The topic of this paper examines cellular and molecular
mechanisms in the PVH in the pathophysiological state of heart failure. A key
aspect of heart failure is the inability to regulate the sympathetic nervous
system. The PVH is a key regulatory brain region responsible for sympathetic
regulation and ultimately arterial pressure. Afferent projections from the
cardiovascular system to the NTS initiate cardiovascular regulation through
projects to the PVH and the RVLM. The PVH and RVLM subsequently adjust their
sympathetic response from the NTS to regulate homeostasis. Furthermore, the PVH
sends efferent projections to the sympathetic preganglionic neurons of the RVLM
and IML to regulate sympathetic tone. The IML is critical in the maintenance of
arterial pressure since it regulates sympathetic preganglionic neurons of the
entire body.
The PVH alone is an important regulator of arterial
pressure. The three important subsets of neurons within the PVH are the
magnocellular, the parvocellular neuroendocrine, and parvocellular
pre-autonomic neurons. The magnocellular neurons synthesize and secrete
vasopressin and oxytocin which are released into circulation through the
posterior pituitary. The parvocellular neuroendocrine hormones release GHRH to
the anterior pituitary via the hypophyseal portal vessels. Finally, the
parvocellular pre autonomic neurons regulate sympathetic nerve activity. An
important aspect of the PVH is that the parvocellular pre autonomic neurons
project reciprocally to the NTS as well as the RVLM and IML to regulate
arterial pressure.
A critical discovery
by Pyner, demonstrated at least 4 pathways from the NTS project target PVH
neurons: spinally projecting neurons, nNOS-magnocellular neurons, GABA
interneurons, and nNOS containing interneurons bordering the PVH. This
discovering is important in being able to assess sensory inputs to the NTS with
the PVH.
The PVH is under tonic inhibitory control via NO mediated
GABA inhibition. Excitation of the PVH requires NMDA mediated glutamate driven
activation in the PVN. A major finding implicated the NDMA glutamate
stimulation in heart failure since no increases in blood pressure were
discovered during tonic glutamate administration. However, when sympathetic
nerve activity is enhanced in conditions of heart failure, administration of a
NMDA antagonist decreased sympathetic nerve activity. This raised the question
of why and how this happens if tonic increases in glutamate did not give rise to
sympathetic nerve activity in normal conditions. Increasing evidence suggests
angiontensin 2 and downregulation of nNOS an enzyme responsible for NO
generation.
The paper elaborates on the PVH and finds new projections to
the PVH from the NTS as well as examines the effects that heart failure has on PVH.
However, information has not been discovered yet to determine a viable drug
target for regulating many of these pathways in heart failure.
