Estrogen-dependent KCa1.1 modulation is essential for retaining neuroexcitation of female-specific subpopulation of myelinated Ah-type baroreceptor neurons in rats.

Female-specific subpopulation of myelinated Ah-type baroreceptor neurons (BRNs) in nodose ganglia is the neuroanatomical base of sexual-dimorphic autonomic control of blood pressure regulation, and KCa1.1 is a key player in modulating the neuroexcitation in nodose ganglia. In this study we investigated the exact mechanisms underlying KCa1.1-mediated neuroexcitation of myelinated Ah-type BRNs in the presence or absence of estrogen. BRNs were isolated from adult ovary intact (OVI) or ovariectomized (OVX) female rats, and identified electrophysiologically and fluorescently. Action potential (AP) and potassium currents were recorded using whole-cell recording. Consistently, myelinated Ah-type BRNs displayed a characteristic discharge pattern and significantly reduced excitability after OVX with narrowed AP duration and faster repolarization largely due to an upregulated iberiotoxin (IbTX)-sensitive component; the changes in AP waveform and repetitive discharge of Ah-types from OVX female rats were reversed by G1 (a selective agonist for estrogen membrane receptor GPR30, 100 nM) and/or IbTX (100 nM). In addition, the effect of G1 on repetitive discharge could be completely blocked by G15 (a selective antagonist for estrogen membrane receptor GPR30, 3 µM). These data suggest that estrogen deficiency by removing ovaries upregulates KCa1.1 channel protein in Ah-type BRNs, and subsequently increases AP repolarization and blunts neuroexcitation through estrogen membrane receptor signaling. Intriguingly, this upregulated KCa1.1 predicted electrophysiologically was confirmed by increased mean fluorescent intensity that was abolished by estrogen treatment. These electrophysiological findings combined with immunostaining and pharmacological manipulations reveal the crucial role of KCa1.1 in modulation of neuroexcitation especially in female-specific subpopulation of myelinated Ah-type BRNs and extend our current understanding of sexual dimorphism of neurocontrol of BP regulation.

FGF-21 ameliorates essential hypertension of SHR via baroreflex afferent function.

Hypertension is a common complication of metabolic abnormalities associated with cardiovascular system and characterized by sexual dimorphism in mammals. Fibroblast growth factor-21 (FGF-21) plays a critical role in metabolic-disorder related hypertension through the afferent loop of baroreflex. However, the gender difference in FGF-21-mediated blood pressure (BP) regulation via sexual dimorphic expression of FGFRs in the nodose (NG) and nucleus tractus solitarius (NTS) were not elucidated in physiological and genomic form of hypertension. The gene and protein expression of FGFRs were tested by qRT-PCR, immunoblotting and immunostaining; the serum level of FGF21 was tested using ELISA; The BP was monitored while FGF21 was nodose microinjected. The results showed that more potent BP reduction was confirmed in female vs. male rats by nodose microinjection of rhFGF-21 along with higher expression of FGFR2 and FGFR4 in the nodose compared with age-match male and ovariectomized (OVX) rats, rather than other receptor subtypes, which is consistent well with immunohistochemical analysis. Additionally, serum FGF-21 was significantly higher in female-WKY, and this level of FGF-21 was dramatically declined in spontaneous hypertensive rats (SHR) with significant down-regulation of FGFR1/R4 for male-SHR and FGFR2/FGFR4 for female-SHR, respectively. Apparently, high BP of SHR of either sex could be reduced by rhFGF-21 nodose microinjection. These data extends our current understanding that sexual-specific distribution/expression of FGF-21/FGFRs is likely to contribute at least partially to sexual dimorphism of baroreflex afferent function on BP regulation in rats. FGF-21-mdiated BP reduction sheds new light on clinical management of primary/genomic form of hypertension.

Contribution of Baroreflex Afferent Pathway to NPY-Mediated Regulation of Blood Pressure in Rats.

