Endothelial NO Synthase Activity in Nucleus Tractus Solitarii Contributes to Hypertension in Spontaneously Hypertensive Rats

Abstract

Abstract-NO is implicated as a major modulator of central nervous circuits regulating cardiovascular activity. Based on previous data, we hypothesized that overactivity of endothelial NO synthase (eNOS) within the nucleus tractus solitarii (NTS) could contribute to the hypertension in the spontaneously hypertensive rat (SHR). Using real-time PCR, we found that endogenous eNOS mRNA was greater in the NTS of mature, but not juvenile prehypertensive SHRs compared with aged-matched Wistar Kyoto (WKY) rats. To test the functional significance of this, we chronically blocked eNOS activity in the NTS in the adult SHR by in vivo adenoviral-mediated gene transfer of a dominant-negative form of eNOS; data were compared with WKY rats. This resulted in a fall in arterial pressure in the SHR but not WKY rats. In both rat strains, cardiac baroreceptor reflex gain and the high-frequency spectral component of heart rate variability increased. Thus, endogenous eNOS activity in the NTS plays a major role in determining the set point of arterial pressure in the SHR and contributes to maintaining high arterial blood pressure in this animal model of human hypertension. Key Words: nitric oxide synthase Ⅲ nitric oxide Ⅲ endothelium Ⅲ blood pressure Ⅲ baroreflex Ⅲ sympathetic nervous system Ⅲ neurogenic hypertension A s described by Doba and Reis, 1 destruction of the nucleus tractus solitarii (NTS) leads to fulminating hypertension. This is highly suggestive that the NTS is a central brain stem structure that plays a vital role in maintaining the set point of arterial pressure. Equally, because baroreceptor afferents terminate in this nucleus, it is also one of the most effective central sites for modulating the gain of the baroreceptor reflex, a process that is critically important for blood pressure homeostasis. A potent neuromodulator of central cardiovascular autonomic activity is angiotensin II (Ang II). NTS microinjections of Ang II evoke concentrationdependent effects composed of either a depressor response 2,3 or a pressor/tachycardic response. 4 In addition, an Ang II antagonist increased cardiac baroreceptor reflex gain in anesthetized mature rats. 5 Because of the work of Casto and Philips, 6 it has been known that Ang II acting on Ang II type 1 receptors depresses cardiac baroreceptor reflex function in NTS. We showed that the depressant effect of Ang II type 1 receptor stimulation on cardiac baroreceptor reflex function in the NTS was mediated by NO. 7 We confirmed recently that Ang II can release NO in the NTS using electron paramagnetic resonance. 8 We also found that the effect of Ang II occurs via a Gq-PLC-IP3 pathway that releases intracellular calcium, 9 which we assume is required for activating endothelial NO synthase (eNOS). Released NO enhances inhibitory GABAergic neurotransmission in the NTS, 10 which may underlie the NO-induced cardiac baroreceptor reflex depression. 7 In conscious normotensive Wistar rats, chronic blockade of eNOS activity in NTS elevated the cardiac baroreceptor reflex gain, supporting a de...

Avaliação da função barorreflexa em ratos jovens espontaneamente hipertensos

“…Bertagnoli et al 20 suggested that exercise training reduces oxidative stress, which is associated to an improvement in baroreflex sensitivity in SHR. Waki et al 21 have shown that endogenous nitric oxide synthase activity in the medulla oblongata of SHR is increased when compared to WKY; it plays a major role in the preservation of the hypertension and decreases the cardiac baroreceptor reflex gain, which are features of this animal model. According to Ito et al 22 , although the inhibition of endogenous rho-kinase in the medulla oblongata augments the baroreflex control of heart rate in WKY and SHR, it improves the impaired baroreflex function in SHR.…”

“…Rossi et al 19 indicated that endogenous endothelin receptor mechanisms are involved in the hypertensive state observed in SHR. Moreover, recent investigations described the importance of oxidative stress 20 , nitric oxide 21 and the small GTPase rho-quinase 22 during baroreflex function development in SHR. Bertagnoli et al 20 suggested that exercise training reduces oxidative stress, which is associated to an improvement in baroreflex sensitivity in SHR.…”

Viral Vectors as Tools to Investigate the Role of Dysregulated Proteins in Nervous System Pathologies: the Case of Acquired Motor Neuropathies

“…As a viral control, a recombinant AVV was used to express the enhanced green fluorescent protein (eGFP) directed by the hCMV (AVV-eGFP). This gene therapy strategy successfully revealed the involvement of eNOS from the nucleus tractus solitarii in hypertension of spontaneously hypertensive rats (Kasparov et al, 2004;Waki et al, 2003;Waki et al, 2006;Paton et al, 2007). The expression of proteins under control of the hCMV promoter is characterized by a very rapid increase in expression, peaking 10 hr after transfection (Stokes et al, 2003).…”

“…Furthermore, when AVV-eGFP and AVV-TeNOS were injected in the nervous system, eGFP and TeNOS were expressed in glia and endothelial cells 7 days after transduction; expression diminished greatly at 14 days after vector injection (Waki et al, 2006). Therefore, a single intranerve injection of AVV-TeNOS could be expected to provide effective chronic inhibition of eNOS for at least 1 week in the transduced cells.…”

Transcriptome analysis of nicotine-exposed cells from the brainstem of neonate spontaneously hypertensive and Wistar Kyoto rats

“…[19][20][21] High-density oligoarrays allow the simultaneous measurement of global gene expression levels and is a valuable tool to study pathologies associated to the central nervous system. [22][23][24] In this study, we aimed to evaluate the effects of nicotine exposure on gene expression of cultured neurons and glia from pons and medulla oblongata of newborn SHR and WKY rats using whole-genome oligoarrays.…”