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
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, SK(Ca) and IK(Ca), respectively) or cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (SK(Ca) opener) were reduced in mesenteric arteries from SHRs. After blocking SK(Ca) 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 Ba(2+)-sensitive, inward-rectifier channel (K(IR)) component; the contribution of ouabain-sensitive, Na(+)/K(+)-ATPases was unaffected. Protein expression of both SK(Ca) 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 IK(Ca) channels and Na(+)/K(+)-ATPases remains intact. The second pathway, initiated by endothelial SK(Ca) channel activation and amplified by K(IR) opening on both endothelial cells and myocytes is compromised in SHRs due to down-regulation of both SK(Ca) and K(IR) and to changes in caveolin-1 oligomers. These impairments in the SK(Ca)-K(IR) pathway shed new light on vascular control mechanisms and on the underlying vascular changes in hypertension.