Nitroxyl donors retain their depressor effects in hypertension

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Nitroxyl (HNO), the redox congener of nitric oxide, has numerous vasoprotective actions including an ability to induce vasodilation and inhibit platelet aggregation. Given HNO is resistant to scavenging by superoxide and does not develop tolerance, we hypothesised that HNO would retain its in vivo vasodilatory action in the setting of hypertension. The in vitro and in vivo vasodilator properties of the HNO donors Angeli s salt (AS) and isopropylamine/NONOate (IPA/NO) were compared with the NO donor diethylamine/NONOate (DEA/NO) in spontaneously hypertensive rats (SHR) and normotensive [Wistar-Kyoto (WKY) rats]. AS (10, 50, and 200 mug/kg), IPA/NO (10, 50, and 200 mug/kg), and DEA/NO (1, 5, and 20 mug/kg) caused dose-dependent depressor responses in conscious WKY rats of similar magnitude. Depressor responses to AS and IPA/NO were significantly attenuated (P <0.01) after infusion of the HNO scavenger N-acetyl-l-cysteine (NAC), confirming that AS and IPA/NO function as HNO donors in vivo. In contrast, responses to DEA/NO were unchanged following NAC infusion. Depressor responses to AS and IPA/NO in conscious SHR retained their sensitivity to the inhibitory effects of NAC (P <0.01), yet those to DEA/NO in SHR were significantly (P <0.05) enhanced following NAC infusion. Importantly, depressor responses to AS, IPA/NO, and DEA/NO were preserved in hypertension and vasorelaxation to AS and DEA/NO, in isolated aorta, unchanged in SHR as compared with WKY rats. This study has shown for the first time that HNO donors exert antihypertensive effects in vivo and may, therefore, offer a therapeutic alternative to traditional nitrovasodilators in the treatment of cardiovascular disorders such as hypertension.
Original languageEnglish
Pages (from-to)939 - 945
Number of pages7
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume305
Issue number6
DOIs
Publication statusPublished - 2013

Cite this

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title = "Nitroxyl donors retain their depressor effects in hypertension",
abstract = "Nitroxyl (HNO), the redox congener of nitric oxide, has numerous vasoprotective actions including an ability to induce vasodilation and inhibit platelet aggregation. Given HNO is resistant to scavenging by superoxide and does not develop tolerance, we hypothesised that HNO would retain its in vivo vasodilatory action in the setting of hypertension. The in vitro and in vivo vasodilator properties of the HNO donors Angeli s salt (AS) and isopropylamine/NONOate (IPA/NO) were compared with the NO donor diethylamine/NONOate (DEA/NO) in spontaneously hypertensive rats (SHR) and normotensive [Wistar-Kyoto (WKY) rats]. AS (10, 50, and 200 mug/kg), IPA/NO (10, 50, and 200 mug/kg), and DEA/NO (1, 5, and 20 mug/kg) caused dose-dependent depressor responses in conscious WKY rats of similar magnitude. Depressor responses to AS and IPA/NO were significantly attenuated (P <0.01) after infusion of the HNO scavenger N-acetyl-l-cysteine (NAC), confirming that AS and IPA/NO function as HNO donors in vivo. In contrast, responses to DEA/NO were unchanged following NAC infusion. Depressor responses to AS and IPA/NO in conscious SHR retained their sensitivity to the inhibitory effects of NAC (P <0.01), yet those to DEA/NO in SHR were significantly (P <0.05) enhanced following NAC infusion. Importantly, depressor responses to AS, IPA/NO, and DEA/NO were preserved in hypertension and vasorelaxation to AS and DEA/NO, in isolated aorta, unchanged in SHR as compared with WKY rats. This study has shown for the first time that HNO donors exert antihypertensive effects in vivo and may, therefore, offer a therapeutic alternative to traditional nitrovasodilators in the treatment of cardiovascular disorders such as hypertension.",
author = "Irvine, {Jennifer Claire} and Ravi, {Ravina Maru} and Harper, {Barbara Kathryn} and Widdop, {Robert Edward}",
year = "2013",
doi = "10.1152/ajpheart.00630.2012",
language = "English",
volume = "305",
pages = "939 -- 945",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
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Nitroxyl donors retain their depressor effects in hypertension. / Irvine, Jennifer Claire; Ravi, Ravina Maru; Harper, Barbara Kathryn; Widdop, Robert Edward.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 305, No. 6, 2013, p. 939 - 945.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Nitroxyl donors retain their depressor effects in hypertension

