| 1. |
- Ahnstedt, Hilda, et al.
(författare)
-
Cytokines and growth factors modify the upregulation of contractile endothelin ET(A) and ET(B) receptors in rat cerebral arteries after organ culture.
- 2012
-
Ingår i: Acta Physiologica. - : Wiley. - 1748-1708. ; 205:2, s. 266-278
-
Tidskriftsartikel (refereegranskat)abstract
- Aim: Experimental cerebral ischemia and organ culture of cerebral arteries induce an increased endothelin ET(B) receptor-mediated contraction. The aim of the present study was to examine if cytokines and growth factors, known to be activated in ischemia, can influence the expression and function of endothelin receptors after organ culture. Methods: Rat middle cerebral arteries were cultured for 24 h at 37°C in humidified 5% CO(2) and air in culture medium alone, or with tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), platelet-derived growth factor (PDGF), epidermal growth factor (EGF) or basic fibroblast growth factor (bFGF). Concentration-response curves were obtained for sarafotoxin 6c (ET(B) receptor agonist) and endothelin-1 (here ET(A) receptor agonist, because of ET(B) receptor desensitization). The receptor mRNA expression was examined by real-time PCR and the protein expression by immunohistochemistry and Western blot. Results: TNF-α (100 ng/ml) and EGF (20 ng/ml) potentiated the ET(B) receptor-mediated contraction (increase in pEC(50) without change in E(max) ). bFGF (10 ng/ml) and IL-1β (10 ng/ml) induced an enhanced ET(A) receptor-mediated contraction. bFGF (10 ng/ml) significantly increased the ET(B) mRNA level, and EGF (20 ng/ml) increased the ET(A) receptor protein. Increased ET(B) receptor mRNA and protein level also were observed after treatment with IL-1β (10 ng/ml). Conclusion: The present study show that TNF-α, IL-1β, EGF and bFGF can modify the expression and function of endothelin receptors during organ culture. Since there is similar receptor upregulation in experimental stroke, the effect of cytokines and growth factors on endothelin receptor upregulation is an interesting aspect to study in vivo.
|
|
| 2. |
|
|
| 3. |
- Henriksson, Marie, et al.
(författare)
-
Importance of ERK1/2 in upregulation of endothelin type B receptors in cerebral arteries
- 2004
-
Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 142:7, s. 1155-1161
-
Tidskriftsartikel (refereegranskat)abstract
- 1 This study examines the importance of mitogen-activated protein kinases (MAPKs) in upregulation of endothelin type B (ETB) receptors. 2 Rat middle cerebral arteries (MCAs) were incubated for 24 h with or without kinase inhibitors. Vessel segments were mounted in myographs and the contractile responses to endothelin-1 (ET-1; ETA and ETB receptor agonist) and sarafotoxin 6c (S6c; ETB receptor agonist) were studied. We used real-time PCR to measure the receptor mRNA levels. An ELISA assay showed the activation of ERK1/2 kinases after 3 h. Immunohistochemistry revealed the presence of ETB receptors on the vessels. 3 After organ culture, S6c induced vasoconstriction. Incubation with the MEK/ERK inhibitors U0126 and SB386023 diminished the contractile response to S6c. The p38 MAPK inhibitor SB239063 did not affect the S6c-induced contraction. 4 The ET-1-induced vasoconstriction was increased after incubation with SB386023 or SB239063, while unaffected by U0126. 5 The ETB receptor mRNA levels were diminished by SB386023 and U0126. The ETA receptor mRNA levels were unaffected. 6 The levels of activated ERK1/2 kinases were significantly higher after 3 h of organ culture as compared to fresh vessels. 7 The level of ETB receptor protein on the smooth muscle cells of the MCA, visualised by immunohistochemistry, was somewhat diminished by SB386023. 8 Our results show that the ERK1/2 MAPK is important in the upregulation of contractile ETB receptors in MCA after organ culture. Since there is a similar upregulation in models of focal ischaemia and subarachnoid haemorrhage, this may be an important pathophysiological event.
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
- Henriksson, Marie, et al.
(författare)
-
MEK1/2 inhibition attenuates vascular ET(A) and ET (B) receptor alterations after cerebral ischaemia.
