Brain-selective overexpression of angiotensin-converting enzyme 2 attenuates sympathetic nerve activity and enhances baroreflex function in chronic heart failure.

Hypertension. 2011 Dec;58(6):1057-65. doi: 10.1161/HYPERTENSIONAHA.111.176636. Epub 2011 Oct 24. Xiao L, Gao L, Lazartigues E, Zucker IH. Most of the papers we read are about ACE, AngII, and AT1/2 receptors, but ths group decided to look at ACE2 and how it can affect production of Ang-(1-7) and activation of the mas receptor. This is important to look at because different groups have shown that microinjection of Ang-(1-7) in to the RVLM can be sympathoexcitatory in rabbits and rats. To do this, they created synapsin-ACE2 (SA) mice that would overexpress ACE2 production in all neurons. They gave SA and wild type control mice CHF by coronary artery ligation (CAL) and saw lower MAP in SA mice. They then got an indirect measure of SNA by measuring urinary NE and saw that while WT mice had increased urinary NE, SA mice didn't. This presumed decrease in SNA was directly observed by seeing lower renal SNA in SA CAL mice than WT CAL mice. They then looked at heart rate and SNA baroreflex during administration of phenylephrine and saw that while little or no reflex was seen in WT CHF mice, SA CHF mice decreased HR and SNA similar to what sham mice showed. But if ACE2 causes Ang-(1-7) that can be sympathoexcitatory, how come mice overexpressing ACE2 have LESS SNA? Possibly because they found attenuated ACE and AT1 receptor upregulation in the RVLM and NTS of SA CHF mice compared to WT CHF... So I guess that's cool and all, but I have to ask a couple of questions... what concentrations of ACE2 are normally in a brain, what concentrations of ACE2 were in these mice brains, and what concentration is normally active in hypertensive critters vs what concentration throws the whole thing out of whack? These are questions that I didn't see addressed in the discussion, but ones that kind of stick out to me. I guess it's time for a mas agonst in the WT mice and antagonists in the SA mice. These drugs exist and it would be cool to see them used in a follow up paper. -DH