Neuropeptide Y (NPY), a metabolism-related cardiovascular factor, plays a crucial role in blood pressure (BP) regulation via peripheral and central pathways. The expression of NPY receptors (Y1R/Y2R) specific to baroreflex afferents impacts on the sexually dimorphic neural control of circulation. This study was designed to investigate the expression profiles of NPY receptors in the nodose ganglion (NG) and nucleus tractus solitary (NTS) under hypertensive conditions. To this end, rats with hypertension induced by NG-nitro-L-arginine methylester (L-NAME) or high fructose drinking (HFD), and spontaneously hypertensive rats (SHRs) were used to explore the effects/mechanisms of NPY on BP using functional, molecular, and electrophysiological approaches. The data showed that BP was elevated along with baroreceptor sensitivity dysfunction in model rats; Y1R was up- or down-regulated in the NG or NTS of male and female HFD/L-NAME groups, while Y2R was only down-regulated in the HFD groups as well as in the NG of the male L-NAME group. In SHRs, Y1R and Y2R were both down-regulated in the NTS, and not in the NG. In addition to NPY-mediated energy homeostasis, leptin-melanocortin activation may be essential for metabolic disturbance-related hypertension. We found that leptin and α-melanocyte stimulating hormone (α-MSH) receptors were aberrantly down-regulated in HFD rats. In addition, α-MSH concentrations were reduced and NPY concentrations were elevated in the serum and NTS at 60 and 90 min after acute leptin infusion. Electrophysiological recordings showed that the decay time-constant and area under the curve of excitatory post-synaptic currents were decreased by Y1R activation in A-types, whereas, both were increased by Y2R activation in Ah- or C-types. These results demonstrate that sex- and afferent-specific NPY receptor expression in the baroreflex afferent pathway is likely to be a novel target for the clinical management of metabolism-related and essential hypertension.

Direct activation of tachykinin receptors within baroreflex afferent pathway and neurocontrol of blood pressure regulation.

AIM: Substance P (SP) causes vasodilation and blood pressure (BP) reduction. However, the involvement of tachykinin receptors (NKRs) within baroreflex afferent pathway in SP-mediated BP regulation is largely unknown. METHODS: Under control and hypertensive condition, NKRs' expressions were evaluated in nodose (NG) and nucleus of tractus solitary (NTS) of male, female, and ovariectomized (OVX) rats; BP was recorded after microinjection of SP and NKRs agonists into NG; Baroreceptor sensitivity (BRS) was tested as well. RESULTS: Immunostaining and immunoblotting data showed that NK1R and NK2R were estrogen-dependently expressed on myelinated and unmyelinated afferents in NG. A functional study showed that BP was reduced dose-dependently by SP microinjection, which was more dramatic in males and can be mimicked by NK1R and NK2R agonists. Notably, further BP elevation and BRS dysfunction were confirmed in desoxycorticosterone acetate (DOCA)-salt model in OVX compared with DOCA-salt model in intact female rats. Additionally, similar changes in NKRs' expression in NG were also detected using DOCA-salt and SHR. Compared with NG, inversed expression profiles of NKRs were also found in NTS with either gender. CONCLUSION: The estrogen-dependent NKRs' expression in baroreflex afferent pathway participates at least partially in sexual-dimorphic and SP-mediated BP regulation under physiological and hypertensive conditions.

Parity-time symmetry in periodically curved optical waveguides.

The coupling strength between two parity-time (PT) symmetric resonators determines whether the PT phase is broken or not. Here we investigate the scenario that two optical waveguides are spatially curved so that they switch periodically between unbroken and broken PT phases. We show that the existence of locally broken PT phase does not necessarily render a broken phase to waves propagating inside. Criteria are proposed to characterize the collective dynamics of wave near the Brillouin zone (BZ) edge, toward the cases of a totally broken phase, a partially broken phase, or a totally unbroken phase. We also discuss the characteristics of two special kinds of exceptional points (EPs) at the BZ edge, and show that their field patterns are displaced by half a period with each other. Full-wave numerical simulation proves our analysis. Potential applications especially these associated with EPs are discussed. This study helps us to understand how the locally PT-symmetric related eigenstate influences the globally collective dynamics of wave in spatially periodic configuration.

