MEK1/2 inhibitor U0126, but not nimodipine, reduces upregulation of cerebrovascular contractile receptors after subarachnoid haemorrhage in rats
| Autor: | Lars Edvinsson, Sara Ellinor Johansson, Simon Topp Christensen, Kristian Agmund Haanes, Aneta Radziwon-Balicka, Karin Warfvinge |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Vascular smooth muscle Science Cerebral arteries Ischemia Pharmacology Muscle Smooth Vascular Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Nitriles Butadienes medicine Animals Channel blocker Receptor Protein Kinase Inhibitors Nimodipine Mitogen-Activated Protein Kinase Kinases Multidisciplinary Electrical impedance myography business.industry Dihydropyridine Cerebral Arteries Subarachnoid Hemorrhage Calcium Channel Blockers medicine.disease Receptor Endothelin B Rats Up-Regulation Disease Models Animal 030104 developmental biology Vasoconstriction Medicine business 030217 neurology & neurosurgery Muscle Contraction medicine.drug |
| Zdroj: | PLoS ONE, Vol 14, Iss 4, p e0215398 (2019) Christensen, S T, Johansson, S E, Radziwon-Balicka, A, Warfvinge, K, Haanes, K A & Edvinsson, L 2019, ' MEK1/2 inhibitor U0126, but not nimodipine, reduces upregulation of cerebrovascular contractile receptors after subarachnoid haemorrhage in rats ', PLoS ONE, vol. 14, no. 4, e0215398 . https://doi.org/10.1371/journal.pone.0215398 |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0215398 |
| Popis: | Vascular pathophysiological changes after haemorrhagic stroke, such as phenotypic modulation of the cerebral arteries and cerebral vasospasms, are associated with delayed cerebral ischemia (DCI) and poor outcome. The only currently approved drug treatment shown to reduce the risk of DCI and improve neurologic outcome after aneurysmal subarachnoid haemorrhage (SAH) is nimodipine, a dihydropyridine L-type voltage-gated Ca2+ channel blocker. MEK1/2 mediated transcriptional upregulation of contractile receptors, including endothelin-1 (ET-1) receptors, has previously been shown to be a factor in the pathology of SAH. The aim of the study was to compare intrathecal and subcutaneous treatment regimens of nimodipine and intrathecal treatment regimens of U0126, a MEK1/2 inhibitor, in a single injection experimental rat SAH model with post 48 h endpoints consisting of wire myography of cerebral arteries, flow cytometry of cerebral arterial tissue and behavioural evaluation. Following ET-1 concentration-response curves, U0126 exposed arteries had a significantly lower ET-1max than vehicle arteries. Arteries from both the intrathecal- and subcutaneous nimodipine treated animals had significantly higher ET-1max contractions than the U0126 arteries. Furthermore, Ca2+ concentration response curves (precontracted with ET-1 and in the presence of nimodipine) showed that nimodipine treatment could result in larger nimodipine insensitive contractions compared to U0126. Flow cytometry showed decreased protein expression of the ETB receptor in U0126 treated cerebral vascular smooth muscle cells compared to vehicle. Only U0126 treatment lowered ET-1max contractions and ETB receptor levels, as well as decreased the contractions involving nimodipine-insensitive Ca2+ channels, when compared to both intrathecal and subcutaneous nimodipine treatment. This indicate that targeting gene expression might be a better strategy than blocking specific receptors or ion channels in future treatments of SAH. |
| Databáze: | OpenAIRE |
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