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.
Highlights
In rat middle cerebral arteries (MCA) endothelium-dependent hyperpolarization (EDH) responses are observed in the presence of NO synthase (NOS) inhibitors, and can be abolished by inhibition of endothelial cell KCa3.1 channels, irrespective of the agonist used to stimulate EDH [1,2]
The aims of the current study were 1) to investigate if disrupting the Rho kinase pathway could protect KCa2.3 functionality following thromboxane receptors (TP) stimulation; 2) to establish if inhibition of Rho kinase signalling might restore the KCa2.3 component of the EDH response suppressed by the presence of NOS inhibitors, and 3) to assess if statins had a similar effects to inhibitors of Rho kinase
Thromboxane Receptors are Expressed in Endothelial Cells of Middle Cerebral Arteries
Summary
In rat middle cerebral arteries (MCA) endothelium-dependent hyperpolarization (EDH) responses (commonly called endothelium derived hyperpolarizing factor, EDHF, response) are observed in the presence of NO synthase (NOS) inhibitors, and can be abolished by inhibition of endothelial cell KCa3.1 (intermediate conductance, IKCa) channels, irrespective of the agonist used to stimulate EDH [1,2]. Following inhibition of NO synthase, input from KCa2.3 to EDH responses is restored in the middle cerebral artery by exposure to antagonists of thromboxane receptors (TP) [6]. 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. KCa2.3 loss is associated with NO synthase inhibition, but is restored if TP receptors are blocked. The possibility that Rho kinase inhibition and statins sustain KCa2.3 hyperpolarization was investigated in rat middle cerebral arteries (MCA)
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