Spontaneous activities in baroreflex afferent pathway contribute dominant role in parasympathetic neurocontrol of blood pressure regulation.

AIM: To study the dominant role of parasympathetic inputs at cellular level of baroreflex afferent pathway and underlying mechanism in neurocontrol of blood pressure regulation. METHODS: Whole-cell patch-clamp and animal study were conducted. RESULTS: For the first time, we demonstrated the spontaneous activities from resting membrane potential in myelinated A- and Ah-type baroreceptor neurons (BRNs, the 1st-order), but not in unmyelinated C-types, using vagus-nodose slice of adult female rats. These data were further supported by the notion that the spontaneous synaptic currents could only be seen in the pharmacologically and electrophysiologically defined myelinated A- and Ah-type baroreceptive neurons (the 2nd-order) of NTS using brainstem slice of adult female rats. The greater frequency and the larger amplitude of the spontaneous excitatory postsynaptic currents (EPSCs) compared with the inhibitory postsynaptic currents (IPSCs) were only observed in Ah-types. The ratio of EPSCs:IPSCs was estimated at 3:1 and higher. These results confirmed that the afferent-specific spontaneous activities were generated from baroreflex afferent pathway in female-specific subpopulation of myelinated Ah-type BRNs in nodose and baroreceptive neurons in NTS, which provided a novel insight into the dominant role of sex-specific baroreflex-evoked parasympathetic drives in retaining a stable and lower blood pressure status in healthy subjects, particularly in females. CONCLUSION: The data from current investigations establish a new concept for the role of Ah-type baroreceptor/baroreceptive neurons in controlling blood pressure stability and provide a new pathway for pharmacological intervention for hypertension and cardiovascular diseases.

Unidirectional Excitation of Radiative-Loss-Free Surface Plasmon Polaritons in PT-Symmetric Systems.

We investigate the excitation and propagation of surface plasmon polaritons (SPPs) at a geometrically flat metal-dielectric interface with a parity-time (PT) symmetric modulation on the permittivity ϵ(x) of the dielectric medium. We show that two striking effects can be simultaneously achieved thanks to the nonreciprocal nature of the Bloch modes in the system. First, SPPs can be unidirectionally excited when light is normally incident on the interface. Secondly, the backscattering of SPPs into the far field is suppressed, producing a radiative-loss-free effect on the unidirectional SPPs. As a result, the lifetime and propagation distance of SPPs can be significantly improved. These results show that PT symmetry can be employed as a new approach to designing transformative nanoscale optical devices, such as low-loss plasmonic routers and isolators for efficient optical computation, communication, and information processing.

Coherent-trapped helical mode in parity-time symmetric metamaterials.

Coaxial optical subwavelength elements support helical modes Lm with different topological indexes m. Here we propose to couple the two bright L±1 modes with the dark one L0 via a parity-time (PT) symmetric perturbation. We show that the cascading coupled configuration is similar to a three-level atomic system, and supports a special hybridized mode Lc via a classic analog of coherent-population-trapping effect. Resonant frequency of Lc is independent of the PT-symmetric perturbation. Populations in L±1 can be manipulated by tuning the PT-symmetric perturbation, and no population is trapped in L0. Since the L±1 modes are associated with optical waves of opposite circular polarizations, the polarization of transmitted wave is independent of the polarization of incidence but solely determined by the PT-symmetric perturbation. Such an effect can be utilized to manipulate the polarization state of light. Numerical simulation in a well-designed coaxial metamaterial verifies our analysis.

Localization and oscillation of optical beams in Moiré lattices.

