Oral Presentation Neuropathophysiology - an ISH satellite 2012

Selective AT1A receptor knockout from catecholaminergic neurons reduces the hypertension induced by chronic low dose infusion of angiotensin II. (#2)

Nikola Jancovski 1 , Jaspreet K Bassi 1 , David Carter 1 , Angela Connelly 1 , Elyse Stevens 1 , Daian Chen 1 , Geoffrey A Head 2 , Andrew M Allen 1
  1. Department of Physiology, University of Melbourne, Parkville, Victoria , Australia
  2. Neuropharmacology Laboratory, Baker IDI Heart and Diabetes Research Institute, Melbourne , Victoria , Australia

Background: Chronic low dose systemic infusion of angiotensin II (Ang II) induces hypertension via activation of the Ang II type 1A receptor (AT1AR). Whilst renal expression of this receptor is important for the hypertension, other sites appear to be involved. We tested the hypothesis that AT1ARs on catecholaminergic neurons are required for Ang II-induced hypertension. Methods: Mice with cell-specific deletion of AT1AR from catecholaminergic neurons were generated by crossing AT1AR floxed mice with mice expressing cre-recombinase (Cre) under the control of the tyrosine hydroxylase (TH) promoter. We generated AT1ARfl/fl;TH-Cre+/- (n=6) and AT1ARfl/fl;TH-Cre-/- (n=6) mice for this study. To eliminate AT1AR only from the C1 neurons in the RVLM, lentivirus expressing Cre under the control of a phox2 binding site promoter, PRSx8 was injected in the RVLM of AT1ARfl/fl mice (n=8). Control AT1ARfl/fl mice were injected with the same virus with a GFP transgene (n=8). Ang II (500ng/kg/minute) was infused subcutaneously via an osmotic minipump for 3 weeks. Telemetry devices (TH-Cre mice) or a noninvasive tail cuff system (lentiviral injected mice) were used to record BP and heart rate. Dihydroethidium (DHE) was used to measure superoxide formation in the brain. Results: Baseline systolic BP was not different between any group. Infusion of Ang II induced a gradual pressor response that was greater in AT1ARfl/fl;TH-Cre-/- mice compared to AT1ARfl/fl;TH-Cre+/- mice (150± 3mmHg vs. 133 ± 2 mmHg at day 13; P<0.05). AT1AR deletion only from C1 neurons also reduced the pressor response compared to the controls (137± 2mmHg vs. 146 ± 2 mmHg at day 11; P<0.01). Superoxide formation in the RVLM was reduced in AT1ARfl/fl;TH-Cre+/- mice compared to controls (P<0.05). Conclusions: These data demonstrate that AT1AR expression by catecholaminergic neurons is required for full development of angiotensin-dependent hypertension.

Funded by the Australian NHMRC