Beneficial effects of γ-aminobutyric acid on right ventricular pressure and pulmonary vascular remodeling in experimental pulmonary hypertension

Suzuki, Rie; Maehara, Rumi; Kobuchi, Shuhei; Tanaka, Ryosuke; Ohkita, Mamoru; Matsumura, Yasuo

doi:10.1016/j.lfs.2012.04.006

Cited by 17 publications

(6 citation statements)

References 33 publications

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“…Moreover, enhanced SNA is associated with RHF 7 . Consistent with these findings are observations of increased plasma NE and beneficial effects of beta-adrenergic receptor antagonists in animal models of PH 8,9 . Although little is known about the role of SNA and microglial activation in PH, considerable evidence exists linking them in systemic hypertension 10 .…”

Section: Introductionsupporting

confidence: 76%

Involvement of Neuroinflammation in the Pathogenesis of Monocrotaline-Induced Pulmonary Hypertension

et al. 2018

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Pulmonary hypertension (PH) is a devastating disease and its successful treatment remains to be accomplished despite recent advances in pharmacotherapy. It has been proposed that PH be considered as a systemic disease, rather than primarily a disease of the pulmonary vasculature. Consequently, an investigation of the intricate interplay between multiple organs such as brain, vasculature, and lung in PH could lead to the identification of new targets for its therapy. However, little is known about this interplay. This study was undertaken to examine the concept that altered autonomic-pulmonary communication is important in PH pathophysiology. Therefore, we hypothesize that activation of microglial cells in the paraventricular nucleus of hypothalamus and neuroinflammation is associated with increased sympathetic drive and pulmonary pathophysiology contributing to PH. We utilized the monocrotaline rat model for PH and intracerebroventricular administration of minocycline for inhibition of microglial cells activation to investigate this hypothesis. Hemodynamic, echocardiographic, histological, immunohistochemical, and confocal microscopic techniques assessed cardiac and pulmonary function and microglial cells. Monocrotaline treatment caused cardiac and pulmonary pathophysiology associated with PH. There were also increased activated microglial cells and mRNA for proinflammatory cytokines (IL [interleukin]-1β, IL-6, and TNF [tumor necrosis factor]-α) in the paraventricular nucleus. Furthermore, increased sympathetic drive and plasma norepinephrine were observed in rats with PH. Intracerebroventricular infusion of minocycline inhibited all these parameters and significantly attenuated PH. These observations implicate a dysfunctional autonomic-lung communication in the development and progression of PH providing new therapeutic targets, such as neuroinflammation, for PH therapy.

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Section: Introductionsupporting

confidence: 76%

Involvement of Neuroinflammation in the Pathogenesis of Monocrotaline-Induced Pulmonary Hypertension

et al. 2018

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“…Marked SNA activation, as assessed by U-NA and P-NA, was Suzuki et al (2012) demonstrated significantly higher P-NA concentrations in MCTtreated rats at 4 weeks after injection than in age-matched control rats.…”

Section: Alterations Of Autonomic Function In Mct-treated Ratsmentioning

confidence: 89%

“…Many studies have reported changes of SNA and haemodynamics in MCT-treated rats Suzuki et al (2012). (a) Representative time recordings of carotid sinus pressure (CSP) and arterial pressure (AP) in a monocrotaline (MCT)-injected rat and a saline-injected age-matched control (CTL) rat at 3.5 weeks after injection.…”

mentioning

confidence: 99%

Suppressed baroreflex peripheral arc overwhelms augmented neural arc and incapacitates baroreflex function in rats with pulmonary arterial hypertension

