Statins and Selective Inhibition of Rho Kinase Protect Small Conductance Calcium-Activated Potassium Channel Function (K 2.3) in Cerebral Arteries

A.J. McNeish, F. Jimenez-Altayo, G.S. Cottrell, C.J. Garland

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

Background: In rat middle cerebral and mesenteric arteries the K 2.3 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, K 2.3 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 K 2.3 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 K 2.3 mediated hyperpolarization, an effect that was reversed by Rho kinase inhibitors or simvastatin. K 2.3 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 K 2.3 function. The ability of statins to prevent isoprenylation and perhaps inhibit of Rho restores/protects the input of K 2.3 to EDH in the MCA, and represents a beneficial pleiotropic effect of statin treatment.
Original languageEnglish
Article number46735
JournalPLoS ONE
Volume7
Issue number10
DOIs
Publication statusPublished - 8 Oct 2012

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