Statins and selective inhibition of Rho kinase protect small conductance calcium-activated potassium channel function (KCa2.3) in cerebral arteries
McNeish, Alister J. (University of Reading. Reading School of Pharmacy)
Jiménez Altayó, Francesc (University of Oxford. Department of Pharmacology)
Cottrell, Graeme S. (University of Bath. Department pf Pharmacy and Pharmacology)
Garland, Christopher J. (University of Oxford. Department of Pharmacology)

Date:	2012
Abstract:	Background: In rat middle cerebral and mesenteric arteries the KCa2. 3 component of endothelium-dependent hyperpolarization (EDH) is lost following stimulation of thromboxane (TP) receptors, an effect that may contribute to the endothelial dysfunction associated with cardiovascular disease. In cerebral arteries, KCa2. 3 loss is associated with NO synthase inhibition, but is restored if TP receptors are blocked. The Rho/Rho kinase pathway is central for TP signalling and statins indirectly inhibit this pathway. The possibility that Rho kinase inhibition and statins sustain KCa2. 3 hyperpolarization was investigated in rat middle cerebral arteries (MCA). Methods: MCAs were mounted in a wire myograph. The PAR2 agonist, SLIGRL was used to stimulate EDH responses, assessed by simultaneous measurement of smooth muscle membrane potential and tension. TP expression was assessed with rt-PCR and immunofluorescence. Results: Immunofluorescence detected TP in the endothelial cell layer of MCA. Vasoconstriction to the TP agonist, U46619 was reduced by Rho kinase inhibition. TP receptor stimulation lead to loss of KCa2. 3 mediated hyperpolarization, an effect that was reversed by Rho kinase inhibitors or simvastatin. KCa2. 3 activity was lost in L-NAME-treated arteries, but was restored by Rho kinase inhibition or statin treatment. The restorative effect of simvastatin was blocked after incubation with geranylgeranyl-pyrophosphate to circumvent loss of isoprenylation. Conclusions: Rho/Rho kinase signalling following TP stimulation and L-NAME regulates endothelial cell KCa2. 3 function. The ability of statins to prevent isoprenylation and perhaps inhibit of Rho restores/protects the input of KCa2. 3 to EDH in the MCA, and represents a beneficial pleiotropic effect of statin treatment.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; Versió publicada
Subject:	Artèries cerebrals ; Cerebral arteries ; Rho kinase
Published in:	PloS one, Vol. 7, Issue 10 (October 2012) , p. e46735, ISSN 1932-6203

DOI: 10.1371/journal.pone.0046735
PMID: 23056429

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