Several studies suggest that changes in the sympathetic nervous system (SNS) are responsible for the initiation, development and maintenance of hypertension. SNS over activity may result from an inappropriately elevated sympathetic drive from brain centers. One important central sympatho-excitatory region is the paraventricular nucleus of the hypothalamus (PVN), which may become more active in hypertensive conditions, as shown in acute studies. Objective: Depress chronically the activity of PVN neurons by the over-expression of an inwardly rectifying potassium channel (hKir2.1) in order to evaluate the consequences upon blood pressure regulation in an animal model of hypertension. In telemetry instrumented spontaneously hypertensive rats (SHRs) lentiviral vectors: LVV-hKir2.1 (LV-TREtight-Kir-cIRES-GFP5 4x10E9: LV-Syn-Eff-G4BS-Syn-Tetoff 6.2x10E9 in a ratio 1:4) were as microinjected bilaterally into PVN stereotaxically. Sham SHRs were bilaterally microinjected with LVV-eGFP (LV-Syn-Eff-G4BS-Syn-Tetoff 6.2x10E9: LV-TREtight-GFP 5.7x10E9 in a ratio 1:4) in the PVN. Blood pressure (BP) and heart rate (HR) were monitored continuously and evaluated using radio-telemetry for 75 days. Baroreflex function was evaluated by measuring HR changes induced by BP variation produced by phenylephrine (25μg/ml, iv) injection. Lobeline (25μg/ml, iv) was used to evaluate peripheral chemoreflex sensitivity. These procedures were performed under anaesthesia. Heart, kidneys and vessels were collected post-mortem to evaluate, by RT-PCR, the expression of 20 key genes involved in the pathways regulating blood vessel tone. Results: LVV-hKir2.1 expression by PVN activity in SHRs produced a time-dependent and significant decrease in systolic (158±1 to 134±1mmHg), diastolic (137±1 to 115±1mmHg) and mean BP (144±1 to 121±1mmHg) as well as in HR (314±3 to 295±3bpm) 60 days post-microinjection of LVV-hKir2.1. In SHRs the cBRG significantly increased after LVV-hKir2.1 microinjection (0.51±0.06 and 1.3±0.18bpm/mmHg). The chemoreceptor reflex evoked pressor response and the LF-band decreased in the LVV-hKir2.1-SHR group (0.71±0.3 to 0.42±0.26mmHg2) suggesting reduced sympathetic vasomotor tone. RT-PCR analysis showed a downregulation of angiotensin II receptors together with a decrease on calcium transport. Conclusion: Our data showed, for the first time, that PVN neuronal excitability plays a major role in the long term control of blood pressure and SNS activity in SHRs. This may be mediated, in part, by improved baroreflex sensitivity and reduced peripheral chemosensitivity and respiratory-sympathetic modulation. Molecular studies showed that the microinjection of LVV-hKir2.1 interfere mainly with the endocrine regulation of BP through angiotensin II. Our results support the PVN as a therapeutic target in the control of blood pressure in neurogenic hypertension.