title: MEK1/2 inhibitor U0126 but not endothelin receptor antagonist clazosentan reduces upregulation of cerebrovascular contractile receptors and delayed cerebral ischemia, and improves outcome after subarachnoid hemorrhage in rats.
abstract: Cerebral vasospasm and late cerebral ischemia (LCI) remain leading causes of mortality in patients experiencing a subarachnoid hemorrhage (SAH). This occurs typically 3 to 4 days after the initial bleeding and peaks at 5 to 7 days. The underlying pathophysiology is still poorly understood. Because SAH is associated with elevated levels of endothelin-1 (ET-1), focus has been on counteracting endothelin receptor activation with receptor antagonists like clazosentan, however, with poor outcome in clinical trials. We hypothesize that inhibition of intracellular transcription signaling will be an effective approach to prevent LCI. Here, we compare the effects of clazosentan versus the MEK1/2 blocker U0126 in a rat model of SAH. Although clazosentan directly inhibits the contractile responses in vivo to ET-1, it did not prevent SAH-induced upregulation of ET receptors in cerebral arteries and did not show a beneficial effect on neurologic outcome. U0126 had no vasomotor effect by itself but counteracts SAH-induced receptor upregulation in cerebral arteries and improved outcome after SAH. We suggest that because SAH induces elevated expression of several contractile receptor subtypes, it is not sufficient to block only one of these (ET receptors) but inhibition of transcriptional MEK1/2-mediated upregulation of several contractile receptors may be a viable way towards alleviating LCI.
authors.affiliation: Department of Experimental Research, Glostrup Research Institute, Copenhagen University, Copenhagen, Denmark.
authors.forename: Gro K
authors.initials: GK
authors.lastname: Povlsen
authors.affiliation: 1] Department of Experimental Research, Glostrup Research Institute, Copenhagen University, Copenhagen, Denmark [2] Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Edvinsson
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002070:Butadienes / Q000494:pharmacology*; D002536:Cerebral Arteries / Q000378:metabolism / Q000473:pathology; D004146:Dioxanes / Q000494:pharmacology*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D009570:Nitriles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000096:biosynthesis*; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D002070:Butadienes; D004146:Dioxanes; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D009570:Nitriles; D011725:Pyridines; D011743:Pyrimidines; D017466:Receptors, Endothelin; D013449:Sulfonamides; D013777:Tetrazoles; C113580:U 0126; C109641:clazosentan; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2