Potentiated angiotensin AT1 receptor activity is associated with age-dependent expansion of adrenal-projecting presympathetic circuitry in hypertension

Heightened sympathetic outflow is a key driver of hypertension development. 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, whether these pathways undergo remodeling during hypertension remains unclear. Here, we mapped presympathetic neural circuits by injecting pseudorabies virus (PRV), a transsynaptic retrograde tracer, into the adrenal gland of male 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 demonstrate an age-dependent expansion of presympathetic neuronal connectivity from the hypothalamus and brainstem to the adrenal gland during the development of hypertension in SHR. Enhanced AT1 receptor activity may contribute to hypertension by increasing excitatory synaptic input and promoting the recruitment of additional presympathetic neurons in the brain.