We study the propagation of optical beams in two-dimensional Moiré lattices, and demonstrate position-dependent beam dynamics when a quasi-Bragg condition is satisfied. We show that when the optical beam is incident to a peak of the lattice envelop, an optical Zitterbewegung is obtained. If the optical beam is incident to a node of the envelop, a field localization effect takes place. The localized beam oscillates with a much larger spatial period than that of the optical Zitterbewegung. Variation of the oscillation period versus the split in periods is discussed. The position-dependent beam dynamics are explained by the excitation of proper bandedge eigenmodes of the Moiré lattice, and can be engineered via tuning the periods of the two superimposed Bragg lattices.

Neuropeptide Y-mediated sex- and afferent-specific neurotransmissions contribute to sexual dimorphism of baroreflex afferent function.

BACKGROUND: Molecular and cellular mechanisms of neuropeptide-Y (NPY)-mediated gender-difference in blood pressure (BP) regulation are largely unknown. METHODS: Baroreceptor sensitivity (BRS) was evaluated by measuring the response of BP to phenylephrine/nitroprusside. Serum NPY concentration was determined using ELISA. The mRNA and protein expression of NPY receptors were assessed in tissue and single-cell by RT-PCR, immunoblot, and immunohistochemistry. NPY was injected into the nodose while arterial pressure was monitored. Electrophysiological recordings were performed on nodose neurons from rats by patch-clamp technique. RESULTS: The BRS was higher in female than male and ovariectomized rats, while serum NPY concentration was similar among groups. The sex-difference was detected in Y1R, not Y2R protein expression, however, both were upregulated upon ovariectomy and canceled by estrogen replacement. Immunostaining confirmed Y1R and Y2R expression in myelinated and unmyelinated afferents. Single-cell PCR demonstrated that Y1R expression/distribution was identical between A- and C-types, whereas, expressed level of Y2R was ~15 and ~7 folds higher in Ah- and C-types than A-types despite similar distribution. Activation of Y1R in nodose elevated BP, while activation of Y2R did the opposite. Activation of Y1R did not alter action potential duration (APD) of A-types, but activation of Y2R- and Y1R/Y2R in Ah- and C-types frequency-dependently prolonged APD. N-type ICa was reduced in A-, Ah- and C-types when either Y1R, Y2R, or both were activated. The sex-difference in Y1R expression was also observed in NTS. CONCLUSIONS: Sex- and afferent-specific expression of Neuropeptide-Y receptors in baroreflex afferent pathway may contribute to sexual-dimorphic neurocontrol of BP regulation.

FGF21 ameliorates the neurocontrol of blood pressure in the high fructose-drinking rats.

Fibroblast growth factor-21 (FGF21) is closely related to various metabolic and cardiovascular disorders. However, the direct targets and mechanisms linking FGF21 to blood pressure control and hypertension are still elusive. Here we demonstrated a novel regulatory function of FGF21 in the baroreflex afferent pathway (the nucleus tractus solitarii, NTS; nodose ganglion, NG). As the critical co-receptor of FGF21, ß-klotho (klb) significantly expressed on the NTS and NG. Furthermore, we evaluated the beneficial effects of chronic intraperitoneal infusion of recombinant human FGF21 (rhFGF21) on the dysregulated systolic blood pressure, cardiac parameters, baroreflex sensitivity (BRS) and hyperinsulinemia in the high fructose-drinking (HFD) rats. The BRS up-regulation is associated with Akt-eNOS-NO signaling activation in the NTS and NG induced by acute intravenous rhFGF21 administration in HFD and control rats. Moreover, the expressions of FGF21 receptors were aberrantly down-regulated in HFD rats. In addition, the up-regulated peroxisome proliferator-activated receptor-γ and -α (PPAR-γ/-α) in the NTS and NG in HFD rats were markedly reversed by chronic rhFGF21 infusion. Our study extends the work of the FGF21 actions on the neurocontrol of blood pressure regulations through baroreflex afferent pathway in HFD rats.

