Nitroxyl gets to the heart of the matter Martin Feelisch* Louisiana State University Health Sciences Center, Department of Molecular and Cellular Physiology, 1501 Kings Highway, Shreveport, LA 71130 eart failure (HF) is a progres- arterial dilatation, allowing to stimulate oxygen consumption and energetics. sively disabling and ultimately cardiac output without increasing oxy- Taken together, these results suggest fatal disease, which is charac- gen consumption. Although conceptually that nitroxyl donors represent a novel terized by a decline in the ideal compounds, currently used inodila- class of inodilator with potential for the Hheart’s ability to pump blood efficiently tors (compounds with positive inotropic treatment of HF. enough to meet the body’s metabolic and vasodilatior properties) tend to in- In most cases, not a single cause but demands. Despite substantial advances crease myocardial oxygen demand at a combination of systolic dysfunction in our understanding of the underlying higher doses, precipitating ischemia in (inability to contract and eject blood pathophysiology (1) and the therapeutic patients with coronary artery disease. normally) and͞or diastolic dysfunction management of acute and chronic HF Clearly, there is room for improvement (inability to relax and fill normally), en- (2) in recent years, the outlook of pa- in HF management, in particular with ergetic and vascular loading factors, tients with these conditions remains regard to quality of life and survival. contributes to the manifestation of HF. poor. Not only are mortality and mor- In this issue of PNAS, Paolocci et al. The type of cardiac dysfunction prevail- bidity discouragingly high, but also the (9) describe the beneficial cardiovascular ing and the accompanying hemodynamic patients’ quality of life remains impaired effects of nitroxyl (HNO)† in the failing situation of the patient have an obvious because of a substantial symptom bur- heart. A well characterized canine impact on the choice of pharmacological den. In the United States alone, HF is model of chronic heart failure was used treatment. The analysis of pressure- responsible for almost 1 million hospital in which cardiac dysfunction is produced volume loops obtained at different load- admissions (more than for all forms of by rapid ventricular pacing over a period ing conditions is among the best of all cancer combined) and Ͼ50,000 deaths of weeks. The authors used sophisti- current approaches to assess the con- each year, with estimated annual costs cated hemodynamic analyses suited to tractile behavior of the heart in vivo. exceeding $20 billion (3, 4). Despite im- discriminate direct cardiac effects from This approach, which also formed the proved patient information, beneficial indirect effects secondary to changes in basis of the present studies by Paolocci changes in lifestyle and better treatment preload and afterload to demonstrate et al. (9), has a long-standing history in options, HF remains to be a major pub- that nitroxyl increases myocardial con- experimental physiology, but its diagnos- lic health problem in industrialized na- tractility and enhances relaxation (posi- tic power in animal studies and clinical tions and the leading cause of hospital- tive lusitropic effect) in failing hearts. investigations has only been realized in ization in people older than 65 years. At These effects were accompanied by ar- the last two decades. In the past, effects a time when other cardiovascular dis- terial and venous dilation. Paolocci’s on myocardial contractility have been eases are on the decline, HF is rising finding that the cardiotonic action of difficult to evaluate because of the load ␤ and likely to further escalate over the HNO was unaffected by -receptor dependence of conventional measures of coming decades because of an aging blockade and additive to that of dobut- ventricular function. Since a couple of population and increased survival from amine is therapeutically significant not years ago, left ventricular end-systolic the underlying causes such as coronary only because the action of dopaminergic pressure-volume relationships can be heart disease and hypertension. A broad agonists and phosphodiesterase inhibi- assessed in the setting of a routine car- spectrum of different drugs and various tors are often attenuated in HF, but diac catheterization procedure. Using a guidelines for the treatment of HF exist also in view of the recent advent of ␤ conductance catheter with a microma- (5, 6). In the past, HF was mainly -blockers and their negative inotropic nometer tip for continuous measure- viewed as a problem of diminished car- effects in certain clinical settings. In ment of intraventricular volume and diac output. Maximization of the latter