Reduced endogenous GABA-mediated inhibition in the PVN  on renal nerve discharge in rats with heart failure

Kun, Zhang; Li, Yi Fan; Patel, Kaushik P.

doi:10.1152/ajpregu.00241.2001

Cited by 127 publications

(162 citation statements)

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“…Similar to previous studies, 4,5,6,22 our data show that BMI microinjected into the PVN in rats infused with vehicle for 7 days significantly increases renal SNA, MAP, and HR. In contrast, rats infused with Ang II had significantly blunted responses.…”

Section: Discussionsupporting

confidence: 91%

“…4 Although mechanisms of GABA-Ang II interaction within the PVN have not been fully defined, in vitro electrophysiological studies indicate that GABA tonically opposes excitatory actions of Ang II on neurosecretory neurons, 18 and excitation of spinally projecting neurons involves presynaptic actions of Ang II to reduce GABA release. 19 In addition, functional studies in rats with sodium-dependent hypertension 20 and heart failure 6 have suggested that Ang II-induced sympathoexcitation involves reduced GABA-mediated inhibition within the PVN. This conclusion is consistent with evidence that both plasma Ang II and SNA are elevated whereas the sympathetic response to blockade of PVN GABA-A receptors is attenuated in these disease models.…”

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confidence: 99%

“…This conclusion is consistent with evidence that both plasma Ang II and SNA are elevated whereas the sympathetic response to blockade of PVN GABA-A receptors is attenuated in these disease models. 6,20 The aim of the present study was to determine more directly the effect of elevated plasma Ang II on cardiovascular and renal SNA responses to acute GABA-A receptor blockade in the PVN. This was accomplished by infusing rats intravenously with Ang II at a rate selected to leave plasma volume undisturbed.…”

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Effect of Intravenous Angiotensin II Infusion on Responses to Hypothalamic PVN Injection of Bicuculline

2003

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Abstract-The hypothalamic paraventricular nucleus (PVN) plays an important role in the sympathoexcitatory response to elevated plasma angiotensin II (Ang II). However, the mechanism by which Ang II influences sympathetic activity is not fully understood.In this study, we tested the hypothesis that GABA(␥-aminobutyric acid)-ergic function in the PVN is reduced by peripheral infusion of Ang II. To accomplish this, rats received either intravenous Ang II (12 ng/kg per minute) or vehicle (D5W) for 7 days, and renal sympathetic nerve activity (SNA), mean arterial pressure (MAP), and heart rate (HR) responses were recorded after unilateral PVN microinjection of the GABA-A receptor antagonist bicuculline methiodide (BMI, 0.1 nmol). Results indicate that in contrast to a significant increase in renal SNA, MAP, and HR observed in vehicle-infused rats (PϽ0.05), BMI injection into the PVN of Ang II-infused animals was without effect on all recorded variables. In a separate groups of animals, ganglionic blockade produced a significantly greater fall in MAP (PϽ0.01) in Ang II-infused rats than in vehicle-infused control rats, indicating that the contribution of SNA to the maintenance of blood pressure was elevated in the Ang II-infused group. Overall, these data indicate that cardiovascular and sympathoexcitatory responses to acute GABA-A receptor antagonism in the PVN are significantly blunted in rats after 7 days of intravenous infusion of Ang II. We conclude that an Ang II-induced reduction in GABAergic inhibition within the PVN may contribute to elevated SNA observed in this study. Key Words: angiotensin II Ⅲ hypothalamus Ⅲ sympathetic nervous system Ⅲ hypertension, arterial A s the dominant inhibitory neurotransmitter in the mammalian brain, ␥-aminobutyric acid (GABA) 1 plays an important role in regulating cardiovascular function. 2,3 In brain regions such as the nucleus tractus solitarius 2 and rostral ventrolateral medulla 2,3 that control sympathetic nerve activity (SNA), GABA tonically suppresses neuronal activity and excitability. In the hypothalamic paraventricular nucleus (PVN), neuronal activity is also regulated by GABA 4 -6 and by a number of excitatory neurotransmitters as well. 7,8 Among the latter is the peptide angiotensin II (Ang II). Ang II-containing fibers arise from Ang II-sensitive regions of the forebrain known as circumventricular organs (CVO), which lack a complete blood-brain barrier. 9,10 Neurons in two forebrain CVOs, the subfornical organ and organum vasculosum of the lamina terminalis, express Ang II AT 1 receptors in high density 11 and appear to sense and respond to circulating Ang II. 9,12-15 Although Ang II increases SNA through these and other central actions, 16,17 the mechanism by which circulating Ang II enhances PVN neuronal excitability is not fully understood.On the basis of literature evidence, it is clear that GABA 4 -6 and Ang II 13-15 can each act individually within the PVN to influence cardiovascular function. More recently, it has been shown that local GABA-Ang II interacti...

