The activation of the sympathetic nervous system and elevation of norepinephrine (NE) are associated with several prevalent cardiovascular disorders including heart failure. Our preliminary results suggest that ACTH (adrenocorticotropic hormone) plays a crucial role in the regulation of the sympathetic nervous system, especially during stress. They also suggest that ACTH may act directly on sympathetic ganglia to activate gene expression of NE biosynthetic enzymes. If proven correct, this would be a novel role for ACTH and may be crucial in further understanding the relationship of NE and serious cardiovascular disorders. We propose that ACTH triggers cAMP mediated transcriptional activation of the NE biosynthetic enzymes (TH and DBH) in sympathetic neurons.
The specific aims are:
Aim 1 : Determine the time course for alterations in plasma ACTH, corticosterone, NE and blood pressure in response to single or repeated daily injections of several concentrations of ACTH. Compare these changes with response to stress.
Aim 2 : Test the hypothesis that in rat sympathetic neurons ACTH up-regulates levels of the ACTH receptor (MC2R) and triggers cAMP mediated transcriptional activation of the genes encoding NE biosynthetic enzymes.
Aim 3 : Test the hypothesis that with stress ACTH has a direct effect on activation of the NE biosynthetic system in sympathetic ganglia independent of its elevation of adrenal glucocorticoids.
Aim 4 : Validate functional ACTH binding to sympathetic ganglia and determine whether there are other ACTH responsive receptors (besides MC2R) that are expressed under basal conditions or following administration of ACTH.
Aim 5 : Determine the ACTH signaling mechanism(s) leading to changes in neurotransmitter related gene expression in superior cervical ganglia cell cultures. Test the hypothesis that ACTH triggers cAMP mediated transcriptional activation of the genes encoding TH and DBH in sympathetic neurons The findings of this study would indicate a novel role for ACTH, and will provide new insight into the mechanism by which stress affects the cardiovascular system. Moreover, it might enable a completely new therapeutic approach to treatment of congestive heart failure and other situations, such as aging, which display elevate sympathetic activity, based on ACTH receptor antagonists.
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