A role for nitroxyl (HNO) as an endothelium-derived relaxing and hyperpolarizing factor in resistance arteries

Karen L. Andrews, Jennifer C. Irvine, Marianne Tare, Jacqueline Apostolopoulos, Joanne L. Favaloro, Christopher Triggle, Barbara K. Kemp-Harper

Research output: Contribution to journalArticle

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Abstract

Background and purpose: Nitroxyl (HNO) is emerging as an important regulator of vascular tone as it is potentially produced endogenously and dilates conduit and resistance arteries. This study investigates the contribution of endogenous HNO to endothelium-dependent relaxation and hyperpolarization in resistance arteries. Experimental approach: Rat and mouse mesenteric arteries were mounted in small vessel myographs for isometric force and smooth muscle membrane potential recording. Key results: Vasorelaxation to the HNO donor, Angeli's salt, was attenuated in both species by the soluble guanylate cyclase inhibitor (ODQ, 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1 -one), the voltage-dependent K - channel inhibitor, 4-aminopyridine (4-AP) and the HNO scavenger, L-cysteine. In mouse mesenteric arteries, nitric oxide (NO) synthase inhibition (with L-NAME, N ω-Nitro-L- arginine methyl ester) markedly attenuated acetylcholine (ACh)-mediated relaxation. Scavenging the uncharged form of NO (NO ̇) with hydroxocobalamin (HXC) or HNO with L-cysteine, or 4-AP decreased the sensitivity to ACh, and a combination of HXC and L-cysteine reduced ACh-mediated relaxation, as did L-NAME alone. ACh-induced hyperpolarizations were significantly attenuated by 4-AP alone and in combination with L-NAME. In rat mesenteric arteries, blocking the effects of endothelium-derived hyperpolarizing factor (EDHF) (charybdotoxin and apamin) decreased ACh-mediated relaxation 10-fold and unmasked a NO-dependent component, mediated equally by HNO and NO ̇, as HXC and L-cysteine in combination now abolished vasorelaxation to ACh. Furthermore, ACh-evoked hyperpolarizations, resistant to EDHF inhibition, were virtually abolished by 4-AP. Conclusions and Implications: The factors contributing to vasorelaxation in mouse and rat mesenteric arteries are NO ̇ = HNO > EDHF and EDHF > HNO = NO ̇ respectively. This study identified HNO as an endothelium-derived relaxing and hyperpolarizing factor in resistance vessels.

Original languageEnglish
Pages (from-to)540-550
Number of pages11
JournalBritish Journal of Pharmacology
Volume157
Issue number4
DOIs
Publication statusPublished - Jun 2009
Externally publishedYes

Fingerprint

Endothelium-Dependent Relaxing Factors
Acetylcholine
Arteries
4-Aminopyridine
Nitric Oxide
Mesenteric Arteries
Hydroxocobalamin
Endothelium
Cysteine
NG-Nitroarginine Methyl Ester
Vasodilation
Charybdotoxin
Apamin
Quinoxalines
nitroxyl
Nitric Oxide Synthase
Membrane Potentials
Smooth Muscle
Blood Vessels

Keywords

  • Endothelial factors
  • Endothelium-derived relaxing factor
  • Nitric oxide
  • Nitroxyl
  • Redox signalling
  • Vasorelaxation

ASJC Scopus subject areas

  • Pharmacology

Cite this

A role for nitroxyl (HNO) as an endothelium-derived relaxing and hyperpolarizing factor in resistance arteries. / Andrews, Karen L.; Irvine, Jennifer C.; Tare, Marianne; Apostolopoulos, Jacqueline; Favaloro, Joanne L.; Triggle, Christopher; Kemp-Harper, Barbara K.

In: British Journal of Pharmacology, Vol. 157, No. 4, 06.2009, p. 540-550.

Research output: Contribution to journalArticle

Andrews, Karen L. ; Irvine, Jennifer C. ; Tare, Marianne ; Apostolopoulos, Jacqueline ; Favaloro, Joanne L. ; Triggle, Christopher ; Kemp-Harper, Barbara K. / A role for nitroxyl (HNO) as an endothelium-derived relaxing and hyperpolarizing factor in resistance arteries. In: British Journal of Pharmacology. 2009 ; Vol. 157, No. 4. pp. 540-550.
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AU - Irvine, Jennifer C.

AU - Tare, Marianne

AU - Apostolopoulos, Jacqueline

AU - Favaloro, Joanne L.

AU - Triggle, Christopher

AU - Kemp-Harper, Barbara K.

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N2 - Background and purpose: Nitroxyl (HNO) is emerging as an important regulator of vascular tone as it is potentially produced endogenously and dilates conduit and resistance arteries. This study investigates the contribution of endogenous HNO to endothelium-dependent relaxation and hyperpolarization in resistance arteries. Experimental approach: Rat and mouse mesenteric arteries were mounted in small vessel myographs for isometric force and smooth muscle membrane potential recording. Key results: Vasorelaxation to the HNO donor, Angeli's salt, was attenuated in both species by the soluble guanylate cyclase inhibitor (ODQ, 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1 -one), the voltage-dependent K - channel inhibitor, 4-aminopyridine (4-AP) and the HNO scavenger, L-cysteine. In mouse mesenteric arteries, nitric oxide (NO) synthase inhibition (with L-NAME, N ω-Nitro-L- arginine methyl ester) markedly attenuated acetylcholine (ACh)-mediated relaxation. Scavenging the uncharged form of NO (NO ̇) with hydroxocobalamin (HXC) or HNO with L-cysteine, or 4-AP decreased the sensitivity to ACh, and a combination of HXC and L-cysteine reduced ACh-mediated relaxation, as did L-NAME alone. ACh-induced hyperpolarizations were significantly attenuated by 4-AP alone and in combination with L-NAME. In rat mesenteric arteries, blocking the effects of endothelium-derived hyperpolarizing factor (EDHF) (charybdotoxin and apamin) decreased ACh-mediated relaxation 10-fold and unmasked a NO-dependent component, mediated equally by HNO and NO ̇, as HXC and L-cysteine in combination now abolished vasorelaxation to ACh. Furthermore, ACh-evoked hyperpolarizations, resistant to EDHF inhibition, were virtually abolished by 4-AP. Conclusions and Implications: The factors contributing to vasorelaxation in mouse and rat mesenteric arteries are NO ̇ = HNO > EDHF and EDHF > HNO = NO ̇ respectively. This study identified HNO as an endothelium-derived relaxing and hyperpolarizing factor in resistance vessels.

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KW - Endothelial factors

KW - Endothelium-derived relaxing factor

KW - Nitric oxide

KW - Nitroxyl

KW - Redox signalling

KW - Vasorelaxation

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