Uhiara, Chukwuemeka Obinna (2012) The role of extracellular signal-regulated kinase in beta-adrenoceptor-mediated vasodilatation. PhD thesis, University of Nottingham.
Beta-Adrenoceptors (B-ARs) mediate vasodilatation by activating various mechanisms that collectively contribute to vascular smooth muscle (VSM) relaxation. It has been shown that B2-AR stimulation in cultured cells results in activation of extracellular signal-regulated kinase (ERK). As the functional relevance of this was not known, the aim of the current investigation was determine the role of ERK in beta-AR-mediated vasodilatation.
Isoprenaline-induced relaxation of porcine coronary artery (PCA) segments pre-contracted with the thromboxane mimetic U46619 was significantly enhanced by inhibition of ERK activation. Relaxations to the beta2-AR agonist salbutamol, but not those to the beta1-AR agonist xamoterol or the adenylyl cyclase activator forskolin, were also enhanced. The intermediate-conductance Ca2+-activated K+ (IKCa) channel blocker TRAM-34 prevented the enhancement of beta2-AR-mediated responses.
Taken together, the data indicate that ERK inhibits beta2-AR-mediated vasodilatation by interacting with a cyclic 3’, 5’-adenosine monophosphate-independent relaxation pathway involving K+ channels. This may occur through a direct regulatory action on the IKCa channel via phosphorylation.
Furthermore, the finding that increased ERK activation in a rat model of Type II diabetes was associated with significantly impaired beta-AR-mediated vasodilatation raises the possibility that ERK may represent a promising therapeutic target in the treatment of disease states characterised by abnormal vascular function.
|Item Type:||Thesis (PhD)|
|Uncontrolled Keywords:||ERK, B-adrenoceptors, porcine coronary artery, statins|
|Faculties/Schools:||UK Campuses > Faculty of Medicine and Health Sciences > School of Biomedical Sciences|
|Deposited By:||Mr C O Uhiara|
|Deposited On:||31 Aug 2012 10:50|
|Last Modified:||31 Aug 2012 10:52|
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