Purinergic signalling in the rostral ventro-lateral medulla controls sympathetic drive and contributes to the progression of heart failure following myocardial infarction in rats

Nephtali Marina, Feige Tang, Melina Figueiredo, Svetlana Mastitskaya, Vitaliy Kasimov, Vidya Mohamed-Ali, Eva Roloff, Anja G Teschemacher, Alexander V Gourine, Sergey Kasparov

Research output: Contribution to journalArticle (Academic Journal)peer-review

48 Citations (Scopus)

Abstract

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 which triggers release of ATP within the CNS circuits controlling sympathetic outflow. Using in vitro and in vivo models we tested two hypotheses: (1) activated brainstem astroglia release 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, progression of left ventricular (LV) remodelling and development heart failure secondary to myocardial infarction. In vitro, optogenetic activation of RVLM astrocytes transduced to express light-sensitive channelrhodopsin-2 activated sympathoexcitatory RVLM neurones in ATP-dependent manner. In anaesthetised rats in vivo, similar optogenetic activation of RVLM astrocytes increased sympathetic renal nerve activity, arterial blood pressure and heart rate. To interfere with ATP-mediated signalling by promoting its extracellular breakdown, we developed a lentiviral vector to express an 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 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. 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 the progression of LV remodelling and heart failure secondary to myocardial infarction.
Original languageEnglish
Pages (from-to)317
JournalBasic Research in Cardiology
Volume108
Issue number1
DOIs
Publication statusPublished - 2013

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