Blood pressure control by caudal ventrolateral medulla

Project Details


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.
Effective start/end date1/09/0931/08/10


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