Chronic AT1 receptor blockade normalizes NMDA-mediated changes in renal sympathetic nerve activity and NR1 expression within the PVN in rats with heart failure

Allison C. Kleiber, Hong Zheng, Neeru M. Sharma, and Kaushik P. Patel

Am J Physiol Heart Circ Physiol. 2010 May;298(5):H1546-55. Epub 2010 Feb 19.

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE 68198-5850, USA.

In my previous post, I summarized the article which discusses about how normalization of glutamatergic mechanisms in the paraventricular nucleus could be a possible mechanism by which exercise training (ExT) normalizes sympathetic outflow in heart failure (HF). As a follow up, I'm summarizing this article in which the authors investigated whether Ang II type 1 (AT1) receptors are involved in the normalization of PVN glutamatergic mechanisms. Studies by the same group have previously observed that ExT reduced the increased plasma Ang II levels associated with HF. Studies have shown that intravenous infusion of Ang II elevated the Fos immunoreactivity within the PVN, suggesting the possibility that PVN gene expression can be regulated by plasma Ang II levels. This let to the hypothesize that chronic AT1 receptor blockade in rats with HF would normalize PVN NMDA mediated renal sympathetic nerve activity (RSNA) responses and increased NR1 expression within the PVN. Chronic AT1 receptor blocker losartan was given at a dose of 50 mg/kg/day for a period of 3 weeks in drinking water. Three weeks of treatment with losartan normalized the NMDA induced (microinjected into the PVN) increase in RSNA.  In addition losartan treatment also normalized the elevated mRNA and protein expression of NMDA receptor subunit NR1. To address the question whether PVN received direct inputs from plasma ANG II since it cannot cross the blood brain barrier the authors suggested the possibility that the circumventricular organs such as subfornical organ (SFO) has direct projections to the PVN and it could have received signals from the SFO. The results from the present study suggest that normalization of plasma Ang II levels is one possible mechanism by which  exercise training normalizes enhanced gluatamatergic mechanisms associated with HF.

-Madhan