Impairment of endothelial SK(Ca) channels and of downstream hyperpolarizing pathways in mesenteric arteries from spontaneously hypertensive rats.
OBJECTIVE
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.


METHODS
Changes in vascular K(+) channel responses and expression were determined by a combination of membrane potential recordings and Western blotting.


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
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.
Faculty of Life Sciences, Core Technology Facility, The University of Manchester, Manchester, UK.
A H
AH
Weston
E L
EL
Porter
E
E
Harno
G
G
Edwards
D000818:Animals; D015153:Blotting, Western; D051242:Caveolin 1 / Q000737:chemistry / Q000378:metabolism; D019281:Dimerization; D015536:Down-Regulation / Q000502:physiology*; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D049990:Membrane Transport Modulators / Q000494:pharmacology; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism
C495537:Cav1 protein, rat; D051242:Caveolin 1; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D049990:Membrane Transport Modulators; D024661:Potassium Channels, Inwardly Rectifying; D021122:Protein Subunits; D051640:Small-Conductance Calcium-Activated Potassium Channels; D000254:Sodium-Potassium-Exchanging ATPase