Nitroxyl (HNO) for Treatment of Acute Heart Failure

Abstract

The loss of contractile function is a hallmark of heart failure. Although increasing intracellular Ca(2+) is a possible strategy for improving contraction, current inotropic agents that achieve this by raising intracellular cAMP levels, such as β-agonists and phosphodiesterase inhibitors, are generally deleterious when administered as long-term therapy due to arrhythmia and myocardial damage. Nitroxyl donors have been shown to improve cardiac function in normal and failing dogs, and in isolated cardiomyocytes they increase fractional shortening and Ca(2+) transients, independently from cAMP/PKA or cGMP/PKG signaling. Instead, nitroxyl targets cysteines in the EC-coupling machinery and myofilament proteins, reversibly modifying them to enhance Ca(2+) handling and myofilament Ca(2+) sensitivity. Phase I-IIa trials with CXL-1020, a novel pure HNO donor, reported declines in left and right heart filling pressures and systemic vascular resistance, and increased cardiac output and stroke volume index. These findings support the concept of nitroxyl donors as attractive agents for the treatment of acute decompensated heart failure.

A change of heart: oxidative stress in governing muscle function?

“…In contrast to the many beneficial effects on myocardial contractile function shown by nitroxyl (Gao et al 2012;Sabbah et al 2013;Arcaro et al 2014). Increased peroxynitrite production also induces MLC1 nitration/nitrosylation, leading to its increased degradation by the proteolytic enzyme MMP-2.…”

The chemical biology of HNO signaling

“…Indeed, HNO-mediated treatment for heart failure has received significant and recent attention [for example, 53,54,55]. In the scenario of heart failure, HNO is capable of enhancing Ca 2+ cycling (i.e.…”

“…In the scenario of heart failure, HNO is capable of enhancing Ca 2+ cycling (i.e. simultaneous increases in Ca 2+ release and reuptake by the sarcoplasmic reticulum (SR)), increasing the Ca 2+ sensitivity of myofilaments, eliciting a combined arterial and venous dilation and all without an increase in heart rate [53]. Taken altogether, these effects represent a near ideal therapeutic profile for the treatment of heart failure.…”

To Transfer or Not to Transfer? Development of a Dinitrosyl Iron Complex as a Nitroxyl Donor for the Nitroxylation of an FeIII–Porphyrin Center

“…[1][2][3] Moreover,apositive myocardial inotropice ffect of nitroxyl, during ac ongestiveh eart failure condition in particular, stimulated the study of am echanism for the endogenousg eneration of nitroxyl and the devel-opmento fa ne xogenous nitroxyl donor as an ovel approach for the acute treatment of heartf ailure. [4][5][6][7] Angeli's salt (Na 2 N 2 O 3 )a nd Piloty's acid (PhSO 2 NHOH) were predominantly exploited as nitroxyl-releasingr eagents at neutral and basic pH, respectively,t oe xplore the vascular and myocardial pharmacology of HNO/NO À .R apid decomposition of Angeli's salt (k = 610 À4 s À1 at 25 8Ca nd k = 4-5 10 À3 s À1 at 37 8C), rapid dimerization of HNO to affordN 2 Oa nd H 2 O( k = 810 6 m À1 s À1 ), and releaseo fN Or ather than nitroxyl from Piloty's acid under neutral aerobic conditions, however,l imit the clinicalp otential of these compounds. [7] As ac onsequence, al ong-lasting HNO/ NO À donor derived from steady nitroxyl-releasing compounds with an ON/OFF switch or from stable compounds with dedicated nitroxyl-transfer reactivityt owardt he Fe III centeri nh eme proteins is am uch-neededt arget for pharmaceutical applications.The intrinsic redox propensity of transitionm etals in metalnitrosyl complexes modulates the oxidation state of NO and allowst he potentialu se of MÀNO complexes in nitroxyl chemistry.…”