期刊
HYPERTENSION
卷 61, 期 1, 页码 202-+出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.111.00105
关键词
hypertension; calcium transient; NO; gene transfer; sympathetic neuron
资金
- British Heart Foundation
- BHF Centre of Research Excellence, Oxford
Hypertension is associated with the early onset of cardiac sympathetic hyperresponsiveness and enhanced intracellular Ca2+ concentration [Ca2+](i) in sympathetic neurons from both prehypertensive and hypertensive, spontaneously hypertensive rats (SHRs). Oxidative stress is a hallmark of hypertension, therefore, we tested the hypothesis that the inhibitory action of the nitric oxide- cGMP pathway on [Ca2+] i transients is impaired in cardiac sympathetic neurons from the SHR. Stellate ganglia were isolated from young prehypertensive SHRs and age- matched normotensive Wistar- Kyoto rats. [Ca2+](i) was measured by ratiometric fluorescence imaging. Neurons from the prehypertensive SHR ganglia had a significantly higher depolarization evoked [Ca2+](i) transient that was also associated with decreased expression of neuronal nitric oxide synthase (nNOS), beta 1 subunit of soluble guanylate cyclase and cGMP when compared with the Wistar-Kyoto rat ganglia. Soluble guanylate cyclase inhibition or nNOS inhibition increased [Ca2+](i) in the Wistar-Kyoto rats but had no effect in SHR neurons. A nitric oxide donor decreased [Ca2+](i) in both sets of neurons, although this was markedly less in the SHR. A novel noradrenergic cell specific vector (Ad.PRSx8-nNOS/Cherry) or its control vector (Ad.PRSx8-Cherry) was expressed in sympathetic neurons. In the SHR, Ad. PRSx8-nNOS/Cherry-treated neurons had a significantly reduced peak [Ca2+](i) transient that was associated with increased tissue levels of nNOS protein and cGMP concentration compared with gene transfer of Ad.PRSx8-Cherry alone. nNOS inhibition significantly increased [Ca2+](i) after Ad.PRSx8-nNOS/Cherry expression. We conclude that artificial upregulation of stellate sympathetic nNOS via targeted gene transfer can directly attenuate intracellular Ca2+ and may provide a novel method for decreasing enhanced cardiac sympathetic neurotransmission. (Hypertension. 2013;61:202-207.) circle Online Data Supplement
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