Gastrin releasing peptide receptor antagonism in the paraventricular nucleus exerts antihypertensive effects in 2K1C rats

Hypertension is a leading global risk factor for cardiovascular diseases marked by sympathetic overactivation. The role of centrally expressed bombesin and its receptors in elevating sympathetic activity and blood pressure has been reported. However, whether gastrin releasing peptide receptor (GRPR), one of bombesin-like peptide receptors, in the paraventricular nucleus (PVN) mediates renovascular hypertension and its potential mechanism remain unclear. In this study, we explored the following: (1) the role of GRPR in the PVN in the development of hypertension in two-kidney one-clip (2K1C) hypertensive rat model; (2) the effects of GRPR antagonist ICI-216140, administered bilaterally to PVN, on blood pressure. The systolic blood pressure (SBP) was recorded weekly throughout the animal experiment stage. At the conclusion of experiment, after four weeks of ICI-216140 administration, samples were collected to analyze the expression of GRPR, reactive oxygen species (ROS), pro-inflammatory cytokines (PICs), and neurotransmitter related parameters in the PVN. The 2K1C rats exhibited increased SBP, increased expression of GRPR, oxidative stress markers including NOX2 and NOX4, PICs markers including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and neurotransmitter related parameter tyrosine hydroxylase (TH). Additionally, these rats showed decreased expression of glutamic acid decarboxylase 67 (GAD67) in the PVN. The elevated SBP and the altered cellular and molecular expressions induced by 2K1C intervention were significantly attenuated by ICI-216140 treatment. These findings demonstrate that GRPR antagonist can effectively blockade 2K1C-induced elevation of SBP and mitigate the pro-hypertensive activity in the PVN. Our results provide novel evidence supporting the therapeutical potential of GRPR antagonism in the treatment of hypertension.