contrast to nitric oxide (NO)-generating pressure in combination with an occlud- with positive inotropic (contractility en- compounds, HNO production was not ing device to rapidly vary venous inflow, hancing) agents led to therapies that associated with increased plasma levels a largely load-independent measure of initially improved functional capacity, of the second messenger, cGMP. In- cardiac contractility can be obtained but increased mortality. Today, the ther- stead, enhanced concentrations of calci- without altering the status of the heart apeutic focus is on reducing elevated tonin gene-related peptide (CGRP) (11). In addition to the assessment of filling pressures that lead to the symp- were detected during HNO, but not NO systolic and diastolic function, additional toms of congestion (7). Although most administration, suggesting that the parameters allow estimation of the rela- recommendations agree on the major former may exert its favorable action, at tive effects of vasodilation on cardiac drug classes for the first-line and ad- least in part, via this endogenous neu- performance. In their studies, Paolocci junct therapy of HF, there is consider- ropeptide. Although the same group et al. (9) used a nitrate (nitroglycerin) able controversy about the role of posi- had previously observed positive inotro- and a NONOate (DEA͞NO) to gener- tive inotropic agents (8). Despite a pic effects of HNO in healthy hearts ate NO and Angelis’ salt to generate documented negative impact on survival, (10), the study outcome with this com- HNO. Although all three compounds these agents are still widely used, often pound in the setting of HF was not were used at equieffective doses as combined with vasodilators, to limit se- obvious. Numerous experimental and vere episodes of HF or as a bridge to clinical studies in the past have demon- transplantation. The rationale for com- strated that the same pharmacological See companion article on page 5537. bining vasodilatation with positive ino- principle capable of increasing contrac- *E-mail: [email protected]. tropic intervention lies in the possibility tility in the normal heart can produce †Not to be confused with nitroxyl radicals, which are to ‘‘unload’’ the heart, i.e., to reduce its negative inotropy in the failing heart spin traps for the detection of radical species by EPR preload and afterload by venous and due to unfavorable effects on cardiac spectroscopy. 4978–4980 ͉ PNAS ͉ April 29, 2003 ͉ vol. 100 ͉ no. 9 www.pnas.org͞cgi͞doi͞10.1073͞pnas.1031571100 Downloaded by guest on September 27, 2021 COMMENTARY judged by the degree of reduction in vertable species (24), NOϪ may not be ing ischemia, nicotine, capsaicin (35), systolic pressure, the cardiac effects of readily oxidized to NO under all condi- nitroglycerin, and a nitroxyl donor (but NO were dramatically different from tions. Select nitroxyl donors, but not not other NO generating compounds) those of HNO. This is most likely due Angeli’s salt, have been shown to un- (36). An alternative way to increase to differences in the chemical properties dergo facile oxidative conversion to re- plasma CGRP is to slow down its enzy- of these two species, which dictates their lax vascular tissue and inhibit platelet matic breakdown by inhibiting neutral reactivity with endogenous biomolecules aggregation in a manner indistinguish- endopeptidase, but this is bound to af- and the signaling pathways affected. able from NO (25). The clear-cut di- fect numerous other pathways. It ap- NO is a ubiquitous endogenous mes- chotomy between the pharmacological pears fair to assume that the HNO- senger and modulator of cell function, profile of Angeli’s salt and that of NO induced CGRP increase in Paolocci’s which is produced from L-arginine by a donors observed by Paolocci et al. (9), study (9) originated from perivascular family of isoenzymes, the NO synthases however, indicates that HNO to NO nerves. It would be interesting to see (NOS) (12). HF is associated with re- conversion does not take place in every whether the inotropic effects of HNO duced expression of endothelial NOS tissue. This conclusion is further sup- are blunted in dogs depleted of endoge- and increased vascular oxidative stress, ported by their cGMP and CGRP mea- nous CGRP by prolonged infusion of which translates into diminished NO surements, which suggest that the car- capsaicin (37). Further insight may also availability, endothelial dysfunction and diac effects of HNO and NO are be gained from studies in CGRP-defi- reduced vasodilator capacity (13). NO is mediated by different signaling path- cient mice (33). Such investigations also the pharmacological principle of a ways. Besides the significance of these would not only confirm the cardiotonic number of drugs