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

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confidence: 99%

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Effect of Intravenous Angiotensin II Infusion on Responses to Hypothalamic PVN Injection of Bicuculline

2003

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“…32). Interestingly, their recent study (45) showed that endogenous GABA effects in the PVN of rats with CHF were reduced. These studies suggest that GABA may be responsible for the sympathoinhibition when NO production is augmented.…”

Section: Discussionmentioning

confidence: 99%

nNOS gene transfer to RVLM improves baroreflex function in rats with chronic heart failure

Wang

Patel

Cornish

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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. nNOS gene transfer to RVLM improves baroreflex function in rats with chronic heart failure. Am J Physiol Heart Circ Physiol 285: H1660-H1667, 2003; 10.1152/ajpheart.00239.2003.-We hypothesized that gene transfer of neuronal nitric oxide synthase (nNOS) into the rostral ventrolateral medulla (RVLM) improves baroreflex function in rats with chronic heart failure (CHF). Six to eight weeks after coronary artery ligation, rats showed hemodynamic signs of CHF. A recombinant adenovirus, either Ad.nNOS or Ad.␤-Gal, was transfected into the RVLM. nNOS expression in the RVLM was confirmed by Western blot analysis, NADPH-diaphorase, and immunohistochemical staining. We studied baroreflex control of the heart rate (HR) and renal sympathetic nerve activity (RSNA) in the anesthetized state 3 days after gene transfer by intravenous injections of phenylephrine and nitroprusside. Baroreflex sensitivity was depressed for HR and RSNA regulation in CHF rats (2.0 Ϯ 0.3 vs. 0.8 Ϯ 0.2 beats ⅐ min Ϫ1 ⅐ mmHg Ϫ1 , P Ͻ 0.01 and 3.8 Ϯ 0.3 vs. 1.2 Ϯ 0.1% max/mmHg, P Ͻ 0.01, respectively). Ad.nNOS transfer into RVLM significantly increased the HR and RSNA ranges (152 Ϯ 19 vs. 94 Ϯ 12 beats/min, P Ͻ 0.05 and 130 Ϯ 16 vs. 106 Ϯ 5% max/mmHg, P Ͻ 0.05) compared with the Ad.␤-Gal in CHF rats. Ad.nNOS also improved the baroreflex gain for the control of HR and RSNA (1.8 Ϯ 0.2 vs. 0.8 Ϯ 0.2 beats ⅐ min Ϫ1 ⅐ mmHg Ϫ1 , P Ͻ 0.01 and 2.6 Ϯ 0.2 vs. 1.2 Ϯ 0.1% max/mmHg, P Ͻ 0.01). In sham-operated rats, we found that Ad.nNOS transfer enhanced the HR range compared with Ad.␤-Gal gene transfer (188 Ϯ 15 vs. 127 Ϯ 14 beats/min, P Ͻ 0.05) but did not alter any other parameter. This study represents the first demonstration of altered baroreflex function following increases in central nNOS in the CHF state. We conclude that delivery of Ad.nNOS into the RVLM improves baroreflex function in rats with CHF. sympathetic nerve activity; heart rate; nitric oxide; adenovirus IT HAS BEEN WELL ESTABLISHED that arterial baroreflex function is impaired in patients (8) and animals (48) with chronic heart failure (CHF) and that it is associated with sympathoexcitation (3, 10, 11). This sympathoexcitation, if sustained, clearly aggravates the progression of the CHF state (6). It has been shown that the neuronal isoform of nitric oxide (NO) synthase (nNOS) message and activity are substantially reduced at various central sites in animals with experimental CHF (33). The rostral ventrolateral medulla (RVLM) is the final site of sympathetic processing in the brain and transmits sympathetic excitatory projections to the spinal cord (41). It plays a critical role in the control of arterial pressure, heart rate (HR), and sympathetic outflow from the central nervous system (CNS) (7). As a neuromodulatory substance, NO is believed to elicit effects on several central pathways, including the regulation of sympathetic tone (13). By using immunohistochemistry and NADPH-diaphorase staining, some studies have already demonstrated that nNOS is present in several regions that make up the ...

