Estrogen-dependent depressor response of melatonin via baroreflex afferent function and intensification of PKC-mediated Nav1.9 activation.

Recent studies suggest that melatonin (Mel) plays an important role in the regulation of blood pressure (BP) via the aortic baroreflex pathway. In this study, we investigated the interaction between the baroreflex afferent pathway and Mel-mediated BP regulation in rats under physiological and hypertensive conditions. Mel (0.1, 0.3, and 1.0 mg/mL) was microinjected into the nodose ganglia (NG) of rats. We showed that Mel-induced reduction of mean arterial pressure in female rats was significantly greater than that in male and in ovariectomized rats under physiological condition. Consistently, the expression of Mel receptors (MTNRs) in the NG of female rats was significantly higher than that of males. In L-NAME-induced hypertensive and spontaneously hypertensive rat models, MTNRs were upregulated in males but downregulated in female models. Interestingly, Mel-induced BP reduction was found in male hypertensive models. In whole-cell recording from identified baroreceptor neurons (BRNs) in female rats, we found that Mel (0.1 µM) significantly increased the excitability of a female-specific subpopulation of Ah-type BRNs by increasing the Nav1.9 current density via a PKC-mediated pathway. Similar results were observed in baroreceptive neurons of the nucleus tractus solitarius, showing the facilitation of spontaneous and evoked excitatory post-synaptic currents in Ah-type neurons. Collectively, this study reveals the estrogen-dependent effect of Mel/MTNRs under physiological and hypertensive conditions is mainly mediated by Ah-type BRNs, which may provide new theoretical basis and strategies for the gender-specific anti-hypertensive treatment in clinical practice.

Parkinson-like early autonomic dysfunction induced by vagal application of DOPAL in rats.

AIM: To understand why autonomic failures, a common non-motor symptom of Parkinson's disease (PD), occur earlier than typical motor disorders. METHODS: Vagal application of DOPAL (3,4-dihydroxyphenylacetaldehyde) to simulate PD-like autonomic dysfunction and understand the connection between PD and cardiovascular dysfunction. Molecular and morphological approaches were employed to test the time-dependent alternation of α-synuclein aggregation and the ultrastructure changes in the heart and nodose (NG)/nucleus tractus solitarius (NTS). RESULTS: Blood pressure (BP) and baroreflex sensitivity of DOPAL-treated rats were significantly reduced accompanied with a time-dependent change in orthostatic BP, consistent with altered echocardiography and cardiomyocyte mitochondrial ultrastructure. Notably, time-dependent and collaborated changes in Mon-/Tri-α-synuclein were paralleled with morphological alternation in the NG and NTS. CONCLUSION: These all demonstrate that early autonomic dysfunction mediated by vagal application of DOPAL highly suggests the plausible etiology of PD initiated from peripheral, rather than central site. It will provide a scientific basis for the prevention and early diagnosis of PD.

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.

Serotonin-Mediated Cardiac Analgesia via Ah-Type Baroreceptor Activation Contributes to Silent Angina and Asymptomatic Infarction.

Silent angina is a critical phenomenon in the clinic and is more commonly associated with women patients suffering from myocardial ischemia. Its underlying cause remains mysterious in medicine. With our recent discovery of female-specific Ah-type baroreceptor neurons (BRNs), we hypothesize that cardiac analgesia is due to the direct activation of Ah-type BRNs by elevated levels of circulating serotonin (5-HT) myocardial infarction (MI) patients. Electromyography and the tail-flick reflex were assessed in control and MI-model rats to evaluate 5-HT-mediated BP regulation as well as peripheral and cardiac nociception. 5-HT or a 5-HT receptor agonist was microinjected into the nodose ganglion to confirm the involvement of the afferent pathway of the baroreflex arc. An inward current was observed in identified BRNs by applying a whole-cell patch-clamp technique in conjunction with qRT-PCR to verify the afferent-specific action of 5-HT and the expression of 5-HT receptors. Although the tail-flick reflex and mean arterial pressure were dramatically reduced in female MI rats with elevated serum 5-HT, intrapericardial capsaicin-evoked muscular discharges were significantly inhibited in comparing with those of males, which were mimicked by microinjection of 5-HT or SR57227A into the nodose. Ah-type BRNs displayed robust inward currents at lower concentrations of 5-HT than the C-type or the A-type, with significantly increased expression and cellular distribution of 5-HT3AR but not 5-HT3BR compared to the A- and C-types. Activation of 5-HT3AR in Ah-type BRNs by 5-HT contributes significantly to cardiac analgesia, which may suggest the pathogenic condition that silent angina occurs mainly in female patients.

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.