Impairment of endothelial SKCa channels and of downstream hyperpolarizing pathways in mesenteric arteries from spontaneously hypertensive rats

Background and purpose: Previous studies have shown that endothelium-dependent hyperpolarization of myocytes is reduced in resistance arteries from spontaneously hypertensive rats (SHRs). The aim of the present study was to determine whether this reflects down-regulation of endothelial K+ channels or their associated pathways. Experimental approach: Changes in vascular K+ channel responses and expression were determined by a combination of membrane potential recordings and Western blotting. Key results: Endothelium-dependent myocyte hyperpolarizations induced by acetylcholine, 6,7-dichloro-1H-indole-2,3-dione 3-oxime (NS309) (opens small- and intermediate-conductance calcium-sensitive K+ channels, SKCa and IKCa, respectively) or cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (SKCa opener) were reduced in mesenteric arteries from SHRs. After blocking SKCa channels with apamin, hyperpolarizations to acetylcholine and NS309 in SHR arteries were similar to those of controls. Hyperpolarization to 5 mM KCl was reduced in SHR arteries due to loss of the Ba2+-sensitive, inward-rectifier channel (K-IR) component; the contribution of ouabain-sensitive, Na+/K+-ATPases was unaffected. Protein expression of both SKCa and K-IR channels was reduced in SHR arteries; the caveolin-1 monomer/dimer ratio was increased. Conclusions and implications: In SHRs, the distinct pathway that generates endothelium-dependent hyperpolarization in vascular myocyte by activation of IKCa channels and Na+/K+-ATPases remains intact. The second pathway, initiated by endothelial SKCa channel activation and amplified by K-IR opening on both endothelial cells and myocytes is compromised in SHRs due to down-regulation of both SKCa and K-IR and to changes in caveolin-1 oligomers. These impairments in the SKCa-K-IR pathway shed new light on vascular control mechanisms and on the underlying vascular changes in hypertension. This article is commented on by Garland, pp. 833-835 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.00692.x.