Serotonin and the catecholamines are known to play a role in the regulation of blood pressure. Serotonin agonists, alpha-2 receptor agonists and dopamine agonists have all been shown to lower blood in hypertensive animals. Humans with hypertension are routinely treated with clonidine and alpha methyldopa, two drugs which lower blood pressure by central stimulation of alpha-2 adrenoreceptors. Despite the therapeutic success of these drugs, there is no detailed knowledge of how individual brainstem nuclei use norepinephrine, epinephrine, dopamine and serotonin during changes in blood pressure. With the new technique of in vivo electrochemistry, we have been able to follow the time course of catechol and 5-HIAA concentrations continuously during drug- induced hypertension and hypotension. During the first award period of this grant, we found that the serotonin metabolite 5- HIAA was increased in most nuclei whenever blood pressure was increased. The catechol peak was generally reduced during hypertension. We found that only in the C1 nucleus were the electrochemical peaks for catechols and indoles reciprocally related to blood pressure for both hypertension and hypotension. In preliminary experiments, we have also found that the catechol peak in the lateral hypothalamus is inversely and linearly related to serum osmolarity. In the renewal of this grant we will study catechol and indole metabolism in nucleus tractus solitarius, locus coeruleus, the C1 and A1 areas, the nucleus ambiguous, the paraventricular nucleus, the preoptic area and lateral hypothalamus during changes in serum osmolarity and circulating volume. In addition to in vivo electrochemistry, we will use in vivo dialysis to study norepinephrine and epinephrine release in C1 nucleus during drug induced changes in blood pressure. Effects of osmotic changes will be compared in Sprague Dawley and vasopressin deficient Brattleboro rats. The ability of vasopressin to reset baroreceptor gain and lower catechols in NTS will be compared with the effect of vasopressin infusions on catechol and indole release in other brainstem nuclei. These experiments should characterize the role of monoamines in individual brainstem nuclei in maintaining blood pressure, serum osmolarity, and circulating volume. Results of these studies already suggest a new therapy for hypertension. Serotonin agonists and alpha-2 agonists may make a potent antihypertensive combination.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL030722-06
Application #
3341774
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1983-07-01
Project End
1992-07-31
Budget Start
1989-08-01
Budget End
1990-07-31
Support Year
6
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Mason, P A; Dev, B R; Freed, C R (1995) Ascorbic acid concentration in the lateral hypothalamus is related to plasma osmolality. Brain Res Bull 37:305-9
Dev, B R; Mason, P A; Freed, C R (1992) Drug-induced changes in blood pressure lead to changes in extracellular concentrations of epinephrine, dihydroxyphenylacetic acid, and 5-hydroxyindoleacetic acid in the rostral ventrolateral medulla of the rat. J Neurochem 58:1386-94
Sabol, K E; Richards, J B; Freed, C R (1990) In vivo dialysis measurements of dopamine and DOPAC in rats trained to turn on a circular treadmill. Pharmacol Biochem Behav 36:21-8
Richards, J B; Sabol, K E; Freed, C R (1990) Unilateral dopamine depletion causes bilateral deficits in conditioned rotation in rats. Pharmacol Biochem Behav 36:217-23
Bhaskaran, D; Freed, C R (1989) Catechol and indole metabolism in rostral ventrolateral medulla change synchronously with changing blood pressure. J Pharmacol Exp Ther 249:660-6
Mason, P A; Durr, J A; Bhaskaran, D et al. (1988) Plasma osmolality predicts extracellular fluid catechol concentrations in the lateral hypothalamus. J Neurochem 51:552-60
Bhaskaran, D; Freed, C R (1988) Changes in arterial blood pressure lead to baroreceptor-mediated changes in norepinephrine and 5-hydroxyindoleacetic acid in rat nucleus tractus solitarius. J Pharmacol Exp Ther 245:356-63
Bhaskaran, D; Freed, C R (1988) Changes in neurotransmitter turnover in locus coeruleus produced by changes in arterial blood pressure. Brain Res Bull 21:191-9
Sabol, K E; Freed, C R (1988) Brain acetaminophen measurement by in vivo dialysis, in vivo electrochemistry and tissue assay: a study of the dialysis technique in the rat. J Neurosci Methods 24:163-8
Diana, M; Garcia-Munoz, M; Freed, C R (1987) Wire electrodes for chronic single unit recording of dopamine cells in substantia nigra pars compacta of awake rats. J Neurosci Methods 21:71-9

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