The role of extracellular signal-regulated kinase in beta-adrenoceptor-mediated vasodilatation

Uhiara, Chukwuemeka Obinna (2012) The role of extracellular signal-regulated kinase in beta-adrenoceptor-mediated vasodilatation. PhD thesis, University of Nottingham.

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Abstract

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)
Supervisors:Roberts, R.
Alexander, S.P.H.
Uncontrolled Keywords:ERK, B-adrenoceptors, porcine coronary artery, statins
Faculties/Schools:UK Campuses > Faculty of Medicine and Health Sciences > School of Biomedical Sciences
ID Code:2695
Deposited By:Mr C O Uhiara
Deposited On:31 Aug 2012 10:50
Last Modified:31 Aug 2012 10:52

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