Heart failure may lead to hypoperfusion and hypooxygenation of tissues and this is often exacerbated by central and obstructive sleep apnoeas associated with recurrent episodes of systemic hypoxia and hypercapnia/hypocapnia. Astrocytes residing in the rostral ventrolateral medulla oblongata (RVLM) may function as specialized brain chemoreceptors. They sense PCO2/pH changes and via release of ATP impart these changes on neurones of the ventral respiratory column triggering adaptive increases in the respiratory activity. We used in vitro and in vivo models to determine whether selective activation of RVLM astrocytes leads to the release of ATP, and via release of ATP increases the activity of sympathoexcitatory (pre-sympathetic) RVLM neurones. We also explored whether ATP actions in the RVLM contribute to maladaptive and detrimental sympathoexcitation in heart failure. It was found that optogenetic activation of RVLM astrocytes transduced to express light-sensitive channelrhodopsin-2 activates sympathoexcitatory RVLM neurones in ATP-dependent manner. In anaesthetized rats in vivo, optogenetic stimulation of RVLM astrocytes increases sympathetic renal nerve activity, arterial blood pressure and heart rate. To interfere with ATP-mediated signalling by promoting extracellular breakdown of ATP, we developed a lentiviral vector to express a potent ectonucleotidase – transmembrane prostatic acid phosphatase (TMPAP) on the cellular membranes. In rats with myocardial infarction-induced heart failure, expression of TMPAP bilaterally in the RVLM led to a lower plasma noradrenaline concentration, maintained left ventricular (LV) end diastolic pressure, attenuated decline in dP/dT(max) and shifted the LV pressure-volume relationship curve to the left. These results demonstrate that activated RVLM astrocytes are capable of increasing the activity of the brainstem sympathoexcitatory neuronal circuits while facilitated breakdown of ATP in the RVLM reduces sympathetic tone, attenuates the progression of LV remodelling and heart failure secondary to myocardial infarction. Our data provide the first experimental evidence suggesting that altered glial activity leading to higher level of “ambient” ATP in the brainstem might be responsible for the increases in sympathetic tone and by doing so contribute to the development and progression of heart disease associated with increased activity of the sympathetic nervous system.