Increased gene expression of neuronal nitric oxide synthase in brain of adult spontaneously hypertensive rats

Neuronal nitric oxide is hypothesized to participate in regulation of autonomic function by decreasing sympathetic output to the periphery. This hypothesis predicts that gene expression of neuronal nitric oxide synthase is increased during states of heightened sympathetic activity. To test the hypothesis, we measured gene expression in the spontaneously hypertensive rat (SHR), a genetic model of hypertension in which sympathetic activity is correlated with increasing pressure. SHRs and two strains of control rats (Wistar-Kyoto [WKY] and Sprague-Dawley [SD]) at 4 weeks (pre-hypertensive) and 14 weeks (established hypertension) of age were used to measure gene expression in hypothalamus, dorsal pens, dorsal medulla, rostral ventrolateral medulla, and caudal ventrolateral medulla. Semi-quantitative reverse transcription-polymerase chain reactions and in situ hybridization were used to measure changes in neuronal nitric oxide synthase mRNA. No significant differences were found in any of the areas studied among the three strains of rats in the 4-week rats. At 14 weeks significant increases in gene expression were found in the hypothalamus (73% compared to WKYs, 104% compared to SDs), dorsal medulla (31% and 45%), and caudal ventrolateral medulla (24% and 27%) of SHRs. In situ hybridization revealed that neurons expressing the synthase gene in the hypothalamus were found primarily in the paraventricular (both parvo- and magnocellular divisions) and supraoptic nuclei. These data show that gene expression of neuronal nitric oxide synthase is increased in central autonomic centers in animals with increased sympathetic activity and they support the hypothesis that nitric oxide plays an important role in maintenance of homeostatic balance through modulation of sympathetic activity.