The central nervous system is important in the regulation of arterial pressure and an abundance of data suggests that the brain plays a critical role in the pathogenesis of some forms of hypertension. Several previous studies have suggested that an attenuation of the baroreceptor reflex occurring within the central nervous system contributes to the development of certain forms of experimental hypertension. The nucleus tractus solitarius (NTS) is the site in the brain which receives all of the input from peripheral baroreceptors, and therefore is prominently involved in the processing of the baroreceptor reflex. Recent data indicate that stimulation of GABA/B receptors in the NTS attenuates the baroreceptor reflex and that neural transmission mediated by GABA/B receptors in the NTS is abnormal in certain forms of experimental hypertension. Thus, the hypothesis is presented that enhanced GABA/B- mediated neural transmission in the NTS, by producing a central attenuation of the baroreceptor reflex, contributes to the pathogenesis of hypertension in two models of experimental hypertension, the spontaneously (genetic) hypertensive rat and the rat treated with deoxycorticosterone and salt. Studies described in this proposal examine this hypothesis by determining the relationship between changes in GABAB receptors in the NTS, GABA release in the NTS, cardiovascular responses to injection into the NTS of drugs which are agonists or antagonists at GABA/B receptors, and the development of hypertension. Additional studies will examine the mechanisms involved in this GABA/B-mediated attenuation of the baroreceptor reflex. The hypothesis to be tested is that GABA acting on GABA/B receptors present presynaptically on baroreceptor afferent nerves attenuates the release of neurotransmitter from baroreceptor afferents, and that this mechanism underlies the frequency-dependent inhibition of baroreceptor afferent transmission in the NTS. It is expected that these studies will increase our understanding of the central neural control of cardiovascular function as it relates to hypertension and may provide new insight into the treatment or prevention of hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL038786-08
Application #
2219044
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1987-09-01
Project End
1996-03-30
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
8
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Schreihofer, A M; Stricker, E M; Sved, A F (2000) Nucleus of the solitary tract lesions enhance drinking, but not vasopressin release, induced by angiotensin. Am J Physiol Regul Integr Comp Physiol 279:R239-47
Ito, S; Sved, A F (1997) Tonic glutamate-mediated control of rostral ventrolateral medulla and sympathetic vasomotor tone. Am J Physiol 273:R487-94
Ito, S; Sved, A F (1997) Influence of GABA in the nucleus of the solitary tract on blood pressure in baroreceptor-denervated rats. Am J Physiol 273:R1657-62
Sved, A F; Schreihofer, A M; Kost Jr, C K (1997) Blood pressure regulation in baroreceptor-denervated rats. Clin Exp Pharmacol Physiol 24:77-82
Schreihofer, A M; Hoffman, G E; Sved, A F (1997) The kidneys stimulate vasopressin release during hemorrhage in rats with chronic NTS lesions. Am J Physiol 272:R1540-51
Ito, S; Sved, A F (1996) Blockade of angiotensin receptors in rat rostral ventrolateral medulla removes excitatory vasomotor tone. Am J Physiol 270:R1317-23
Yin, M; Sved, A F (1996) Role of gamma-aminobutyric acid B receptors in baroreceptor reflexes in hypertensive rats. Hypertension 27:1291-8
Graham, J C; Hoffman, G E; Sved, A F (1995) c-Fos expression in brain in response to hypotension and hypertension in conscious rats. J Auton Nerv Syst 55:92-104
Tsukamoto, K; Yin, M; Sved, A F (1994) Effect of atropine injected into the nucleus tractus solitarius on the regulation of blood pressure. Brain Res 648:9-15
Sved, A F; Mancini, D L; Graham, J C et al. (1994) PNMT-containing neurons of the C1 cell group express c-fos in response to changes in baroreceptor input. Am J Physiol 266:R361-7

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