Over the last few years, the pharmacological perspective of the potential utility of HNO donors has changed. Originally, they were considered primarily useful (at least with regards to the cardiovascular system) as vasodilators. However, more recently HNO-donors have been found to be capable of profoundly affecting myocardial contractility [Wink et al., 2003]. In 1999 came the first demonstration that HNO may affect myocardial contractility in the setting of ischemia-reperfusion [Ma et al., 1999]. HNO, derived from Angeli’s salt, given to reperfused myocardium (after ischemia) is detrimental, as opposed to the beneficial effects exerted by hemodynamically equi-effective doses of the NO donor, nitrosoglutathione (GSNO) (vide infra). This paper raised the question: “How does HNO modulate myocardial properties, namely contractility, under normal and failing conditions?”. Using a pressure-volume relationship approach to dissect primary effects on the heart from changes in vascular loading conditions [Senzaki et al., 2001], it was demonstrated for the first time that Angeli’s salt-derived HNO is capable of increasing the inotropic status of the heart while hastening ventricular relaxation and unloading the heart [Paolocci et al., 2001]. One example of the effect of Angeli’s salt-derived HNO on normal canine myocardium is illustrated in Fig. 1.