Activation of GPER ameliorates experimental pulmonary hypertension in male rats

Alencar, Alexandre; Montes, Guilherme Carneiro; Montagnoli, Tadeu L.; Silva, Ananssa M; Martinez, Sabrina T.; Fraga, Aline Guerra Manssour; Wang, Hao; Groban, Leanne; Sudo, Roberto T.; Zapata‐Sudo, Gisele

doi:10.1016/j.ejps.2016.11.009

Cited by 33 publications

(40 citation statements)

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“…Changes in the PA artery flow profile might be related to the severity of PH, mainly when a triangular flow and a mid-systolic notching are observed [ 22 ]. Two weeks after MCT or saline administration, echocardiographic evaluation showed evidence of PH in the MCT-treated rats, including a change in the shape of the PA waveform ( Fig 1 ) in accordance with previous reports [ 21 , 22 ]. After the echocardiographic examination, the MCT-treated rats were divided into six treatment groups (n = 6 per group): 1.…”

Section: Methodssupporting

confidence: 91%

“…Rats in the MCT group were given a single i.p. injection of MCT at 60 mgkg -1 body weight to induce PH using previously published methods [ 9 , 11 , 20 , 21 ]. Rats in the C group were injected with the same volume of sterile saline.…”

Section: Methodsmentioning

confidence: 99%

“…Cardiac function was assessed by a high-resolution ultrasound imaging system equipped with a RMV-710B transducer with a frequency of 25 MHz and a fixed focal length of 15 mm mounted on an integrated rail system (Vevo 770, Visualsonics, Toronto, Canada). The procedures followed were previously described [ 21 ]. Cardiac function was measured before MCT injection (baseline), 14 days after MCT injection, and 28 days after MCT injection ( Fig 1 ).…”

Section: Methodsmentioning

confidence: 99%

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Synergistic interaction between a PDE5 inhibitor (sildenafil) and a new adenosine A2A receptor agonist (LASSBio-1359) improves pulmonary hypertension in rats

et al. 2018

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IntroductionPulmonary hypertension (PH) is characterized by enhanced pulmonary vascular resistance, which causes right ventricle (RV) pressure overload and results in right sided heart failure and death. This work investigated the effectiveness of a combined therapy with PDE5 inhibitor (PDE5i) and a new adenosine A2A receptor (A2AR) agonist in mitigating monocrotaline (MCT) induced PH in rats.MethodsAn in vitro isobolographic analysis was performed to identify possible synergistic relaxation effect between sildenafil and LASSBio 1359 in rat pulmonary arteries (PAs). In the in vivo experiments, PH was induced in male Wistar rats by a single intraperitoneal injection of 60 mg/kg MCT. Rats were divided into the following groups: control (saline injection only), MCT + vehicle, MCT + sildenafil, MCT + LASSBio 1359 and MCT + combination of sildenafil and LASSBio 1359. Fourteen days after the MCT injection, rats were treated daily with oral administration of the regimen therapies or vehicle for 14 days. Cardiopulmonary system function and structure were evaluated by echocardiography. RV systolic pressure and PA endothelial function were measured.ResultsIsobolographic analysis showed a synergistic interaction between sildenafil and LASSBio 1359 in rat PAs. Combined therapy with sildenafil and LASSBio 1359 but not monotreatment with low dosages of either sildenafil or LASSBio 1359 ameliorated all of PH related abnormalities in cardiopulmonary function and structure in MCT challenged rats.ConclusionsThe combination of sildenafil and LASSBio 1359 has a synergistic interaction, suggesting that combined use of these pharmacological targets may be an alternative to improve quality of life and outcomes for PH patients.

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Section: Methodssupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Synergistic interaction between a PDE5 inhibitor (sildenafil) and a new adenosine A2A receptor agonist (LASSBio-1359) improves pulmonary hypertension in rats

et al. 2018

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“…Hence, G1 did not seem a direct target for pulmonary vascular system diseases. However, it was demonstrated that prophylactic G1 treatment reduced the pulmonary hypertension (PH)-induced right ventricle dysfunction, it can be the results of G1-dependent releasing of nitric oxide [21,22].…”

Section: Discussionmentioning

confidence: 99%

Effects of GPER-1 Receptor Activation on the Reactivity of Pulmonary Vascular Bed and Its Possible Protective Role on Ischemia /Reperfusion Injury

