Aorta from angiotensin II hypertensive mice exhibit preserved nitroxyl anion mediated relaxation responses

Wynne, Brandi M.; Labazi, Hicham; Tostes, Rita C.; Webb, R. Clinton

doi:10.1016/j.phrs.2011.07.002

Cited by 23 publications

(18 citation statements)

References 43 publications

(64 reference statements)

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“…The latter shift in membrane potential was, at least partly, induced by reduced basal NO bio-availability in the vessel wall. Endothelial dysfunction is a common feature in AHT [23], leading to impaired NO synthesis and/or bioavailability [3,13,35,36,42]. We did, however, not find evidence for attenuated NO release evoked by acetylcholine or sensitivity of the VSMCs for exogenous NO.…”

Section: Discussioncontrasting

confidence: 76%

Effect of angiotensin II-induced arterial hypertension on the voltage-dependent contractions of mouse arteries

Fransen

Hove

Leloup

et al. 2015

Pflugers Arch - Eur J Physiol

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Arterial hypertension (AHT) affects the voltage dependency of L-type Ca(2+) channels in cardiomyocytes. We analyzed the effect of angiotensin II (AngII)-induced AHT on L-type Ca(2+) channel-mediated isometric contractions in conduit arteries. AHT was induced in C57Bl6 mice with AngII-filled osmotic mini-pumps (4 weeks). Normotensive mice treated with saline-filled osmotic mini-pumps were used for comparison. Voltage-dependent contractions mediated by L-type Ca(2+) channels were studied in vaso-reactive studies in vitro in isolated aortic and femoral arteries by using extracellular K(+) concentration-response (KDR) experiments. In aortic segments, AngII-induced AHT significantly sensitized isometric contractions induced by elevated extracellular K(+) and depolarization. This sensitization was partly prevented by normalizing blood pressure with hydralazine, suggesting that it was caused by AHT rather than by direct AngII effects on aortic smooth muscle cells. The EC50 for extracellular K(+) obtained in vitro correlated significantly with the rise in arterial blood pressure induced by AngII in vivo. The AHT-induced sensitization persisted when aortic segments were exposed to levcromakalim or to inhibitors of basal nitric oxide release. Consistent with these observations, AngII-treatment also sensitized the vaso-relaxing effects of the L-type Ca(2+) channel blocker diltiazem during K(+)-induced contractions. Unlike aorta, AngII-treatment desensitized the isometric contractions to depolarization in femoral arteries pointing to vascular bed specific responses of arteries to hypertension. AHT affects the voltage-dependent L-type Ca(2+) channel-mediated contraction of conduit arteries. This effect may contribute to the decreased vascular compliance in AHT and explain the efficacy of Ca(2+) channel blockers to reduce vascular stiffness and central blood pressure in AHT.

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Section: Discussioncontrasting

confidence: 76%

Effect of angiotensin II-induced arterial hypertension on the voltage-dependent contractions of mouse arteries

Fransen

Hove

Leloup

et al. 2015

Pflugers Arch - Eur J Physiol

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“…HNO activates sGC to induce vasorelaxation (Bullen et al, 2011). In a model of vessel injury (angiotensin II-treated mice), HNO-mediated relaxation has been shown to be inhibited by 4-AP, whereas in sham mice, HNO donor-induced relaxation is insensitive to 4-AP (Wynne et al, 2012). As L-NAME-resistant EDR is partially inhibited by ODQ in eET-1/Apoe 2/2 mice, it will be necessary in the future to investigate the role of HNO in 4-AP-sensitive EDR in these mice.…”

Section: Discussionmentioning

confidence: 99%

Preservation of Endothelium-Dependent Relaxation in Atherosclerotic Mice with Endothelium-Restricted Endothelin-1 Overexpression

