Angiotensin AT1 Receptors Promote Age-Dependent Expansion of Presympathetic Networks in Spontaneously Hypertensive Rats

Heightened sympathetic outflow is a major contributor to the development of hypertension. The hypothalamic paraventricular nucleus (PVN) and the rostral ventrolateral medulla (RVLM) are critical regions for generating and regulating sympathetic activity associated with hypertension. Although presympathetic neural circuitry in the healthy brain is well characterized, it remains unclear whether these pathways undergo alterations in hypertension. Here, we determined presympathetic neural circuits by injecting pseudorabies virus (PRV), a transsynaptic retrograde tracer, into the adrenal gland of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Adult SHR exhibited a significantly greater number of PRV-labeled neurons in the PVN and RVLM, but not in the spinal intermediolateral column, compared with WKY. In contrast, the numbers of PRV-labeled neurons in the PVN and RVLM were comparable between young, prehypertensive SHR and age-matched WKY. Remarkably, long-term treatment with losartan-a brain-penetrant angiotensin II AT1 Receptor antagonist- initiated in young, prehypertensive SHR blunted the age-dependent hypertension development and reversed the increase in neuronal labeling in both the PVN and RVLM. However, losartan treatment had no effects in WKY. Additionally, electrophysiological recordings showed an elevated frequency of miniature excitatory postsynaptic currents in PVN presympathetic neurons of SHR, which was also normalized by long-term losartan treatment. These findings reveal an age-dependent expansion of presympathetic neuronal connectivity from the hypothalamus and brainstem to the adrenal gland during hypertension development in SHR. Enhanced AT1 Receptor activity contributes to hypertension by increasing active glutamatergic synaptic input and promoting the recruitment of additional presympathetic neurons in the hypothalamus and brainstem.

Key points: 1. The numbers of neurons labeled by PRV injected into the adrenal gland are increased in the PVN and RVLM, but not in the spinal cord IML, in adult SHR compared to normotensive WKY. 2. The numbers of neurons in the PVN, RVLM, and spinal cord labeled by PRV injected into the adrenal gland are comparable in young, prehypertensive SHR and age-matched WKY. 3. Losartan treatment, initiated at a young age, blunts the hypertension development and reverses the increased numbers of PRV-labeled neurons in the PVN and RVLM of adult SHR but has no such effects in WKY. 4. The active glutamatergic synapses in PVN presympathetic neurons are elevated in adult SHR, and this elevation is reversed by long-term losartan treatment.