AT1 receptor on glutamatergic neurons regulate cardiac function through modulation of excitability and sympathetic outflow

Previously we generated a mouse model with Angiotensin (Ang)‐II type 1 (AT 1 ) receptor deletion from the central nervous system (CNS) neurons. Compared to their control littermates, those mice exhibited attenuated hypertension and improved autonomic function after DOCA‐salt treatment (DOCA 1mg/g body weight sc + 1% saline po for 3 weeks). Moreover, unlike controls, no increase in left ventricle (LV) mass or decrease in cardiac systolic function was observed, suggesting those mice with neuronal AT 1 R deficiency were protected from the cardio‐hypertrophic process induced by DOCA‐salt treatment, indicating a possible role of neuronal AT 1 R in regulation of cardiac function. To further investigate this hypothesis, a new mouse model (AT1G) was generated, in which AT 1a R was knocked‐out from glutamatergic neurons. Interestingly, at baseline, AT1G mice (n=7) already exhibit impaired cardiac function, as reflected by reductions in ejection fraction (−11.63 ±3.95%; P=0.0048 ) and fractional shortening (−6.61 ±2.25%; P=0.0049 ), despite no significant changes in morphology (such as LV mass, chamber size, and wall thickness). Blood pressure (BP) and heart rate (HR) were also unaltered even though spontaneous baroreflex sensitivity was slightly reduced (2.31 ±0.29 vs. 3.01 ±0.23 msec/mmHg, P=0.04 ). After 2 weeks of DOCA‐salt treatment (n=5/group), control mice exhibited a significant decrease in cardiac systolic function ( P=0.01 ) and increase in the LV chamber size ( P<0.01 ), which were not observed in DOCA‐salt‐treated AT1G mice. Moreover, when echocardiography was performed (14 day of DOCA‐salt treatment), there was no significant difference in BP and HR between AT1G mice and their control littermates, both of which were hypertensive due to DOCA‐salt treatment (127.3 ±8.89 vs. 131.5 ±1.84, P=0.27 ), suggesting the change in cardiac function is mediated directly by the CNS and not secondary to a BP rise. To further dissect the mechanism, qRT‐PCR and patch‐clamp recording were performed. In the hypothalamus of AT1G mice, mRNA levels for GABA A receptors and glutamic acid decarboxylase (GAD) 67 were significantly higher, by +52 ±17% and +36 ±14% respectively, compared to controls (n=4/group, P<0.01 ). Meanwhile, lower action potential (AP) frequency was recorded in kidney‐related PVN neurons of AT1G mice (0.43 ±0.06 vs. 2.04±0.96 Hz, n=3, P=0.01 ), suggesting that those neurons indeed have lower excitability compared to controls. Altogether, our data provide evidence that central renin‐angiotensin system has an essential role in regulating cardiac function by mediating neuronal excitability and sympathetic outflow. Support or Funding Information This work was supported by research grants from the National Institutes to Health (HL093178 and GM106392 to E.L.) and The American Heart Association to E.L. (12EIA8030004), J.X. (15POST25000010).