Distortion of KB estimates of endothelin‐1 ETA and ETB receptor antagonists in pulmonary arteries: Possible role of an endothelin‐1 clearance mechanism

Angus, James A.; Hughes, Richard J.; Wright, Christine E.

doi:10.1002/prp2.374

Cited by 6 publications

(2 citation statements)

References 36 publications

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“…On the other hand, the selective ETA receptor antagonist (BQ123) only statistically increased ET-1 levels in HPA, this unexpected result and a role in clearance for ETA should be confirmed (Figure 3). Our results may not only involve endothelial cells but also other cells present in the lung preparations, and a previous study suggested that ET-1 clearance occurs in both endothelial cells and hPASMCs 53 . Several studies have shown elevated levels of ET-1 in plasma and HPA derived from PH Group-III patients 13-15, 54 .…”

Section: Even Though We Have Demonstrated a Higher Eta/etb Receptor Esupporting

confidence: 63%

Interaction between PGI2 and ET-1 pathways in vascular smooth muscle from Group-III pulmonary hypertension patients

Özen

Benyahia

Amgoud

et al. 2020

Prostaglandins & Other Lipid Mediators

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Pulmonary hypertension (PH) is characterized by an elevation of mean pulmonary artery pressure and it is classified into five groups. Among these groups, PH Group-III is defined as PH due to lung disease or hypoxia. Prostacyclin (PGI2) analogues (iloprost, treprostinil) and endothelin-1 (ET-1) receptor antagonists (ERA) (used alone or in combination) are therapies used for treating PH. The mechanisms underlying the positive/negative effects of combination treatment are not well documented, and in this study, we tested the hypothesis that the combination of a PGI2 analogue (iloprost, treprostinil) and an ERA may be more effective than either drug alone to treat vasculopathies observed in PH Group-III patients. Using Western blotting, ETA and ETB receptor expression were determined in human pulmonary artery (HPA) preparations derived from control and PH Group-III patients, and the physiologic impact of altered expression ratios was assessed by measuring ET-1 induced contraction of ex vivo HPA and human pulmonary veins (HPV) in an isolated organ bath system. In addition, the effects of single agent or combination treatments with a PGI2 analogue and an ERA on ET-1 release and HPA smooth muscle cells (hPASMCs) proliferation were determined by ELISA and MTT techniques, respectively. Our results indicate that the increased ETA/ETB receptor expression ratio in HPA derived from PH Group-III patients is primarily governed by a greatly depressed ETB receptor expression. However, contractions induced by ET-1 are not impacted in HPA and HPV derived from PH Group-III patients as compared to controls. Also, we found that the combination of an ETA receptor antagonist (BQ123) with iloprost provides greater inhibition of hPASMCs proliferation (-48±14% control;-32±06% PH) than either agent alone. Of note, while the ETB receptor antagonist (BQ788) increases ET-1 production from PH Group-III patients' preparations (HPA, parenchyma), even under these more proliferative conditions, iloprost and treprostinil are still effective to inhibit hPASMCs proliferation (-22/-24%). Our findings may provide new insights for the treatment of PH Group-III by combining a PGI2 analogue and a selective ETA receptor antagonist.

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Section: Even Though We Have Demonstrated a Higher Eta/etb Receptor Esupporting

confidence: 63%

Interaction between PGI2 and ET-1 pathways in vascular smooth muscle from Group-III pulmonary hypertension patients

Özen

Benyahia

Amgoud

et al. 2020

Prostaglandins & Other Lipid Mediators

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“…The protocol of using only a single concentration of each venom was chosen due to rapid desensitization in vascular relaxation responses observed with various Australian elapid snake venoms ( Chaisakul et al, 2012 ; Chaisakul et al, 2013 ; Chaisakul et al, 2014 ). In a separate set of experiments, P. textilis venom (30 µg/ml) was tested after pretreatment (30 min; literature supporting each chosen antagonist concentration shown) with one of 1) the CGRP antagonist CGRP 8–37 (3 µM) ( Wisskirchen et al, 1998 ); 2) the cyclooxygenase inhibitor indomethacin (3 µM) ( Kassab et al, 2017 ); or 3) the nitric oxide synthase inhibitor L-NAME (100 µM) ( Angus et al, 2017 ).…”

Section: Methodsmentioning

confidence: 99%

Role of Phospholipases A2 in Vascular Relaxation and Sympatholytic Effects of Five Australian Brown Snake, Pseudonaja spp., Venoms in Rat Isolated Tissues

2021

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Human envenoming by Australian brown snakes (Pseudonaja spp.) may result in potentially life-threatening hypotension and subsequent cardiovascular collapse. There have been relatively few studies of the cardiovascular and sympathetic effects of Pseudonaja spp. venoms. In this study, we have examined the effects of venom from five brown snake species—P. affinis, aspidorhyncha, inframacula, nuchalis, and textilis—on cardiac inotropic and chronotropic responses, vascular tone, and sympathetic nerve-induced vascular contractions in rat isolated tissues. The role of phospholipases A2 (PLA2s) in venom-induced effects was assessed with the sPLA2 inhibitor varespladib. In rat isolated left and right atria, there were no physiologically relevant effects of Pseudonaja venoms (0.1–30 µg/ml) on left atrial force of contraction (inotropy) or right atrial rate (chronotropy). In contrast, in isolated small mesenteric arteries precontracted with a thromboxane mimetic, each of the five brown snake venoms (at 30 µg/ml) caused marked vasorelaxation (−60 to –90% of contractile tone). Pretreatment with varespladib (1 µM) significantly inhibited the vasorelaxation caused by P. aspidorhyncha, P. nuchalis, and P. textilis venoms. Electrically induced sympathetic nerve-mediated contractions of mesenteric arteries were significantly attenuated by only P. textilis, and P. affinis venoms (30 µg/ml) and these sympatholytic effects were inhibited by varespladib (1 µM). Based on their inhibition with the sPLA2 inhibitor varespladib, we conclude that PLA2 toxins in P. aspidorhyncha, P. nuchalis, and P. textilis venoms are involved in brown snake venom-induced vasorelaxation and the sympatholytic effects of P. affinis, and P. textilis venoms. Our study supports the promising potential role of varespladib as an initial (pre-referral) and/or adjunct (in combination with antivenom) therapeutic agent for brown snake envenoming.

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Endothelin B receptor dysfunction mediates elevated myogenic tone in cerebral arteries from aged male Fischer 344 rats

et al. 2021

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Distortion of K_B estimates of endothelin‐1 ET_A and ET_B receptor antagonists in pulmonary arteries: Possible role of an endothelin‐1 clearance mechanism

Cited by 6 publications

References 36 publications

Interaction between PGI2 and ET-1 pathways in vascular smooth muscle from Group-III pulmonary hypertension patients

Interaction between PGI2 and ET-1 pathways in vascular smooth muscle from Group-III pulmonary hypertension patients

Role of Phospholipases A2 in Vascular Relaxation and Sympatholytic Effects of Five Australian Brown Snake, Pseudonaja spp., Venoms in Rat Isolated Tissues

Endothelin B receptor dysfunction mediates elevated myogenic tone in cerebral arteries from aged male Fischer 344 rats

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