AbstractThe imbalance of neurotransmitters and excessive oxidative stress responses contribute to the pathogenesis of hypertension. In this study, we determined whether blockade of p44/42 MAPK pathway in the hypothalamic paraventricular nucleus (PVN) ameliorates the development of hypertension through modulating neurotransmitters and attenuating oxidative stress. Dahl salt-sensitive (S) rats received a high-salt diet (HS, 8% NaCl) or a normal-salt diet (NS, 0.3% NaCl) for 6 weeks and were treated with bilateral PVN infusion of PD-98059 (0.025 μg/h), a p44/42 MAPK inhibitor, or vehicle via osmotic minipump. HS resulted in higher mean arterial pressure (MAP) and Fra-like (Fra-LI) activity, and plasma and PVN levels of norepinephrine (NE), tyrosine hydroxylase (TH), NOX2 and NOX4, lower PVN levels of gamma-aminobutyric acid (GABA), copper/zinc superoxide dismutase (Cu/Zn-SOD) and the 67-kDa isoform of glutamate decarboxylase (GAD67), as compared with NS group. PD-98059 infusion reduced NE, TH, NOX2 and NOX4 in the PVN, and induced Cu/Zn-SOD and GAD67 in the PVN. It suggests that PVN blockade of p44/42 MAPK attenuates hypertension through modulating neurotransmitters and attenuating oxidative stress.