Abstract 088: At 1 Receptor on Glutamatergic Neurons Regulate Autonomic Function Through Modulation of Neuronal Excitability and Sympathetic Outflow

Abstract

Using a mouse model with Angiotensin II type 1 receptor (AT 1a R) deletion from the central nervous system neurons, we previously reported attenuated hypertension, improved autonomic function, and importantly, blunted ADAM17 (A Disintegrin And Metalloprotease 17) activation after deoxycorticosterone-salt treatment (DOCA 1mg/g body weight sc + 1% saline po for 3 weeks) compared to their control littermates. Since neuronal AT 1a R has a pivotal role in ADAM17-mediated ACE2 shedding and the maintenance of neurogenic hypertension, we further investigated the role of central AT 1a R and ADAM17 in excitatory neurons. New mouse models were generated with deletion of AT 1a R (AT1G) or ADAM17 (A17G) specifically from glutamatergic neurons. AT1G (n=9), A17G (n=9), and their control littermates (n=10) were implanted with telemetry probes for continuous recording of blood pressure. Following DOCA-salt treatment, both strains showed increased mean arterial pressure, however the pressor responses were significantly lower in both transgenic lines (AT1G: +16 ±3 mmHg, A17G: +21 ±3 mmHg), compared to the controls (+31 ±2 mmHg). Meanwhile, the pulse pressure in the AT1G and A17G mice were not significantly increased compared to their baseline, while it was elevated in the control littermates by around 20 mmHg ( P<0.01 ). In addition to a reduced hypertension, AT1G mice exhibited preserved baroreflex sensitivity and autonomic function at the end of the DOCA-salt protocol. The DOCA-salt-induced dysautonomia was also attenuated in A17G mice but still exhibited decreased cardiac parasympathetic tone and increased vascular sympathetic tone, indicating that glutamatergic AT 1 R can modulate autonomic regulation independently of ADAM17. To further dissect this mechanism, patch-clamp recording was performed in AT1G and control mice. Interestingly, lower action potential frequency was recorded in kidney-projecting PVN neurons of AT1G mice (0.43 ±0.06 vs. 2.04 ±0.96 Hz, n=3, P=0.01 ), suggesting that AT 1a R-knockdown neurons have a lower excitability compared to controls. Altogether, our data provide evidence that AT 1a R located on glutamatergic neurons regulate autonomic function and the development of hypertension through ADAM17-dependent and independent pathways.