Shinoda

Saku

Oga

et al. 2019

Experimental Physiology

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New Findings What is the central question of this study?The impact of pulmonary arterial hypertension on open‐loop baroreflex function, which determines how powerfully and rapidly the baroreflex operates to regulate arterial pressure, remains poorly understood. What is the main finding and its importance?The gain of the baroreflex total arc, indicating the baroreflex pressure‐stabilizing function, is markedly attenuated in rats with monocrotaline‐induced pulmonary arterial hypertension. This is caused by a rightward shift of the baroreflex neural arc and a downward shift of the peripheral arc. These findings contribute greatly to our understanding of arterial pressure regulation by the sympathetic nervous system in pulmonary arterial hypertension. Abstract Sympathoexcitation has been documented in patients with established pulmonary arterial hypertension (PAH). Although the arterial baroreflex is the main negative feedback regulator of sympathetic nerve activity (SNA), the way in which PAH impacts baroreflex function remains poorly understood. In this study, we conducted baroreflex open‐loop analysis in a rat model of PAH. Sprague–Dawley rats were injected with monocrotaline (MCT) s.c. to induce PAH (60 mg kg−1; n = 11) or saline as a control group (CTL; n = 8). At 3.5 weeks after MCT injection, bilateral carotid sinuses were isolated, and intrasinus pressure (CSP) was controlled while SNA at the coeliac ganglia and arterial pressure (AP) were recorded. To examine the static baroreflex function, CSP was increased stepwise while steady‐state AP (total arc) and SNA (neural arc) responses to CSP and the AP response to SNA (peripheral arc) were measured. Monocrotaline significantly decreased the static gain of the baroreflex total arc at the operating AP compared with CTL (−0.80 ± 0.31 versus −0.22 ± 0.22, P < 0.05). Given that MCT markedly increased plasma noradrenaline, an index of SNA, by approximately 3.6‐fold compared with CTL, calibrating SNA by plasma noradrenaline revealed that MCT shifted the neural arc to a higher SNA level and shifted the peripheral arc downwards. Monocrotaline also decreased the dynamic gain of the baroreflex total arc (−0.79 ± 0.16 versus −0.35 ± 0.17, P < 0.05), while the corner frequencies that reflect the speed of the baroreflex remained unchanged (0.06 ± 0.02 versus 0.08 ± 0.02 Hz, n.s.). In rats with MCT‐induced PAH, the suppressed baroreflex peripheral arc overwhelms the augmented neural arc and, in turn, attenuates the gain of the total arc, which determines the pressure‐stabilizing capacity of the baroreflex.

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“…Though, Suzuki et al . 67 showed that monocrotaline-induced pulmonary vascular remodelling was attenuated, if rats were pre-treated with GABA leading to decreased levels of norepinephrine. To the best of our knowledge, the presence of GABA-receptors has been proven in the lung 56,57 , but not specifically in the pulmonary circulation, even if the activity of GABA-transaminase was verified in PAs or PVs of guinea pigs, with dominance for PAs suggesting the presence of GABA-receptors 68 .…”

Section: Discussionmentioning

confidence: 99%

“…In that study, ET-1 levels were increased in the bronchoalveolar lavage of bicuculline-treated rats 74 and conversely, the occurrence of lung oedema was attenuated by phosphoramidon or by the ET A -antagonist BQ-123 74 . In addition, GABA reduces the release of norepinephrine 65,67 which highly contributes to the formation of neurogenic lung oedema 75,76 .…”

Section: Discussionmentioning

confidence: 99%

Argon reduces the pulmonary vascular tone in rats and humans by GABA-receptor activation

Suleiman

Klassen

Katz

et al. 2019

Sci Rep

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Argon exerts neuroprotection. Thus, it might improve patients’ neurological outcome after cerebral disorders or cardiopulmonary resuscitation. However, limited data are available concerning its effect on pulmonary vessel and airways. We used rat isolated perfused lungs (IPL) and precision-cut lung slices (PCLS) of rats and humans to assess this topic. IPL: Airway and perfusion parameters, oedema formation and the pulmonary capillary pressure (Pcap) were measured and the precapillary and postcapillary resistance (Rpost) was calculated. In IPLs and PCLS, the pulmonary vessel tone was enhanced with ET-1 or remained unchanged. IPLs were ventilated and PCLS were gassed with argon-mixture or room-air. IPL: Argon reduced the ET-1-induced increase of Pcap, Rpost and oedema formation (p < 0.05). PCLS (rat): Argon relaxed naïve pulmonary arteries (PAs) (p < 0.05). PCLS (rat/human): Argon attenuated the ET-1-induced contraction in PAs (p < 0.05). Inhibition of GABAB-receptors abolished argon-induced relaxation (p < 0.05) in naïve or ET-1-pre-contracted PAs; whereas inhibition of GABAA-receptors only affected ET-1-pre-contracted PAs (p < 0.01). GABAA/B-receptor agonists attenuated ET-1-induced contraction in PAs and baclofen (GABAB-agonist) even in pulmonary veins (p < 0.001). PLCS (rat): Argon did not affect the airways. Finally, argon decreases the pulmonary vessel tone by activation of GABA-receptors. Hence, argon might be applicable in patients with pulmonary hypertension and right ventricular failure.

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Beneficial effects of γ-aminobutyric acid on right ventricular pressure and pulmonary vascular remodeling in experimental pulmonary hypertension

Abstract: These results suggest that plasma NE levels play an important role in the development of MCT-induced PH in rats and that GABA exerts a preventive effect against MCT-induced PH by suppressing the sympathetic nervous system but not the cardiac ET-1 system.

Cited by 17 publications

References 33 publications

Involvement of Neuroinflammation in the Pathogenesis of Monocrotaline-Induced Pulmonary Hypertension

Involvement of Neuroinflammation in the Pathogenesis of Monocrotaline-Induced Pulmonary Hypertension

Suppressed baroreflex peripheral arc overwhelms augmented neural arc and incapacitates baroreflex function in rats with pulmonary arterial hypertension

Argon reduces the pulmonary vascular tone in rats and humans by GABA-receptor activation

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