Nitroxyl donors retain their depressor effects in hypertension

Abstract

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...

Haemodynamic effects of the nitroxyl donor cimlanod (BMS‐986231) in chronic heart failure: a randomized trial

“…13 Secondly, while we administered infusions over 5 h to achieve steady-state drug bioavailability, this period is shorter than that often used for NTG in clinical practice. NTG-mediated vasomotor effects are associated with tachyphylaxis 19 and, although there are data to suggest that this may not be an issue with HNO donors, 20,21 infusions in the current study were not of sufficient duration to address this question. The StandUP-AHF trial randomized patients to 48 h IV infusion of cimlanod or placebo 13 and should provide some insight to this question, albeit without direct comparison to NTG.…”

Nitroxyl (HNO) targets phospholamban cysteines 41 and 46 to enhance cardiac function

“…Finally, high in vitro concentrations of HNO that may mimic excessive in vivo HNO production and signaling are expected to result in sulfinamide formation on cysteine residues, which is not readily reversible under physiologically relevant conditions (Keceli and Toscano, 2012; Keceli et al, 2013; Fukuto, 2019). Conversely, HNO-positive inotropic and lusitropic actions in vivo have been observed with low (nM range) concentrations (Paolocci et al, 2003; Tocchetti et al, 2007) and reported to be reversible (Paolocci et al, 2003; Tocchetti et al, 2007; Irvine et al, 2013; Kemp-Harper et al, 2016). Given the few viable methodologies able to detect HNO in biological systems, it is difficult to determine HNO concentrations accurately in vivo (Kemp-Harper, 2011; Doctorovich et al, 2014; Rivera-Fuentes and Lippard, 2015).…”

Rationale and design for the development of a novel nitroxyl donor in patients with acute heart failure

“…HNO also mediates peripheral vasodilatation in a manner dependent on soluble guanylate cyclase in the endothelium. Importantly, unlike the activity of NO, tachyphylaxis does not appear to impact the effects of HNO in the peripheral vasculature . The effects of HNO do not appear to be mediated by adrenergic receptors, which may be important given the nearly ubiquitous use of beta‐blockers in HF .…”

“…Importantly, unlike the activity of NO, tachyphylaxis does not appear to impact the effects of HNO in the peripheral vasculature. 16 The effects of HNO do not appear to be mediated by adrenergic receptors, which may be important given the nearly ubiquitous use of beta-blockers in HF. 17 A schematic of the putative mechanisms of action of HNO on the heart is shown in Figure 1.…”