardiovascular disease that greatly increases the risks of morbidity and mortality. Many forms of essential hypertension are associated with augmented sympathetic nerve activity (SNA), although the basis of the sympatho-activation is not well understood. Respiratory regulatory neurons in the brain provide a significant influence on SNA, and altered respiratory-related modulation of SNA is present in several models of hypertension. Links between central respiratory neurons and those that regulate the SNA that maintains arterial pressure (AP) are completely unknown. This project will elucidate connections from central respiratory neurons to cardiovascular regulatory neurons and determine whether the influences of these respiratory-related inputs are changed in a hypertensive model associated with altered respiratory-related modulation of SNA, namely exposure to chronic intermittent hypoxia (CIH). The long range goals of this research are to elucidate central neural circuits that regulate the SNA that maintains AP and pinpoint alterations that may lead to elevated SNA and hypertension. This SNA is driven by neurons in the rostral ventrolateral medulla (RVLM), and the RVLM is powerfully restrained by GABAergic neurons in the caudal ventrolateral medulla (CVLM). The role of GABAergic CVLM neurons in the baroreflex control of SNA is well established, but baro-activated GABAergic CVLM neurons also tonically inhibit the RVLM independent of baroreceptor inputs. In the previous period of this project we showed that individual baro-activated GABAergic CVLM neurons in anesthetized rats display distinct patterns of respiratory-related activity, though sources of these inputs are unknown. We also showed the CVLM is essential to evoke respiratory-related sympathetic responses to acute hypoxia. These observations suggest the CVLM is an important site for cardio-respiratory integration and respiratory-related regulation of SNA. Previous studies have identified 2 respiratory-related regions that appear to send glutamatergic projections to the CVLM, namely the Kolliker-Fuse nucleus and the pre-Botzinger nucleus.
In Aims 1 and 2 of this renewal we will perform electrophysiological experiments in anesthetized rats to determine whether the Kolliker-Fuse and pre- Botzinger nuclei influence the activity of baro-activated GABAergic CVLM neurons, and whether these inputs are selective for particular baro-activated CVLM neurons or phases of the respiratory cycle. We will also determine whether these inputs impact acute hypoxia-induced changes in CVLM neuronal activity and SNA.
In Aims 3 and 4 we will determine whether regulation of the CVLM is altered in rats exposed to chronic intermittent hypoxia, a hypertensive model for obstructive sleep apnea in humans. These studies will produce novel information regarding a powerful baroreceptor-independent influence upon the CVLM neurons that are likely to influence the RVLM, SNA, and AP. In addition, these studies will further our understanding of the impact of cardio-respiratory integration upon the regulation of AP in health and hypertension.
Essential hypertension is a leading cause of cardiovascular complications in patients. Obstructive sleep apnea, which produces exposure to chronic intermittent hypoxia, is present in 30- 50% of patients with essential hypertension, and the majority of patients with sleep apnea develop hypertension. Elevated sympathetic nerve activity of unknown etiology is a contributor to both conditions. Because the hypertension and elevated sympathetic nerve activity observed with sleep apnea are partially alleviated by physically altering breathing, a better understanding of the coupling between regulatory centers in the brain for respiration and sympathetic nerve activity are crucial for elucidating causes and treatment for many cases of essential hypertension.
|Huber, Domitila A; Schreihofer, Ann M (2011) Altered regulation of the rostral ventrolateral medulla in hypertensive obese Zucker rats. Am J Physiol Heart Circ Physiol 301:H230-40|
|Silva, Ana Q; Schreihofer, Ann M (2011) Altered sympathetic reflexes and vascular reactivity in rats after exposure to chronic intermittent hypoxia. J Physiol 589:1463-76|
|Mandel, Daniel A; Schreihofer, Ann M (2009) Modulation of the sympathetic response to acute hypoxia by the caudal ventrolateral medulla in rats. J Physiol 587:461-75|
|Llewellyn-Smith, Ida J; Martin, Carolyn L; Fenwick, Natalie M et al. (2007) VGLUT1 and VGLUT2 innervation in autonomic regions of intact and transected rat spinal cord. J Comp Neurol 503:741-67|
|Mobley, Susan C; Mandel, Daniel A; Schreihofer, Ann M (2006) Systemic cholecystokinin differentially affects baro-activated GABAergic neurons in rat caudal ventrolateral medulla. J Neurophysiol 96:2760-8|
|Mandel, Daniel A; Schreihofer, Ann M (2006) Central respiratory modulation of barosensitive neurones in rat caudal ventrolateral medulla. J Physiol 572:881-96|
|Schreihofer, Ann M; Ito, Satoru; Sved, Alan F (2005) Brain stem control of arterial pressure in chronic arterial baroreceptor-denervated rats. Am J Physiol Regul Integr Comp Physiol 289:R1746-55|