The importance of the sympathetic nervous system in control of heart and blood vessels is well established. Recently a potent system that involves peptidergic modulation of sympathetic release of norepinephrine (NE) has been described. Met- and leu-enkephalin presynaptically inhibit release of NE from sympathetic nerve terminals. These peptides have been shown to be costored with NE and epinephrine in adrenal medullary chromaffin and other postganglionic sympathetic cells. They are coreleased with the catecholamines by a variety of stimuli. Thus, the eixstence of a mechanism for modulation of sympathetic release of NE at the level of the nerve terminal is firmly established. However, the role of this mechanism in any physiological or pathophysiological state in the intact organism has not been established. Although this mechanism may function in a variety of stressful situations, we propose to initially focus our investigation on its role in the hypotension associated with hemorrhage in the conscious rabbit. We have identified a paradoxical decrease in sympathetic activity during hemorrhage at the transition from normo- to hypotension. Our pilot experiments strongly suggest that adrenal medullary enkephalins may be responsible for this decrease. Our general hypothesis is that met-enkephalin released by the adrenal medulla depresses sympathetic release of NE and causes the transition to hypotension. We will test the following specific hypotheses: 1) plasma enkephalin levels rise during hemorrhage and the time course of the rise correlates with the transition to hypotension; 2) the adrenal medulla is the source of the enkephalins that produce the CV depression; 3) the enkephalins inhibit sympathetically induced peripheral vasoconstriction by a presynaptic inhibitory mechanism; and 4) the reversal by naloxone of the hypotension associated with hemorrhage is due to antagonism of peripheral rather than central opiate receptors. These studies will be performed using chronically instrumented conscious rabbits. Plasma and adrenal tissue met-enkephalin will be measured using radioimmunoassay. Plasma and adrenal catecholamines will be measured by high pressure liquid chromatography with electrochemical detection. The proposed study is an important first step in documenting the hypothetically potent role of this enkephalinergic system in modulation of sympathetic activity and thus, in cardiovascular control in the intact organism.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL031218-03
Application #
3342296
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1984-04-01
Project End
1987-11-30
Budget Start
1986-04-01
Budget End
1987-11-30
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Missouri-Columbia
Department
Type
Graduate Schools
DUNS #
112205955
City
Columbia
State
MO
Country
United States
Zip Code
65211
Schadt, J C; Hasser, E M (2001) Defense reaction alters the response to blood loss in the conscious rabbit. Am J Physiol Regul Integr Comp Physiol 280:R985-93
Schadt, J C; Hasser, E M (1998) Hemodynamic effects of acute stressors in the conscious rabbit. Am J Physiol 274:R814-21
Koch, M A; Hasser, E M; Schadt, J C (1995) Influence of nitric oxide on the hemodynamic response to hemorrhage in conscious rabbits. Am J Physiol 268:R171-82
Jang, W; Schadt, J C; Gaddis, R R (1993) Peripheral opioidergic mechanisms do not mediate naloxone's pressor effect in the conscious rabbit. Circ Shock 39:121-7
Hasser, E M; Schadt, J C (1992) Sympathoinhibition and its reversal by naloxone during hemorrhage. Am J Physiol 262:R444-51
Schadt, J C; Ludbrook, J (1991) Hemodynamic and neurohumoral responses to acute hypovolemia in conscious mammals. Am J Physiol 260:H305-18
Schadt, J C; Hasser, E M (1991) Interaction of vasopressin and opioids during rapid hemorrhage in conscious rabbits. Am J Physiol 260:R373-81
Schadt, J C; Gaddis, R R (1990) Renin-angiotensin system and opioids during acute hemorrhage in conscious rabbits. Am J Physiol 258:R543-51
Schadt, J C (1989) Sympathetic and hemodynamic adjustments to hemorrhage: a possible role for endogenous opioid peptides. Resuscitation 18:219-28
Schadt, J C; Gaddis, R R (1988) Role of adrenal medulla in hemodynamic response to hemorrhage and naloxone. Am J Physiol 254:R559-65

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