The overall goal of this proposal is to gain a better understanding of how the brain integrates the information it receives from the arterial baroreceptors. Such understanding provides insights into how the central nervous system regulates blood pressure and heart rate under normal and pathological situations. During the tenure of this award we have shown that the physiological and pharmacological mechanisms responsible for the integration of baroreceptor afferent inputs are altered in chronically hypertensive animals. The specific goal of this competitive renewal is to further define the nature, the time course and the functional significance of these alterations. To this end, experiments have been designed to test the general hypothesis that the central resetting of the arterial baroreflex observed in chronic renal wrap hypertension is mediated, at least in part, by inhibition of transmission within the NTS. Previous work during the tenure of this award has provided insights into specific alterations that occur in hypertension; therefore 4 specific aims are proposed to test hypotheses that arise from these studies.
Specific Aim 1 : Chronic hypertension is associated with increased GABAA mediated inhibition within the NTS. This inhibition is the result of an increase in the discharge of GABAergic neurons in the NTS. These GABAergic neurons inhibit other NTS neurons that integrate baroreceptor afferent inputs; therefore these changes contribute to a blunting of NTS neuronal responses and reflex resetting.
Specific Aim 2 : Chronic hypertension induces increased post-synaptic expression of GABAB receptors in NTS neurons receiving monosynaptic aortic nerve inputs. This increase in GABAB receptor function contributes to a blunting of NTS neuronal responses and reflex resetting in chronic hypertension.
Specific Aim 3 : Alterations in GABAA and GABAB mechanisms within the NTS of chronically hypertensive rats result from a tonically elevated level of peripheral afferent input from the arterial baroreceptors and cardiopulmonary mechanoreceptors.
Specific Aim 4 : In chronically hypertensive rats the number of NTS neurons active at the resting level of arterial pressure and the number of neurons activated in response to graded increases in pressure is increased compared to the number of neurons active and activated in normotensive rats. The level of baroreceptor afferent input to the NTS is increased in hypertension. It is hypothesized that during chronic hypertension alterations occur in the physiology and pharmacology of NTS neurons that result in enhanced inhibition and counteract the elevated afferent input. This normalizes NTS neuronal discharge and thereby reflex gain. These adaptations confer a baroreflex buffering capability that might otherwise be greatly reduced in hypertension. Therefore, understanding the mechanisms that induce and underlie these adaptations will be of great importance in our understanding of cardiovascular regulation in hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056637-09
Application #
6751658
Study Section
Special Emphasis Panel (ZRG1-SSS-3 (03))
Program Officer
Velletri, Paul A
Project Start
1996-07-01
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2006-06-30
Support Year
9
Fiscal Year
2004
Total Cost
$325,125
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Pharmacology
Type
Other Domestic Higher Education
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Zhang, Weirong; Mifflin, Steve (2010) Plasticity of GABAergic mechanisms within the nucleus of the solitary tract in hypertension. Hypertension 55:201-6
Zhang, Weirong; Mifflin, Steve (2010) Chronic hypertension enhances presynaptic inhibition by baclofen in the nucleus of the solitary tract. Hypertension 55:481-6
Tolstykh, Gleb; de Paula, Patricia M; Mifflin, Steve (2007) Voltage-dependent calcium currents are enhanced in nucleus of the solitary tract neurons isolated from renal wrap hypertensive rats. Hypertension 49:1163-9
Zhang, Weirong; Herrera-Rosales, Myrna; Mifflin, Steve (2007) Chronic hypertension enhances the postsynaptic effect of baclofen in the nucleus tractus solitarius. Hypertension 49:659-63
Cunningham, J Thomas; Herrera-Rosales, Myrna; Martinez, Michelle A et al. (2007) Identification of active central nervous system sites in renal wrap hypertensive rats. Hypertension 49:653-8
Belugin, Sergei; Mifflin, Steve (2005) Transient voltage-dependent potassium currents are reduced in NTS neurons isolated from renal wrap hypertensive rats. J Neurophysiol 94:3849-59
Dias, Ana Carolina Rodrigues; Vitela, Melissa; Colombari, Eduardo et al. (2005) Nitric oxide modulation of glutamatergic, baroreflex, and cardiopulmonary transmission in the nucleus of the solitary tract. Am J Physiol Heart Circ Physiol 288:H256-62
Vitela, M; Herrera-Rosales, M; Haywood, J R et al. (2005) Baroreflex regulation of renal sympathetic nerve activity and heart rate in renal wrap hypertensive rats. Am J Physiol Regul Integr Comp Physiol 288:R856-62
Dias, Ana Carolina Rodrigues; Colombari, Eduardo; Mifflin, Steven W (2003) Effect of nitric oxide on excitatory amino acid-evoked discharge of neurons in NTS. Am J Physiol Heart Circ Physiol 284:H234-40
Tolstykh, Gleb; Belugin, Sergei; Tolstykh, Olga et al. (2003) Responses to GABA(A) receptor activation are altered in NTS neurons isolated from renal-wrap hypertensive rats. Hypertension 42:732-6

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