Heart failure is a major cause of premature mortality and increased morbidity. It is characterised by perturbed excitation contraction coupling and associated with autonomic dysfunction, in particular altered cyclic nucleotide (cAMP/cGMP) signalling. Classical therapies for heart failure such as beta-blockers attenuate cAMP signalling, however the current study aimed to test whether activation of the cGMP pathway may similarly improve cardiac function and β-adrenergic sensitivity in the failing myocardium. Heart failure was induced in sheep. Animals were anaesthetised for pacemaker implantation (isoflurane, 1-3% in oxygen) and perioperative analgesia provided (meloxicam, 0.5 mg/kg). After 7 days recovery, right ventricular pacing (210-220 bpm) was applied until clinical symptoms of HF were evident. Cardiac dimension and function were measured in vivo using echocardiography. At end stage heart failure animals were sacrificed by I.V. injection of pentobarbitone (200 mg/kg). Post-mortem the heart was taken and individual myocytes isolated enzymatically. In vitro, whole cell patch clamping with corresponding fluorescent imaging was used to measure intracellular calcium, which rises rapidly during systole, and provides a function of myocyte contractility. In heart failure, cardiac dimension was increased (p<0.01, n=7) and contractility was reduced both in vivo (p<0.01, n=7) and in vitro (p<0.01, n=9). Furthermore, in vivo response to sympathetic nervous system stimulation (dobutamine, 20 mg/kg/min) was attenuated (p<0.01, n=5). After 4 weeks of tachypacing a subset of heart failure animals (n=20), were commenced on a 3-week treatment with a phosphodiesterase 5 inhibitor (tadalafil, 20 mg/day), which aims to increase cytosolic cGMP. In these animals cardiac dimension was no different to before the commencement of treatment, showing no further change in chamber dilation than untreated animals. Furthermore, treated animals had augmented contractility in vitro (p<0.01, n=20), and increased sensitivity to sympathetic stimulation in vivo (p<0.01, n=5). Finally, treated animals lived longer than untreated animals (15.9±8.4%, p=0.03, n=20). In conclusion this study shows that chronic phosphodiesterase 5 inhibition is beneficial in heart failure, facilitating longevity and improved cardiac function at the whole heart and cellular level. The data presented here suggests a promising future target, which may have important implications for the management of heart failure in clinical practice. Experiments were carried out in accordance with the UK Home Office Animals (Scientific Procedures) Act 1986.