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Endothelium-dependent relaxation is resistant to inhibition of nitric oxide synthesis, but sensitive to blockade of calcium-activated potassium channels in essential hypertension

Journal of Human Hypertension volume 21, pages 808–814 (2007)Cite this article

Abstract

In human essential hypertension (EH), endothelium-dependent relaxation can occur independent of nitric oxide (NO) and prostacyclin (PGI2). Recent in vivo data suggest that rapid compensatory upregulation of endothelial cytochrome P450 epoxygenase 2C9 occurs to preserve vasorelaxation under conditions of decreased NO bioavailability. As one of the vascular actions of CYP2C9 is to modulate small and intermediate conductance endothelial calcium-activated potassium channels (SKCa and IKCa), we examined whether endothelium-dependent relaxation is sensitive to inhibitors of these channels (apamin and charybdotoxin) in resistance-sized vessels from human with EH. Subcutaneous gluteal biopsies were performed on 12 humans with EH and 12 matched control subjects. Resistance arteries were dissected and relaxation responses to carbachol were assessed ex vivo using wire myography in the presence of: (i) NG-nitro-L-arginine (L-NOARG)/indomethacin; and (ii) apamin/charybdotoxin. Maximal carbachol relaxation was impaired in EH vs control subjects. No differences in responses were observed with the endothelium-independent agonist, S-nitroso-N-acetyl-penicillamine. Relaxation to carbachol was attenuated following incubation with L-NOARG/indomethacin in vessels from control subjects (P<0.01 analysis of variance (ANOVA)), but not in vessels from patients with EH. The reverse pattern was seen following apamin/charybdotoxin with carbachol relaxation attenuated only in EH vessels (P<0.001 ANOVA). Endothelium-dependent relaxation is resistant to endothelial nitric oxide synthase inhibition but sensitive to blockade of calcium-activated potassium channels in human EH. Studies with more specific inhibitors are required to determine whether this response is mediated by endothelial potassium channel subtypes (SKCa and IKCa).

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Abbreviations

BKCa:

large conductance calcium-activated potassium channels

COX:

cyclooxygenase

CYP2C9:

cytochrome P450 epoxygenase 2C9

EDHF:

endothelium-derived hyperpolarising factor

eNOS:

endothelial nitric oxide synthase

11,12 EET:

11,12 epoxyeicosatrienoic acids

IKCa:

intermediate conductance calcium-activated potassium channels

NE:

norepinephrine

NO:

nitric oxide

L-NOARG:

NG-nitro-L-arginine

PGI2:

prostacyclin

SKCa:

small conductance calcium-activated potassium channels

SNAP:

S-nitroso-N-acetyl-penicillamine

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Acknowledgements

Dr Sainsbury was supported at the time of this work by a fellowship from the Hypertension Trust of the British Hypertension Society.

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Authors and Affiliations

  1. BHF Glasgow Cardiovascular Research Centre, Glasgow, UK

    C A R Sainsbury, A J Brady & J M C Connell

  2. Division of Medicine and Therapeutics, Diabetes Section, University of Dundee, Dundee, UK

    J Coleman & J R Petrie

  3. Vascular Assessment Group, Glasgow Caledonian University, Glasgow, UK

    C Hillier

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  1. C A R Sainsbury
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  2. J Coleman
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Correspondence to C A R Sainsbury.

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Sainsbury, C., Coleman, J., Brady, A. et al. Endothelium-dependent relaxation is resistant to inhibition of nitric oxide synthesis, but sensitive to blockade of calcium-activated potassium channels in essential hypertension. J Hum Hypertens 21, 808–814 (2007). https://doi.org/10.1038/sj.jhh.1002226

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