Estrogen Replacement Reduces Oxidative Stress in the Rostral Ventrolateral Medulla of Ovariectomized Rats.

Cardiovascular disease prevalence rises rapidly after menopause, which is believed to be derived from the loss of estrogen. It is reported that sympathetic tone is increased in postmenopause. The high level of oxidative stress in the rostral ventrolateral medulla (RVLM) contributes to increased sympathetic outflow. The focus of this study was to determine if estrogen replacement reduces oxidative stress in the RVLM and sympathetic outflow in the ovariectomized (OVX) rats. The data of this study showed that OVX rat increased oxidative stress in the RVLM and sympathetic tone; estrogen replacement improved cardiovascular functions but also reduced the level of oxidative stress in the RVLM. These findings suggest that estrogen replacement decreases blood pressure and sympathoexcitation in the OVX rats, which may be associated with suppression in oxidative stress in the RVLM through downregulation of protein expression of NADPHase (NOX4) and upregulation of protein expression of SOD1. The data from this study is beneficial for our understanding of the mechanism of estrogen exerting cardiovascular protective effects on postmenopause.

Losartan reduces oxidative stress within the rostral ventrolateral medulla of rats with renovascular hypertension.

BACKGROUND: Previous studies showed that the microinjection of antioxidants or the overexpression of superoxide dismutase within the rostral ventrolateral medulla (RVLM) reduces hypertension and sympathoexcitation in the 2-kidney, 1-clip (2K-1C) model. In this study, we hypothesized that angiotensin II (ANG II) type 1 receptor (AT1R) is involved in the oxidative stress within the RVLM and contributes to cardiovascular dysfunction in renovascular hypertension. METHODS: Losartan (30mg/kg/day, oral gavage) was administered for 7 consecutive days by week 5 after implantation of the clip (gap width = 0.2mm). Mean arterial pressure, baroreflex, and renal sympathetic nerve activity (rSNA) were evaluated. Superoxide production was evaluated by dihydroethidium (DHE) staining within the RVLM and within a control area. Systemic oxidative stress was characterized by measurement of thiobarbituric acid reactive substances (TBARS) and total glutathione (tGSH) in the blood. RESULTS: AT1R blockade significantly (P < 0.05) reduced hypertension by approximately 20% (n = 11) and sympathoexcitation to the kidneys by approximately 41% (n = 6) in the 2K-1C rats. Losartan treatment increased the baroreflex sensitivity of rSNA to pressor (67%) and depressor (140%) stimuli in the 2K-1C rats. AT1R blockade caused a significant (66%) reduction in DHE staining within the RVLM but not within the control area, reduced plasma TBARS (from 1.6±0.1 to 1.0±0.1 nmol/ml), and increased tGSH (from 3.4±0.4 to 5.2±0.3 µmol/g Hb) in the 2K-1C group only. CONCLUSIONS: Our findings suggest that the beneficial effects of ANG II blockade in renovascular hypertension are partly due to preferential reduction of oxidative stress in the RVLM.

Role of inducible nitric oxide synthase in rostral ventrolateral medulla in blood pressure regulation in spontaneously hypertensive rats.

Nitric oxide (NO) in the brainstem modulates blood pressure (BP). Overexpression of inducible NO synthase (iNOS) in the rostral ventrolateral medulla (RVLM) increases BP in normotensive Wistar-Kyoto rats (WKY), but its role in BP regulation in spontaneously hypertensive rats (SHR) is unknown. We examined iNOS expression and the effect of iNOS inhibitors in the RVLM on BP and heart rate in SHR and WKY. iNOS levels in the RVLM were significantly higher in SHR than in WKY. Bilateral microinjection of aminoguanidine into the RVLM dose-dependently decreased BP and heart rate in SHR, but not in WKY. These findings suggest that iNOS expression in the RVLM of SHR contributes to increase BP.

Involvement of protein kinase A in patterning of the mouse somatosensory cortex.

Patterning of the mouse somatosensory cortex is unusually evident because of the presence of a "barrel field." Presynaptic serotonin and postsynaptic glutamate receptors regulate barrel formation, but little is known of the intracellular signaling pathways through which they act. To determine whether protein kinase A (PKA) plays a role in the development of the barrel field, we examined five viable PKA subunit-specific knock-out (KO) mouse lines for barrel field abnormalities. Barrels are present in these mice, but those lacking the RIIbeta subunit display significantly reduced contrast between the cell densities of barrel hollows and sides compared with wild-type animals. Thalamocortical afferent segregation in the posterior medial barrel subfield appeared normal, suggesting a postsynaptic site of gene action for the RIIbeta protein. Immunoelectron microscopy confirmed that RIIbeta was selectively localized to dendrites and dendritic spines. Mice lacking RIIbeta show reduced glutamate receptor A (GluRA) subunit insertion into the postsynaptic density in postnatal day 7 somatosensory cortex; however, GluRA KO mice developed normal barrels. Our results clearly demonstrate a role for postsynaptic PKA signaling pathways in barrel differentiation. They also demonstrate a clear dissociation between the regulation of GluRA trafficking by PKA and its role in barrel formation. Finally, although a role for PKA downstream of cAMP cannot be ruled out, these data suggest that PKA may not be the principle downstream target because none of the mutants showed a barrelless phenotype similar to that observed in adenylate cyclase type 1 KO mice. These results give insight into activity-dependent mechanisms that regulate barrel formation.

Protein kinase C gamma-like immunoreactivity of trigeminothalamic neurons in the medullary dorsal horn of the rat.

We examined protein kinase C gamma-like immunoreactivity (PKCgamma-LI) of trigeminothalamic neurons in the rat medullary dorsal horn (MDH) after injecting a retrograde tracer, Fluoro-Gold (FG), into the thalamus. Over 90% of FG-labeled neurons in the marginal layer (lamina I) and a few FG-labeled neurons in the superficial part of the magnocellular layer (lamina III) showed PKCgamma-LI. No PKCgamma-neurons in the substantia gelatinosa (lamina II) were labeled with FG. PKCgamma-mediated regulation of trigeminothalamic neurons may contribute to the changes in MDH activity during persistent pain.

Cutaneous receptive field organization in the ventral posterior nucleus of the thalamus in the common marmoset.

The organization of cutaneous receptive fields in the ventroposterior (VP) thalamus of the common marmosets (Callithrix jacchus) was determined from single-unit recordings, and these data were correlated with the cytochrome oxidase (CO) histochemistry of the thalamus in the same animals. Under continuously maintained ketamine anesthesia, the receptive fields of a total of 192 single units were recorded from the right VP thalamus using 2 MOhms glass electrodes. After the receptive fields were mapped, the brains were reacted for CO histochemistry on 50-microm coronal frozen sections through the entire VP thalamus. The majority of units were localized to the CO-reactive regions that define the medial and lateral divisions of VP (VPm and VPl). Apart from the expected finding of the face being represented in VPm and the body in VPl, reconstructing the electrode tracks and unit locations in the histological sections revealed a general association between discrete regions of CO reactivity and the representation of specific body regions. Some low-threshold cutaneous units were apparently localized to VPi (the CO weak regions dorsal, ventral, and interdigitating with, the CO regions of VP). These VPi units were clearly part of the same representational map as the VPl and VPm units. We conclude that the low-threshold cutaneous receptive fields of the marmoset are organized in a single continuous representation of the contralateral body surface, and that this representation can most simply be interpreted as being folded or crumpled into the three-dimensional space of VP thalamus. The folded nature of the body map in VP may be related to the folded nature of VP as revealed by CO histochemistry.