Statins and Selective Inhibition of Rho Kinase Protect Small Conductance Calcium-Activated Potassium Channel Function (KCa2.3) in Cerebral Arteries

Abstract

BackgroundIn 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).MethodsMCAs 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.ResultsImmunofluorescence 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.ConclusionsRho/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.

Acute Simvastatin Inhibits KATP Channels of Porcine Coronary Artery Myocytes

“…Previous studies have demonstrated that statins can modify the activities of different ion channels in blood vessels including L-type Ca 2+ channel and BK Ca channel [3], [9], [10], [11]. In addition to Ca 2+ channels and BK Ca channels, ATP-sensitive K + (K ATP ) channels are abundant in vascular tissues and K ATP channels are also important in regulating the vascular tone [12].…”

Effect of Simvastatin on the Prognosis and the Changes of the Clinical Status in Patients With Acute Ischemic Stroke. The Results of the 12 Month Randomized, Open Comparative Study

“…Статины продемонстри-ровали также положительное влияние на артерии го-ловного мозга за счет защиты и восстановления К + Са 2+ -насоса после эндотелий-зависимой гиперполяризации. Последняя вызывается стимуляцией тромбоксановых рецепторов, что часто наблюдается при эндотелиаль-ной дисфункции [35]. Таким образом, решающее значение в снижении смертности и инвалидизации после перенесенного инсульта принадлежит первичной и вторичной про-филактике.…”

Peroxynitrite formed during a transient episode of brain ischaemia increases endothelium‐derived hyperpolarization‐type dilations in thromboxane/prostaglandin receptor‐stimulated rat cerebral arteries

“…Middle cerebral artery function was studied in vessels mounted on an isometric wire myograph (model 410 A; Danish Myo Technology, Aarhus, Denmark) following the protocol described (McNeish et al 2012, Gauthier et al 2014. Constricted tone was induced with the stable TxA 2 mimetic 9,11-dideoxy-9a, 11amethano-epoxy prostaglandin F2a (U46619; 30-100 nmol L À1 ; EMD Millipore, Billerica, MA, USA) or endothelin-1 (1-10 nmol L À1 ; Enzo Life Sciences, Farmingdale, NY, USA).…”

“…Concentrations of most inhibitors were chosen based on previous studies (McNeish & Garland 2007, McNeish et al 2012, Gauthier et al 2014. Concentrations of most inhibitors were chosen based on previous studies (McNeish & Garland 2007, McNeish et al 2012, Gauthier et al 2014.…”

“…We submitted HMVEC to H/R, a cell culture model of I/R (Koo et al 2001). Rho activation is an important regulator of the activity of some ion channels (Ghisdal et al 2003, Luykenaar et al 2009), which may play a role on TP-dependent inhibition of SK Ca channel function in the endothelium (McNeish et al 2012, Gauthier et al 2014. 2a and Figure S2, expression of hypoxia-inducible factor 1a (HIF-1a) was higher in cells that have undergone H/R than in those kept in normoxia.…”