Mian

Idris-Khodja

et al. 2013

J Pharmacol Exp Ther

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In human atherosclerosis, which is associated with elevated plasma and coronary endothelin (ET)-1 levels, ET A receptor antagonists improve coronary endothelial function. Mice overexpressing ET-1 specifically in the endothelium (eET-1) crossed with atherosclerosis-prone apolipoprotein E knockout mice (Apoe 2/2 ) exhibit exaggerated high-fat diet (HFD)-induced atherosclerosis. Since endothelial dysfunction often precedes atherosclerosis development, we hypothesized that mice overexpressing endothelial ET-1 on a genetic background deficient in apolipoprotein E (eET-1/Apoe 2/2 ) would have severe endothelial dysfunction. To test this hypothesis, we investigated endothelium-dependent relaxation (EDR) to acetylcholine in eET-1/Apoe 2/2 mice. EDR in mesenteric resistance arteries from 8-and 16-week-old mice fed a normal diet or HFD was improved in eET-1/Apoe 2/2 compared with Apoe 2/2 mice. Nitric oxide synthase (NOS) inhibition abolished EDR in Apoe 2/2 . EDR in eET-1/Apoe 2/2 mice was resistant to NOS inhibition irrespective of age or diet. Inhibition of cyclooxygenase, the cytochrome P450 pathway, and endothelium-dependent hyperpolarization (EDH) resulted in little or no inhibition of EDR in eET-1/Apoe 2/2 compared with wild-type (WT) mice. In eET-1/Apoe 2/2 mice, blocking of EDH or soluble guanylate cyclase (sGC), in addition to NOS inhibition, decreased EDR by 36 and 30%, respectively. The activation of 4-aminopyridine-sensitive voltage-dependent potassium channels (K v ) during EDR was increased in eET-1/Apoe 2/2 compared with WT mice. We conclude that increasing eET-1 in mice that develop atherosclerosis results in decreased mutual dependence of endothelial signaling pathways responsible for EDR, and that NOS-independent activation of sGC and increased activation of K v are responsible for enhanced EDR in this model of atherosclerosis associated with elevated endothelial and circulating ET-1.

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“…The retained activity of the HNO donors in vivo correlates with our demonstration that the sensitivity of vasorelaxant responses to AS remains unchanged in the isolated aorta of SHR versus WKY rats. Similarly, a recent study by Wynne and colleagues (33) demonstrated preserved HNO-mediated relaxation in isolated aorta from ANG II-treated hypertensive mice. Based upon studies in isolated arteries, we assume that in WKY rats and SHR, the depressor effects of HNO are mediated predominantly via the activation of sGC and the subsequent increase in cGMP accumulation (11).…”

Section: Discussionmentioning

confidence: 66%

“…Although not studied directly, the vasodepressor actions of HNO (24) appear to be sustained in the setting of acute experimental heart failure (23). In addition, recent studies in isolated arteries from hypercholesterolemic (5) and ANG II-induced hypertensive mice (33) have shown that the vasorelaxant actions of HNO are preserved in these diseases, which are associated with elevated vascular O 2 ·Ϫ generation and reduced endogenous NO˙bioavailability. Whether such observations translate to the in vivo situation is unclear.…”

mentioning

confidence: 99%

Nitroxyl donors retain their depressor effects in hypertension

Irvine

Ravi

Kemp-Harper

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Irvine JC, Ravi RM, Kemp-Harper BK, Widdop RE. Nitroxyl donors retain their depressor effects in hypertension. Am J Physiol Heart Circ Physiol 305: H939 -H945, 2013. First published July 12, 2013 doi:10.1152/ajpheart.00630.2012, 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 NOḋ onor diethylamine/NONOate (DEA/NO) in spontaneously hypertensive rats (SHR) and normotensive [Wistar-Kyoto (WKY) rats]. AS (10, 50, and 200 g/kg), IPA/NO (10, 50, and 200 g/kg), and DEA/NO (1, 5, and 20 g/kg) caused dose-dependent depressor responses in conscious WKY rats of similar magnitude. Depressor responses to AS and IPA/NO were significantly attenuated (P Ͻ 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 Ͻ 0.01), yet those to DEA/NO in SHR were significantly (P Ͻ 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. nitric oxide; vasorelaxation; blood pressure; Angeli's salt; isopropylamine/NONOate THE VASOACTIVE PROPERTIES of nitric oxide (NO) donors such as glyceryl trinitrate (GTN) are well recognized, and nitrovasodilators have been used clinically to treat disorders such as angina, heart failure, and hypertension for more than 100 years (26). Yet NO can exist in different redox states, and although the physiological activity of NO has been traditionally attributed to its uncharged form (NO˙), it is becoming increasingly apparent that nitroxyl (HNO), the reduced and protonated congener of NO˙, exhibits distinct pharmacology from NO( 13) and may itself have significant therapeutic potential.The unique actions of HNO, as compared with its redox sibling, are readily apparent in the cardiovascular system. Thus, unlike NO˙, HNO increases myocardial contractility (via direct thiol interaction) (28,29) and is protective in the setting of acute experimental heart failure (23, 28). The positive cardiac inotropic actions of HNO are complemented by its ability to cause vasodilatation and unload the heart (19, 24, 28).Indeed HNO serv...

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Aorta from angiotensin II hypertensive mice exhibit preserved nitroxyl anion mediated relaxation responses

Cited by 23 publications

References 43 publications

Effect of angiotensin II-induced arterial hypertension on the voltage-dependent contractions of mouse arteries

Effect of angiotensin II-induced arterial hypertension on the voltage-dependent contractions of mouse arteries

Preservation of Endothelium-Dependent Relaxation in Atherosclerotic Mice with Endothelium-Restricted Endothelin-1 Overexpression

Nitroxyl donors retain their depressor effects in hypertension

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