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

Figure 2

Effect of inhibition of Rho Kinase on TP induced constriction and EDH responses obtained in the presence of TP stimulation in the rat middle cerebral artery.

(A) Concentration response curve showing the vasoconstrictor response produced by the thromboxane A2 mimetic U46619 (1 nM-1 µM; n = 5) in rat middle cerebral arteries in the presence and absence of the selective Rho kinase inhibitor Y27632 (1 and 10 µM; n = 5). Inhibition of Rho kinase significantly and concentration dependently reduced the maximum constriction produced by U46619 and significantly shifted the concentration response curve to the right. (B) Histogram showing SLIGRL (20 µM) induced EDH evoked in the presence of U46619 (50–100 nM) in vessels able to synthesise NO. Also shown are EDH in the presence of KCa3.1 blockade (1 µM, TRAM-34), blockade of both KCa2.3 and 3.1 (100 nM apamin+TRAM-34) and blockade of KCa1.1, 2.3 and 3.1 (100 nM Iberiotoxin+apamin+TRAM-34). Block of KCa3.1 alone was sufficient to significantly reduce EDH; subsequent block of KCa2.3 had no further effect indicating this channel was not functional. Residual EDH was inhibited by further blockade of KCa1.1. (C) Histogram showing SLIGRL induced EDH in the presence of U46619 and the Rho Kinase inhibitor Y27632 in vessels able to synthesise NO. EDH was only significantly reduced following combined blockade of both KCa3.1 and 2.3, indicating that the KCa2.3 channel was now functional. *P<0.05 indicates a significant difference from control (U46619 alone) using one-way ANOVA with Tukey’s post-test, n = 5–6) φP<0.05 indicates a significant difference from Y27632 as determined by one-way ANOVA with Tukey’s post-test, n = 5–6.

Figure 2

doi: https://doi.org/10.1371/journal.pone.0046735.g002