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“…Gammaaminobutyric acid (GABA) is the predominant inhibitory neurotransmitter within the PVN (Cole and Sawchenko 2002;Chen et al 2003). Patel et al previously suggested that a GABA-mediated inhibitory mechanism within the PVN contributed to sympathoexcitation in HF rats (Zhang, Li et al 2002). In addition, nitric oxide (NO) levels are inversely related to sympathetic activity and are downregulated in the PVN of HF rats.…”

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confidence: 99%

TNF-.ALPHA. in Hypothalamic Paraventricular Nucleus Contributes to Sympathoexcitation in Heart Failure by Modulating AT1 Receptor and Neurotransmitters

Kang

Wang

Yang

et al. 2010

Tohoku J. Exp. Med.

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Proinflammatory cytokines, including tumor necrosis factor (TNF)-α , augment the progression of heart failure (HF) that is characterized by sympathoexcitation. In this study, we explored the role of TNF-α in hypothalamic paraventricular nucleus (PVN) in the exaggerated sympathetic activity observed in HF. Heart failure rats were made by ligating the left anterior descending coronary artery. The expression levels of angiotensin type 1 receptor (AT1-R) and neurotransmitters were analyzed in the PVN of HF rats that received direct PVN infusion of a TNF-α blocker (pentoxifylline or etanercept) or vehicle. Sham-operated control (SHAM) or HF rats were treated for 4 weeks through PVN infusion with each TNF-α blocker or vehicle. Rats with HF had higher levels of glutamate, norepinephrine, AT1-R and tyrosine hydroxylase (TH), and lower levels of gamma-aminobutyric acid (GABA), neuronal nitric oxide synthase (nNOS) and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN when compared to SHAM rats. Plasma levels of cytokines, norepinephrine and angiotensin II and renal sympathetic nerve activity (RSNA) were increased in HF rats. PVN infusion of pentoxifylline or etanercept attenuated the decreases in PVN GABA, nNOS and GAD67, and the increases in RSNA and PVN glutamate, norepinephrine, TH and AT1-R observed in HF rats. We have developed a novel method for chronic and continuous infusion of drugs directly into the PVN and provided evidence that TNF-α in the PVN modulates neurotransmitters and the expression of AT1 receptor, which could account for exaggerated sympathetic activity in HF.

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Reduced endogenous GABA-mediated inhibition in the PVN on renal nerve discharge in rats with heart failure

Cited by 127 publications

References 43 publications

Effect of Intravenous Angiotensin II Infusion on Responses to Hypothalamic PVN Injection of Bicuculline

Effect of Intravenous Angiotensin II Infusion on Responses to Hypothalamic PVN Injection of Bicuculline

nNOS gene transfer to RVLM improves baroreflex function in rats with chronic heart failure

TNF-.ALPHA. in Hypothalamic Paraventricular Nucleus Contributes to Sympathoexcitation in Heart Failure by Modulating AT1 Receptor and Neurotransmitters

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