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  • Title: Gene transfer of neuronal nitric oxide synthase to the paraventricular nucleus reduces the enhanced glutamatergic tone in rats with chronic heart failure.
    Author: Zheng H, Liu X, Li Y, Sharma NM, Patel KP.
    Journal: Hypertension; 2011 Nov; 58(5):966-73. PubMed ID: 21968757.
    Abstract:
    Our previous studies have shown that the decreased NO and increased glutamatergic mechanisms on sympathetic regulation within the paraventricular nucleus (PVN) may contribute to the elevated sympathoexcitation during chronic heart failure (CHF). In the present study, we investigated the effects of neuronal NO synthase (nNOS) gene transfer on N-methyl-D-aspartic acid receptor subunit NR(1) in the rats with a coronary ligation model of CHF. Adenovirus vectors encoding nNOS (AdnNOS) or adenovirus vectors encoding β-galactosidase were transfected into the PVN in vivo. Five days after application of AdnNOS, the increased expression of nNOS within the PVN was confirmed by NADPH-diaphorase staining, real-time PCR, and Western blot. In anesthetized rats, AdnNOS treatment significantly enhanced the blunted renal sympathetic nerve activity, blood pressure, and heart rate responses to NO synthase inhibitor N(G)-monomethyl-L-arginine in the rats with CHF compared with CHF-adenovirus vectors encoding β-galactosidase group. AdnNOS significantly decreased the enhanced renal sympathetic nerve activity, blood pressure, and heart rate responses to N-methyl-D-aspartic acid in the rats with CHF (renal sympathetic nerve activity: 44±2% versus 79±6%; P<0.05) compared with CHF-adenovirus vectors encoding the β-galactosidase group. AdnNOS transfection significantly reduced the increased NR(1) receptor mRNA expression (Δ35±5%) and protein levels (Δ24±4%) within the PVN in CHF rats. Furthermore, in neuronal NG-108 cells, NR(1) receptor protein expression decreased in a dose-dependent manner after AdnNOS transfection. According to our results, nNOS downregulation enhances glutamate transmission in the PVN by increasing NR(1) subunit expression. This mechanism may enhance renal sympathetic nerve activity in CHF rats.
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