DESCRIPTION (provided by applicant): Urocortin III belongs to the corticotropin releasing factor (CRF) family of peptides which are known to play an important role in the regulation of autonomic, endocrine and behavioral responses to stress. Urocortin III mediates its actions via CRF-2 receptors and it has been suggested that it may be the endogenous ligand for these receptors. Neurons containing urocortin III are located primarily in the hypothalamus. Within the hypothalamus, urocortin-III neurons are distributed mainly in the paraventricular nucleus and the perifornical area lateral to this nucleus. Urocortin III has been implicated in several physiological functions including regulation of feeding and stress responses. Adjustment of cardiovascular responses is one of the mechanisms for coping with stress. Since urocortin III has been identified relatively recently (2001), little is known about its cardiovascular actions. There is only one report in the literature in which intracerebroventricular injections of stresscopin (structurally almost identical to urocortin III) were shown to elicit increases in blood pressure and heart rate. A clear understanding of the central cardiovascular actions of urocortin III is a prerequisite for unraveling the mechanism of cardiovascular responses of this peptide in stress. The hypothesis central to this project is that urocortin III is excitatory to neurons located in medullo-spinal cardiovascular regulatory regions. The hypothesis is based on our preliminary results in which it was demonstrated, for the first time, that urocortin III may play a role in medullo-spinal cardiovascular regulatory areas. The overall goal of this project is to characterize and understand the mechanism of cardiovascular actions of urocortin III in selected medullo-spinal cardiovascular regulatory areas including the medial subnucleus of the nucleus tractus solitarius (mNTS), the caudal ventrolateral medullary depressor area (CVLM), the rostral ventrolateral medullary pressor area (RVLM), the nucleus ambiguus (nAmb) and the intermediolateral cell column of the thoraco-lumbar spinal cord (IML). A multi-disciplinary approach, involving physiological, pharmacological and electrophysiological techniques, will be used to accomplish these aims. The central nervous system plays a significant role in development and/or maintenance of some cardiovascular disorders associated with stress. Substantiation of our preliminary results regarding cardiovascular effects of urocortin III will eventually be helpful in understanding the mechanisms involved in cardiovascular disorders associated with stress and developing novel regimens of treatment for combating deleterious cardiovascular effects of stress. PROJECT NARRATIVE The brain plays a significant role in the development and maintenance of some cardiovascular disorders associated with stress. Urocortin III is a new stress hormone found in the human brain. The present proposal is designed to characterize the mechanisms of cardiovascular actions of urocortin III in different regions of the hind brain and spinal cord. Completion of this research will eventually be helpful in understanding the mechanisms involved in cardiovascular disorders associated with stress and developing rational treatment for ameliorating the harmful cardiovascular effects of stress.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL024347-28
Application #
8235823
Study Section
Special Emphasis Panel (ZRG1-CVS-B (03))
Program Officer
Maric-Bilkan, Christine
Project Start
1983-04-01
Project End
2013-06-30
Budget Start
2012-04-01
Budget End
2013-06-30
Support Year
28
Fiscal Year
2012
Total Cost
$259,315
Indirect Cost
$93,087
Name
University of Medicine & Dentistry of NJ
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
Kawabe, Tetsuya; Kawabe, Kazumi; Sapru, Hreday N (2014) Cardiovascular effect of angiotensin-(1-12) in the caudal ventrolateral medullary depressor area of the rat. Am J Physiol Heart Circ Physiol 306:H438-49
Sapru, Hreday N (2013) Role of the hypothalamic arcuate nucleus in cardiovascular regulation. Auton Neurosci 175:38-50
Kawabe, Tetsuya; Kawabe, Kazumi; Sapru, Hreday N (2013) Tonic ýý-aminobutyric acid-ergic activity in the hypothalamic arcuate nucleus is attenuated in the spontaneously hypertensive rat. Hypertension 62:281-7
Chitravanshi, Vineet C; Kawabe, Kazumi; Sapru, Hreday N (2013) Mechanisms of cardiovascular actions of urocortins in the hypothalamic arcuate nucleus of the rat. Am J Physiol Heart Circ Physiol 305:H182-91
Iwasa, Masamitsu; Kawabe, Kazumi; Sapru, Hreday N (2013) Activation of melanocortin receptors in the intermediolateral cell column of the upper thoracic cord elicits tachycardia in the rat. Am J Physiol Heart Circ Physiol 305:H885-93
Chitravanshi, Vineet C; Sapru, Hreday N (2011) Cardiovascular responses elicited by a new endogenous angiotensin in the nucleus tractus solitarius of the rat. Am J Physiol Heart Circ Physiol 300:H230-40
Arakawa, Hideki; Chitravanshi, Vineet C; Sapru, Hreday N (2011) The hypothalamic arcuate nucleus: a new site of cardiovascular action of angiotensin-(1-12) and angiotensin II. Am J Physiol Heart Circ Physiol 300:H951-60
Chitravanshi, Vineet C; Sapru, Hreday N (2011) Microinjections of urocortin1 into the nucleus ambiguus of the rat elicit bradycardia. Am J Physiol Heart Circ Physiol 300:H223-9
Kawabe, Tetsuya; Chitravanshi, Vineet C; Nakamura, Takeshi et al. (2009) Mechanism of heart rate responses elicited by chemical stimulation of the hypothalamic paraventricular nucleus in the rat. Brain Res 1248:115-26
Nakamura, Takeshi; Bhatt, Suresh; Sapru, Hreday N (2009) Cardiovascular responses to hypothalamic arcuate nucleus stimulation in the rat: role of sympathetic and vagal efferents. Hypertension 54:1369-75

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