Dr Nephtali Marina-Gonzalez, a cardiovascular neuroscientist based in the UCL Department of Clinical Pharmacology, gave a guest lecture on July 3 titled ‘Astroglial Control of Sympathetic Drive: Role in the Pathogenesis of Heart Faillure and Neurogenic Hypertension’.

Increased activity of the sympathetic nervous system is intimately linked to the development and progression of chronic heart failure and essential hypertension. The hypothalamic and brainstem neuronal networks responsible for the sympathetic control of cardiovascular activities have been extensively studied. However, no attention has been paid to the modulatory role played by their non-neuronal neighbours. Recent evidence shows that astrocytes, the most abundant type of glial cells, are involved in the central mechanisms which maintain cardio-respiratory homeostasis. Using in vitro and in vivo models we tested two hypotheses: (1) activated brainstem astroglia release (glio)transmitters (ATP) and via release of ATP activate sympathoexcitatory neurones of the rostral ventrolateral medulla (RVLM); and (2) ATP actions in the RVLM contribute to sympathoexcitation and development of heart failure secondary to myocardial infarction and neurogenic hypertension.

In vitro, optogenetic activation of astrocytes residing in the RVLM evokes the release of ATP which acts locally, increasing the excitability of bulbospinal sympathoexcitatory neurones. In vivo, astrogilal cell activation produced robust elevations in renal sympathetic activity and arterial blood pressure (ABP) in anaesthetised rats. To determine whether increased ATP tone in the RVLM underlies the abnormal sympathoexcitation in chronic heart failure and hypertension, we recently developed a lentiviral vector to express a potent ectonucleotidase—transmembrane prostatic acid phosphatase (TMPAP), the effect of which is to promote extracellular breakdown of ATP. In rats with myocardial infarction-induced heart failure, expression of TMPAP bilaterally in the RVLM led to lower plasma noradrenaline concentration, maintained left ventricular end diastolic pressure, attenuated decline in dP/dT (max) and shifted the LV pressure-volume relationship curve to the left. In a similar fashion, spontaneously hypertensive rats (SHRs) transduced to express TMPAP in the RVLM showed a significant reductions in ABP. These results show that activated RVLM astrocytes are capable of increasing sympathetic activity via release of ATP while facilitated breakdown of ATP in the RVLM attenuates both the progression of LV remodelling and heart failure secondary to myocardial infarction and the development of neurogenic hypertension.