Telli¹,

Tel²,

Büyükafşar³

et al. 2018

jrp

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How to cite this article: Telli G, Tel BC, Büyükafşar K, Gümüşel B. Effects of GPER-1 receptor activation on the reactivity of pulmonary vascular bed and its possible protective role on ischemia /reperfusion injury. Marmara Pharm J. ABSTRACT: Estrogens have remarkable roles in various diseases and physiological events. The recent studies indicate that estrogens exhibit rapid effects such as calcium influx or release of nitric oxide via receptors on the cell membrane or on endoplasmic reticulum. This receptor is called GPER-1 (G protein-coupled estrogen receptor-1). In many previous studies, acute administration of GPER-1 selective agonist G1 reduced ischemia/reperfusion (I/R) injury in heart. In this study, the effect of G1 on the pulmonary vascular bed was investigated using isolated organ bath and isolated lung perfusion. The effect of pre-ischemic acute G1 treatment on lung I/R injury was assessed with post-I/R acetylcholine (ACh) or sodium nitroprusside (SNP) administration. Lungs wet/dry weight ratios were measured to determine the role of acute G1 administration on lung edema due to I/R injury. G1 was not cause a vasorelaxation in precontracted pulmonary arteries. The acute G1 pre-administration was increased the responses of ACh and SNP in I/R injury, however this increase was not statistically significant compared to control. There was no change on lung wet/dry weight ratio between the treatment and control groups. The vasorelaxation responses to ACh and SNP were not different between male and female rats. In our study, G1 caused a slight vasorelaxation in pulmonary vascular bed. There was no significant increase in the vasorelaxations with G1 treatment after I/R injury. Our results suggest that considering the presence of GPER-1 in lung tissue, GPER-1 should be evaluated in detail with further studies.

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“…Cardiac and vascular protection of E2 has been linked to the activation of GPER located on the cell membrane [109]. More importantly, the activation of GPER reverses PH-related cardiopulmonary dysfunction and exercise intolerance in both male and female MCT-PH rats [110,111]. In this regard, 2ME binds the membrane GPER and, via GPER-mediated transactivation of EGFR and ERK1/2 phosphorylation, downregulates AT1 receptor expression [90,91].…”

Section: Other Effects Of the 2-methylation Pathway Relevant To Pahmentioning

confidence: 99%

Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension

Tofovic

Jackson

2019

IJMS

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Pulmonary arterial hypertension (PAH) is a debilitating and progressive disease that predominantly develops in women. Over the past 15 years, cumulating evidence has pointed toward dysregulated metabolism of sex hormones in animal models and patients with PAH. 17β-estradiol (E2) is metabolized at positions C2, C4, and C16, which leads to the formation of metabolites with different biological/estrogenic activity. Since the first report that 2-methoxyestradiol, a major non-estrogenic metabolite of E2, attenuates the development and progression of experimental pulmonary hypertension (PH), it has become increasingly clear that E2, E2 precursors, and E2 metabolites exhibit both protective and detrimental effects in PH. Furthermore, both experimental and clinical data suggest that E2 has divergent effects in the pulmonary vasculature versus right ventricle (estrogen paradox in PAH). The estrogen paradox is of significant clinical relevance for understanding the development, progression, and prognosis of PAH. This review updates experimental and clinical findings and provides insights into: (1) the potential impacts that pathways of estradiol metabolism (EMet) may have in PAH; (2) the beneficial and adverse effects of estrogens and their precursors/metabolites in experimental PH and human PAH; (3) the co-morbidities and pathological conditions that may alter EMet and influence the development/progression of PAH; (4) the relevance of the intracrinology of sex hormones to vascular remodeling in PAH; and (5) the advantages/disadvantages of different approaches to modulate EMet in PAH. Finally, we propose the three-tier-estrogen effects in PAH concept, which may offer reconciliation of the opposing effects of E2 in PAH and may provide a better understanding of the complex mechanisms by which EMet affects the pulmonary circulation–right ventricular interaction in PAH.

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Activation of GPER ameliorates experimental pulmonary hypertension in male rats

Cited by 33 publications

References 67 publications

Synergistic interaction between a PDE5 inhibitor (sildenafil) and a new adenosine A2A receptor agonist (LASSBio-1359) improves pulmonary hypertension in rats

Synergistic interaction between a PDE5 inhibitor (sildenafil) and a new adenosine A2A receptor agonist (LASSBio-1359) improves pulmonary hypertension in rats

Effects of GPER-1 Receptor Activation on the Reactivity of Pulmonary Vascular Bed and Its Possible Protective Role on Ischemia /Reperfusion Injury

Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension

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