Gene delivery of endothelial nitric oxide synthase into nucleus tractus solitarii induces biphasic response in cardiovascular functions of hypertensive rats

Abstract

Background Nitric oxide (NO) plays an important role in central control of blood pressure (BP). An intrinsic defect in NO availability in brain nucleus contributes to the elevated BP in the spontaneously hypertensive rats (SHR). This study was aimed to investigate the effect of endothelial NO synthase (eNOS) gene delivery in the nucleus tractus solitarii (NTS) on the cardiovascular functions of SHR. Methods Adenovirus vectors encoding either eNOS (Ad-eNOS) or green fluorescent protein (Ad-GFP) were used for gene transfer study. The cardiovascular functions in SHR received NTS gene delivery that were monitored by an oscillometric device. Results Infection of neuronal cells with Ad-eNOS increased the nitrite production but decreased the level of superoxide anion (O 2 −), indicating that eNOS gene delivery increased NO availability. After microinjection into NTS, adenovirus-mediated GFP or eNOS expression was confirmed by fluorescence microscopy and immunohistochemical analysis. On days 3 to 14 after injection, a significant decrease in mean BP (MBP and heart rate (HR) was observed in Ad-eNOS-treated SHR, but not in Ad-GFP- or saline-treated SHR. Within this period, microinjection of the soluble guanylate cyclase inhibitor significantly reversed the Ad-eNOS-mediated depressor effect. However, on days 24 to 40, the MBP of Ad-eNOS-treated animals escalated, then returned to the normal range after day 50. The mechanism underlying the rebound of BP in Ad-eNOS-injected SHR remains to be elucidated. Conclusions Intra-NTS eNOS gene delivery causes a depressor response in SHR, but a transient increase in MBP was observed after the Ad-eNOS-induced hypotension disappeared.