Unique Expression of Angiotensin Type-2 Receptor in Sex-Specific Distribution of Myelinated Ah-Type Baroreceptor Neuron Contributing to Sex-Dimorphic Neurocontrol of Circulation.

This study aims to understand the special expression patterns of angiotensin-II receptor (AT1R and AT2R) in nodose ganglia and nucleus of tractus solitary of baroreflex afferent pathway and their contribution in sex difference of neurocontrol of blood pressure regulation. In this regard, action potentials were recorded in baroreceptor neurons (BRNs) using whole-cell patch techniques; mRNA and protein expression of AT1R and AT2R in nodose ganglia and nucleus of tractus solitary were evaluated using real time-polymerase chain reaction, Western blot, and immunohistochemistry at both tissue and single-cell levels. The in vivo effects of 17ß-estradiol on blood pressure and AT2R expression were also tested. The data showed that AT2R, rather than AT1R, expression was higher in female than age-matched male rats. Moreover, AT2R was downregulated in ovariectomized rats, which was restored by the administration of 17ß-estradiol. Single-cell real time-polymerase chain reaction data indicated that AT2R was uniquely expressed in Ah-type BRNs. Functional study showed that long-term administration of 17ß-estradiol significantly alleviated the blood pressure increase in ovariectomized rats. Electrophysiological recordings showed that angiotensin-II treatment increased the neuroexcitability more in Ah- than C-type BRNs, whereas no such effect was observed in A-types. In addition, angiotensin-II treatment prolonged action potential duration, which was not further changed by iberiotoxin. The density of angiotensin-II-sensitive K(+) currents recorded in Ah-types was equivalent with iberiotoxin-sensitive component. In summary, the unique, sex- and afferent-specific expression of AT2R was identified in Ah-type BRNs, and AT2R-mediated KCa1.1 inhibition in Ah-type BRNs may exert great impacts on baroreflex afferent function and blood pressure regulation in females.

Ketamine-mediated afferent-specific presynaptic transmission blocks in low-threshold and sex-specific subpopulation of myelinated Ah-type baroreceptor neurons of rats.

BACKGROUND: Ketamine enhances autonomic activity, and unmyelinated C-type baroreceptor afferents are more susceptible to be blocked by ketamine than myelinated A-types. However, the presynaptic transmission block in low-threshold and sex-specific myelinated Ah-type baroreceptor neurons (BRNs) is not elucidated.  METHODS: Action potentials (APs) and excitatory post-synaptic currents (EPSCs) were investigated in BRNs/barosensitive neurons identified by conduction velocity (CV), capsaicin-conjugated with Iberiotoxin-sensitivity and fluorescent dye using intact nodose slice and brainstem slice in adult female rats. The expression of mRNA and targeted protein for NMDAR1 was also evaluated.  RESULTS: Ketamine time-dependently blocked afferent CV in Ah-types in nodose slice with significant changes in AP discharge. The concentration-dependent inhibition of ketamine on AP discharge profiles were also assessed and observed using isolated Ah-type BRNs with dramatic reduction in neuroexcitability. In brainstem slice, the 2nd-order capsaicin-resistant EPSCs were identified and ~50% of them were blocked by ketamine concentration-dependently with IC50 estimated at 84.4 µM compared with the rest (708.2 µM). Interestingly, the peak, decay time constant, and area under curve of EPSCs were significantly enhanced by 100 nM iberiotoxin in ketamine-more sensitive myelinated NTS neurons (most likely Ah-types), rather than ketamine-less sensitive ones (A-types).  CONCLUSIONS: These data have demonstrated, for the first time, that low-threshold and sex-specific myelinated Ah-type BRNs in nodose and Ah-type barosensitive neurons in NTS are more susceptible to ketamine and may play crucial roles in not only mean blood pressure regulation but also buffering dynamic changes in pressure, as well as the ketamine-mediated cardiovascular dysfunction through sexual-dimorphic baroreflex afferent pathway.