- 2007
-
Ingår i: Experimental Brain Research. - : Springer Science and Business Media LLC. - 0014-4819 .- 1432-1106. ; 178:4, s. 470-476
-
Tidskriftsartikel (refereegranskat)abstract
- Cerebral ischaemia is associated with elevated levels of endothelin B (ETB) receptors in the ipsilateral middle cerebral artery (MCA). This up-regulation of ET receptors occurs via de novo transcription involving mitogen-activated protein kinases (MAPK). The aim of this study was to examine the effect of inhibition of the MAP kinase/ERK kinase (MEK)1/2 on ET receptor alteration, brain damage, and neurology in experimental cerebral ischaemia. Transient middle cerebral artery occlusion (MCAO) was induced in male Wistar rats by the intraluminal filament technique. The animals received 100 mg/kg intraperitoneally of the MEK1/2 inhibitor U0126 or vehicle in conjunction with the occlusion. After 24 h, the rats were decapitated and the brains removed. The middle cerebral arteries were dissected out and examined with myographs or immunohistochemistry. The ischaemic areas of the brains were compared. After the MCAO, the contractile responses of the ETA and ETB receptors were augmented in the ipsilateral MCA. U0126 decreased this alteration in ET receptor response. Furthermore, treatment with U0126 significantly decreased the brain damage and improved neurological scores. Immunohistochemistry showed that there were lower protein levels of phosphorylated extracellular signal-regulated kinases (ERK)1/2 and phosphorylated transcription factor Elk-1 in the U0126-treated rats compared to control. The results show that treatment with the MEK1/2 inhibitor U0126 in ischaemic stroke decreases brain damage, neurological symptoms, and ET receptor alteration. The vascular effects of U0126 provide new perspective on possible mechanisms of actions of MAPK inhibition in cerebral ischaemia.
|
|
| 7. |
- Henriksson, Marie, et al.
(författare)
-
Protein kinase C inhibition attenuates vascular ETB receptor upregulation and decreases brain damage after cerebral ischemia in rat.
- 2007
-
Ingår i: BMC Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 8, s. 7-7
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Protein kinase C (PKC) is known to be involved in the pathophysiology of experimental cerebral ischemia. We have previously shown that after transient middle cerebral artery occlusion, there is an upregulation of endothelin receptors in the ipsilateral middle cerebral artery. The present study aimed to examine the effect of the PKC inhibitor Ro-32-0432 on endothelin receptor upregulation, infarct volume and neurology outcome after middle cerebral artery occlusion in rat. Results: At 24 hours after transient middle cerebral artery occlusion (MCAO), the contractile endothelin B receptor mediated response and the endothelin B receptor protein expression were upregulated in the ipsilateral but not the contralateral middle cerebral artery. In Ro-32-0432 treated rats, the upregulated endothelin receptor response was attenuated. Furthermore, Ro-32-0432 treatment decreased the ischemic brain damage significantly and improved neurological scores. Immunohistochemistry showed fainter staining of endothelin B receptor protein in the smooth muscle cells of the ipsilateral middle cerebral artery of Ro-32-0432 treated rats compared to control. Conclusion: The results suggest that treatment with Ro-32-0432 in ischemic stroke decreases the ischemic infarction area, neurological symptoms and associated endothelin B receptor upregulation. This provides a new perspective on possible mechanisms of actions of PKC inhibition in cerebral ischemia.
|
|
| 8. |
- Stenman, Emelie, et al.
(författare)
-
Cooperative effect of angiotensin AT, and endothelin ETA receptor antagonism limits the brain damage after ischemic stroke in rat
- 2007
-
Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 570:1-3, s. 142-148
-
Tidskriftsartikel (refereegranskat)abstract
- Cerebral ischemia results in enhanced expression of smooth muscle cell endothelin and angiotensin receptors in cerebral arteries. We hypothesise that this phenomenon may be detrimental and that acute treatment with a combined non-hypotensive dose of the angiotensin AT, receptor inhibitor candesartan and the endothelin ETA receptor antagonist ZD 1611 reduces the infarct in experimental ischemic stroke. Transient middle cerebral artery occlusion was induced in male Wistar rats by the intraluminal filament technique for 2 h followed by recirculation. The animals received systemic candesartan (0.05 mg/kg/day), ZD1611 (0.15 mg/kg/day), both combined or vehicle with start immediately after the occlusion. After 48 h the rats were sacrificed, the brains sliced and stained with 1% 2, 3, 5-triphenyltetrazolium chloride (TTC) and the volume of ischemic damage determined. The middle cerebral arteries were harvested for immunocytochemical studies of angiotensin AT, and endothelin ETA receptor expression. Candesartan or ZD1611 did alone not significantly decrease the brain damage or improve neurological scores as compared to vehicle controls. The combined inhibition of angiotensin AT, and endothelin ETA receptors however decreased the brain damage and improved the neurological scores (both P < 0.05). The treatment did not change resting mean arterial blood pressure. In addition, there was an upregulation of angiotensin AT, receptors in the ischemic middle cerebral artery smooth muscle cells, which was normalised by the combined treatment. In conclusion, the present study shows that combined inhibition of angiotensin AT, and endothelin ETA receptors reduces the brain damage and improves the neurological outcome after ischemic stroke in rat. (c) 2007 Elsevier B.V. All rights reserved.
|
|
| 9. |
|
|
| 10. |
|
|
