title: Role of GABAergic neurones in the nucleus tractus solitarii in modulation of cardiovascular activity.
abstract: GABAergic neurones are interspersed throughout the nucleus tractus solitarii (NTS), and their tonic activity is crucial to the maintenance of cardiorespiratory homeostasis. However, the mechanisms that regulate the magnitude of GABAergic inhibition in the NTS remain unknown. We hypothesized that the level of GABAergic inhibition is proportionally regulated by the level of excitatory synaptic input to the NTS from baroreceptors. Using the in situ working heart-brainstem preparation in normotensive and spontaneously hypertensive rats, we blocked GABA(A) receptor-mediated neurotransmission in the NTS with gabazine (a specific GABA(A) receptor antagonist) at two levels of perfusion pressure (low PP, 60-70 mmHg; and high PP, 105-125 mmHg) while monitoring the immediate changes in cardiorespiratory variables. In normotensive rats, gabazine produced an immediate bradycardia consistent with disinhibition of NTS circuit neurones that regulate heart rate (HR) which was proportional to the level of arterial pressure (HR at low PP, 57 +/- 9 beats min(1); at high PP, 177 +/- 9 beats min(1); P < 0.001), suggesting that GABAergic circuitry in the NTS modulating heart rate was arterial pressure dependent. In contrast, there was no significant difference in the magnitude of gabazine-induced bradycardia in spontaneously hypertensive rats at low or high PP (HR at low PP, 45 +/- 10 beats min(1); at high PP, 58 +/- 7 beats min(1)). With regard to thoracic sympathetic nerve activity (tSNA), at high PP there was a significant reduction in tSNA during the inspiratory (I) phase of the respiratory cycle, but only in the normotensive rat (tSNA = 18.7 +/- 10%). At low PP, gabazine caused an elevation of the postinspiration phase of tSNA in both normotensive (tSNA = 23.7 +/- 2.9%) and hypertensive rats (tSNA = 44.2 +/- 14%). At low PP, gabazine produced no change in tSNA during the mid-expiration phase in either rat strain, but at high PP we observed a significant reduction in the mid-expiration phase tSNA, but only in the spontaneously hypertensive rat (tSNA = 25.2 +/- 8%). Gabazine at both low and high PP produced a reduction in the late expiration phase of tSNA in the hypertensive rat (low PP, tSNA = 29.4 +/- 4.4%; high PP, tSNA = 22.8 +/- 3%), whereas in the normotensive rat this was only significant at high PP (tSNA = 42.5 +/- 6.1%). Therefore, in the spontaneously hypertensive rat, contrary to the GABA(A) receptor-mediated control of HR, it appears that GABA(A) receptor-mediated control of tSNA in the NTS is arterial pressure dependent. This study provides new insight into the origin of GABAergic inhibition in NTS circuitry affecting heart rate and sympathetic activity.
authors.affiliation: Department of Integrative Physiology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA. jasenka.zubcevic@uphs.upenn.edu
authors.forename: Jasenka
authors.initials: J
authors.lastname: Zubcevic
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Potts
mesh_terms: D000818:Animals; D017704:Baroreflex / Q000187:drug effects; D001794:Blood Pressure; D002319:Cardiovascular System / Q000187:drug effects / Q000294:innervation*; D004195:Disease Models, Animal; D058787:GABA-A Receptor Antagonists / Q000008:administration & dosage; D006339:Heart Rate; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D008845:Microinjections; D009433:Neural Inhibition; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010477:Perfusion; D010791:Phrenic Nerve / Q000503:physiopathology; D011724:Pyridazines / Q000008:administration & dosage; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D015656:Respiratory Mechanics; D017552:Solitary Nucleus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D058787:GABA-A Receptor Antagonists; D011724:Pyridazines; D005680:gamma-Aminobutyric Acid; C049853:gabazine