Mas‐related G protein‐coupled receptor type D antagonism improves portal hypertension in cirrhotic rats
Abstract Splanchnic vasodilatation contributes to the development and aggravation of portal hypertension (PHT). We previously demonstrated that in cirrhosis, angiotensin‐ mediates splanchnic vasodilatation through the Mas receptor (MasR). In this study, we investigated whether the recently character...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wolters Kluwer Health/LWW
2022-09-01
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| Series: | Hepatology Communications |
| Online Access: | https://doi.org/10.1002/hep4.1987 |
| _version_ | 1827883758411317248 |
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| author | Lakmie S. Gunarathne Indu G. Rajapaksha Stephen Casey Tawar Qaradakhi Anthony Zulli Harinda Rajapaksha Jonel Trebicka Peter W. Angus Chandana B. Herath |
| author_facet | Lakmie S. Gunarathne Indu G. Rajapaksha Stephen Casey Tawar Qaradakhi Anthony Zulli Harinda Rajapaksha Jonel Trebicka Peter W. Angus Chandana B. Herath |
| author_sort | Lakmie S. Gunarathne |
| collection | DOAJ |
| description | Abstract Splanchnic vasodilatation contributes to the development and aggravation of portal hypertension (PHT). We previously demonstrated that in cirrhosis, angiotensin‐ mediates splanchnic vasodilatation through the Mas receptor (MasR). In this study, we investigated whether the recently characterized second receptor for angiotensin‐(1–7), Mas‐related G protein‐coupled receptor type D (MrgD), contributes to splanchnic vasodilatation in cirrhotic and noncirrhotic PHT. Splanchnic vascular hemodynamic and portal pressure were determined in two rat models of cirrhotic PHT and a rat model with noncirrhotic PHT, treated with either MrgD blocker D‐Pro7‐Ang‐(1‐7) (D‐Pro) or MasR blocker A779. Gene and protein expression of MrgD and MasR were measured in splanchnic vessels and livers of cirrhotic and healthy rats and in patients with cirrhosis and healthy subjects. Mesenteric resistance vessels isolated from cirrhotic rats were used in myographs to study their vasodilatory properties. MrgD was up‐regulated in cirrhotic splanchnic vessels but not in the liver. In cirrhotic rats, treatment with D‐Pro but not A779 completely restored splanchnic vascular resistance to a healthy level, resulting in a 33% reduction in portal pressure. Mesenteric vessels pretreated with D‐Pro but not with A779 failed to relax in response to acetylcholine. There was no splanchnic vascular MrgD or MasR up‐regulation in noncirrhotic PHT; thus, receptor blockers had no effect on splanchnic hemodynamics. Conclusion: MrgD plays a major role in the development of cirrhotic PHT and is a promising target for the development of novel therapies to treat PHT in cirrhosis. Moreover, neither MrgD nor MasR contributes to noncirrhotic PHT. |
| first_indexed | 2024-03-12T19:17:44Z |
| format | Article |
| id | doaj.art-2b4d0e94c1144880adb97ad9f6f0059e |
| institution | Directory Open Access Journal |
| issn | 2471-254X |
| language | English |
| last_indexed | 2024-03-12T19:17:44Z |
| publishDate | 2022-09-01 |
| publisher | Wolters Kluwer Health/LWW |
| record_format | Article |
| series | Hepatology Communications |
| spelling | doaj.art-2b4d0e94c1144880adb97ad9f6f0059e2023-08-02T05:25:22ZengWolters Kluwer Health/LWWHepatology Communications2471-254X2022-09-01692523253710.1002/hep4.1987Mas‐related G protein‐coupled receptor type D antagonism improves portal hypertension in cirrhotic ratsLakmie S. Gunarathne0Indu G. Rajapaksha1Stephen Casey2Tawar Qaradakhi3Anthony Zulli4Harinda Rajapaksha5Jonel Trebicka6Peter W. Angus7Chandana B. Herath8Department of Medicine University of Melbourne Austin Health Heidelberg Victoria AustraliaDepartment of Medicine University of Melbourne Austin Health Heidelberg Victoria AustraliaLiver Unit Austin Health Heidelberg Victoria AustraliaCollege of Health and Biomedicine Victoria University Werribee Victoria AustraliaCollege of Health and Biomedicine Victoria University Werribee Victoria AustraliaOracle Australia Melbourne Victoria AustraliaDepartment of Internal Medicine University Clinic Frankfurt Frankfurt GermanyDepartment of Medicine University of Melbourne Austin Health Heidelberg Victoria AustraliaDepartment of Medicine University of Melbourne Austin Health Heidelberg Victoria AustraliaAbstract Splanchnic vasodilatation contributes to the development and aggravation of portal hypertension (PHT). We previously demonstrated that in cirrhosis, angiotensin‐ mediates splanchnic vasodilatation through the Mas receptor (MasR). In this study, we investigated whether the recently characterized second receptor for angiotensin‐(1–7), Mas‐related G protein‐coupled receptor type D (MrgD), contributes to splanchnic vasodilatation in cirrhotic and noncirrhotic PHT. Splanchnic vascular hemodynamic and portal pressure were determined in two rat models of cirrhotic PHT and a rat model with noncirrhotic PHT, treated with either MrgD blocker D‐Pro7‐Ang‐(1‐7) (D‐Pro) or MasR blocker A779. Gene and protein expression of MrgD and MasR were measured in splanchnic vessels and livers of cirrhotic and healthy rats and in patients with cirrhosis and healthy subjects. Mesenteric resistance vessels isolated from cirrhotic rats were used in myographs to study their vasodilatory properties. MrgD was up‐regulated in cirrhotic splanchnic vessels but not in the liver. In cirrhotic rats, treatment with D‐Pro but not A779 completely restored splanchnic vascular resistance to a healthy level, resulting in a 33% reduction in portal pressure. Mesenteric vessels pretreated with D‐Pro but not with A779 failed to relax in response to acetylcholine. There was no splanchnic vascular MrgD or MasR up‐regulation in noncirrhotic PHT; thus, receptor blockers had no effect on splanchnic hemodynamics. Conclusion: MrgD plays a major role in the development of cirrhotic PHT and is a promising target for the development of novel therapies to treat PHT in cirrhosis. Moreover, neither MrgD nor MasR contributes to noncirrhotic PHT.https://doi.org/10.1002/hep4.1987 |
| spellingShingle | Lakmie S. Gunarathne Indu G. Rajapaksha Stephen Casey Tawar Qaradakhi Anthony Zulli Harinda Rajapaksha Jonel Trebicka Peter W. Angus Chandana B. Herath Mas‐related G protein‐coupled receptor type D antagonism improves portal hypertension in cirrhotic rats Hepatology Communications |
| title | Mas‐related G protein‐coupled receptor type D antagonism improves portal hypertension in cirrhotic rats |
| title_full | Mas‐related G protein‐coupled receptor type D antagonism improves portal hypertension in cirrhotic rats |
| title_fullStr | Mas‐related G protein‐coupled receptor type D antagonism improves portal hypertension in cirrhotic rats |
| title_full_unstemmed | Mas‐related G protein‐coupled receptor type D antagonism improves portal hypertension in cirrhotic rats |
| title_short | Mas‐related G protein‐coupled receptor type D antagonism improves portal hypertension in cirrhotic rats |
| title_sort | mas related g protein coupled receptor type d antagonism improves portal hypertension in cirrhotic rats |
| url | https://doi.org/10.1002/hep4.1987 |
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