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. Obstructive sleep apnea is present in 30-50% of patients with essential hypertension, and the majority of patients with obstructive sleep apnea develop elevated SNA and arterial pressure (AP). Sleep apnea, characterized by chronic intermittent hypoxia, also alters central respiratory drive and the respiratory-related regulation of SNA. Cardio- respiratory integration appears to be at the heart of deficits observed with sleep apnea, because the elevated SNA and AP with sleep apnea are partially alleviated by altering nighttime breathing. Unfortunately, there is a paucity of information regarding the link between central respiratory drive and the elevated SNA that occurs with chronic intermittent hypoxia. 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 AP. 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 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 central respiratory neurons provide multiple inputs to baro-activated GABAergic CVLM neurons in rats, although the sources are unknown. We also showed the CVLM is essential for evoking respiratory-related sympathetic responses to acute activation of peripheral chemoreceptors by hypoxia. These observations suggest that the CVLM is an important site for cardio-respiratory integration. The SNA that regulates AP is influenced by central respiratory neurons, but mechanisms underlying cardio-respiratory integration in the CNS are not understood.
In Aims 1 and 2 of this renewal we will perform electrophysiological experiments in anesthetized rats to determine whether two central respiratory nuclei that project to the CVLM, the Kolliker-Fuse and pre- Botzinger nuclei, influence the activity of baro-activated CVLM neurons, and whether these inputs are selective for particular CVLM neurons or phases of the respiratory cycle. In addition, we will determine whether these inputs impact hypoxia-induced changes in CVLM neuronal activity and SNA.
In Aims 3 and 4 we will determine whether regulation of the CVLM is altered by chronic intermittent hypoxia, as a model for obstructive sleep apnea. These studies will provide 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 blood pressure in health and hypertension.
Essential hypertension is a leading cause of cardiovascular complications in patients. Obstructive sleep apnea 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.
| 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 |
