The paraventricular-brainstem axis acts as an integrator of autonomic and endocrine function. We hypothesize that oxytocin, a peptidergic transmitter in this pathway, modulates cardiovascular responses and that this is accentuated by sodium. Further we suggest that central oxytocin may be an important an unappreciated neuroendocrine modulator of cardiovascular and hydromineral balance. A key finding in the initial grant period was that interruption of this PVN-brainstem circuit via baroreceptor denervation produces chronic changes in the hypothalamic neurosecretory cells, making them hypersensitive to the effects of sodium. The increased response of the oxytocin system in terms of mRNA expression and peptide secretion is especially intriguing in view of the postulated role of oxytocin as a link between cardiovascular control and salt balance. A research program is proposed to study the peptidergic interactions between PVN and brainstem, the influence of brainstem oxytocin on cardiovascular and sympathetic nervous function, the influence of baroreceptor input and central stimulation on oxytocin mRNA expression and the role of oxytocin in baroreceptor-induced changes in salt intake. The proposal will employ techniques which will allow for the evaluation of central neuronal function, peptide mRNA expression, peptide secretion and physiological responses. Microdialysis will be used for measuring central and systemic oxytocin release, microinjection for the study of cardiovascular and sympathetic responses and in situ hybridization methods for the evaluating of the changes in cellular mRNA levels.
The specific aims of the proposal are: 1) to study PVN-brainstem interactions by examining the effect of PVN stimulation on brainstem oxytocin release and cardiovascular parameters 2) to examine the role of oxytocinergic brainstem pathways to the dorsal vagal complex of the medulla in the regulation of autonomic outflow and cardiovascular function 3) to evaluate the peptide mRNA responses to baroreceptor denervation (time course), hypertonic saline and angiotensin and 4)To determine the role of central oxytocin in baroreceptor-mediated changes in salt intake.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL043178-08
Application #
2445191
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1990-04-01
Project End
1999-06-30
Budget Start
1997-09-01
Budget End
1998-06-30
Support Year
8
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Wright State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Dayton
State
OH
Country
United States
Zip Code
45435
Michelini, Lisete C; Marcelo, Marialuisa C; Amico, Janet et al. (2003) Oxytocinergic regulation of cardiovascular function: studies in oxytocin-deficient mice. Am J Physiol Heart Circ Physiol 284:H2269-76
Higa, Keila T; Mori, Eliana; Viana, Fabiano F et al. (2002) Baroreflex control of heart rate by oxytocin in the solitary-vagal complex. Am J Physiol Regul Integr Comp Physiol 282:R537-45
Green, L; Fein, D; Modahl, C et al. (2001) Oxytocin and autistic disorder: alterations in peptide forms. Biol Psychiatry 50:609-13
Morris, M; Means, S; Oliverio, M I et al. (2001) Enhanced central response to dehydration in mice lacking angiotensin AT(1a) receptors. Am J Physiol Regul Integr Comp Physiol 280:R1177-84
Braga, D C; Mori, E; Higa, K T et al. (2000) Central oxytocin modulates exercise-induced tachycardia. Am J Physiol Regul Integr Comp Physiol 278:R1474-82
Li, P; Sur, S H; Mistlberger, R E et al. (1999) Circadian blood pressure and heart rate rhythms in mice. Am J Physiol 276:R500-4
Morris, M; Li, P; Callahan, M F et al. (1999) Neuroendocrine effects of dehydration in mice lacking the angiotensin AT1a receptor. Hypertension 33:482-6
Nishioka, T; Callahan, M F; Li, P et al. (1999) Increased central angiotensin and osmotic responses in the Ren-2 transgenic rat. Hypertension 33:385-8
Nishioka, T; Anselmo-Franci, J A; Li, P et al. (1998) Stress increases oxytocin release within the hypothalamic paraventricular nucleus. Brain Res 781:56-60
Modahl, C; Green, L; Fein, D et al. (1998) Plasma oxytocin levels in autistic children. Biol Psychiatry 43:270-7

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