AU - Irvine, Jennifer Claire

AU - Ravi, Ravina Maru

AU - Harper, Barbara Kathryn

AU - Widdop, Robert Edward

PY - 2013

Y1 - 2013

N2 - Nitroxyl (HNO), the redox congener of nitric oxide, has numerous vasoprotective actions including an ability to induce vasodilation and inhibit platelet aggregation. Given HNO is resistant to scavenging by superoxide and does not develop tolerance, we hypothesised that HNO would retain its in vivo vasodilatory action in the setting of hypertension. The in vitro and in vivo vasodilator properties of the HNO donors Angeli s salt (AS) and isopropylamine/NONOate (IPA/NO) were compared with the NO donor diethylamine/NONOate (DEA/NO) in spontaneously hypertensive rats (SHR) and normotensive [Wistar-Kyoto (WKY) rats]. AS (10, 50, and 200 mug/kg), IPA/NO (10, 50, and 200 mug/kg), and DEA/NO (1, 5, and 20 mug/kg) caused dose-dependent depressor responses in conscious WKY rats of similar magnitude. Depressor responses to AS and IPA/NO were significantly attenuated (P <0.01) after infusion of the HNO scavenger N-acetyl-l-cysteine (NAC), confirming that AS and IPA/NO function as HNO donors in vivo. In contrast, responses to DEA/NO were unchanged following NAC infusion. Depressor responses to AS and IPA/NO in conscious SHR retained their sensitivity to the inhibitory effects of NAC (P <0.01), yet those to DEA/NO in SHR were significantly (P <0.05) enhanced following NAC infusion. Importantly, depressor responses to AS, IPA/NO, and DEA/NO were preserved in hypertension and vasorelaxation to AS and DEA/NO, in isolated aorta, unchanged in SHR as compared with WKY rats. This study has shown for the first time that HNO donors exert antihypertensive effects in vivo and may, therefore, offer a therapeutic alternative to traditional nitrovasodilators in the treatment of cardiovascular disorders such as hypertension.

AB - Nitroxyl (HNO), the redox congener of nitric oxide, has numerous vasoprotective actions including an ability to induce vasodilation and inhibit platelet aggregation. Given HNO is resistant to scavenging by superoxide and does not develop tolerance, we hypothesised that HNO would retain its in vivo vasodilatory action in the setting of hypertension. The in vitro and in vivo vasodilator properties of the HNO donors Angeli s salt (AS) and isopropylamine/NONOate (IPA/NO) were compared with the NO donor diethylamine/NONOate (DEA/NO) in spontaneously hypertensive rats (SHR) and normotensive [Wistar-Kyoto (WKY) rats]. AS (10, 50, and 200 mug/kg), IPA/NO (10, 50, and 200 mug/kg), and DEA/NO (1, 5, and 20 mug/kg) caused dose-dependent depressor responses in conscious WKY rats of similar magnitude. Depressor responses to AS and IPA/NO were significantly attenuated (P <0.01) after infusion of the HNO scavenger N-acetyl-l-cysteine (NAC), confirming that AS and IPA/NO function as HNO donors in vivo. In contrast, responses to DEA/NO were unchanged following NAC infusion. Depressor responses to AS and IPA/NO in conscious SHR retained their sensitivity to the inhibitory effects of NAC (P <0.01), yet those to DEA/NO in SHR were significantly (P <0.05) enhanced following NAC infusion. Importantly, depressor responses to AS, IPA/NO, and DEA/NO were preserved in hypertension and vasorelaxation to AS and DEA/NO, in isolated aorta, unchanged in SHR as compared with WKY rats. This study has shown for the first time that HNO donors exert antihypertensive effects in vivo and may, therefore, offer a therapeutic alternative to traditional nitrovasodilators in the treatment of cardiovascular disorders such as hypertension.

UR - http://ajpheart.physiology.org/content/ajpheart/305/6/H939.full.pdf

U2 - 10.1152/ajpheart.00630.2012

DO - 10.1152/ajpheart.00630.2012

M3 - Article

VL - 305

SP - 939

EP - 945

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 6

ER -