Angiotensin II-mediated vascular brain inflammation emerged as a novel pathophysiological mechanism in neurogenic hypertension. However, the precise underlying mechanisms and functional consequences in relation to blood brain barrier integrity and central angiotensin II actions mediating neurohumoral activation in hypertension are poorly understood. Here, we aimed to determine whether blood brain barrier permeability within critical hypothalamic and brainstem regions involved in neurohumoral regulation was altered during hypertension. Using digital imaging quantification following intravascularly injected fluorescent dyes and immunohistochemistry, we found increased blood brain barrier permeability, along with altered key blood brain barrier protein constituents, in spontaneously hypertensive rats within the hypothalamic paraventricular nucleus, the nucleus of the solitary tract, and the rostral ventrolateral medulla, all critical brain regions known to contribute to neurohumoral activation during hypertension. Blood brain barrier disruption, including increased permeability and down-regulation of constituent proteins, was prevented in spontaneously hypertensive rats treated with the AT1 receptor antagonist Losartan, but not with hydralazine, a direct vasodilator. Importantly, we found circulating angiotensin II to extravasate into these brain regions, co-localizing with neurons and microglial cells. Taken together, our studies reveal a novel angiotensin II-mediated feed-forward mechanism during hypertension, by which circulating angiotensin II evokes increased blood brain barrier permeability, facilitating in turn its access to critical brain regions known to participate in blood pressure regulation.

SUMMARY Although communication between neurons is considered a function of the synapse, neurons also release neurotransmitter from their dendrites. We found that dendritic transmitter release coordinates activity across distinct neuronal populations to generate integrative homeostatic responses. We show that activity-dependent vasopressin release from hypothalamic neuroendocrine neurons in the paraventricular nucleus stimulates neighboring (~100 μm soma-to-soma) presympathetic neurons, resulting in a sympathoexcitatory population response. This interpopulation crosstalk was engaged by an NMDA-mediated increase in dendritic Ca2+, influenced by vasopressin’s ability to diffuse in the extracellular space, and involved activation of CAN channels at the target neurons. Furthermore, we demonstrate that this interpopulation crosstalk plays a pivotal role in the generation of a systemic, polymodal neurohumoral response to a hyperosmotic challenge. Because dendritic release is emerging as a widespread process, our results suggest that a similar mechanism could mediate interpopulation crosstalk in other brain systems, particularly those involved in generating complex behaviors.

Angiotensin II is a key neuropeptide that acting within the brain hypothalamic paraventricular nucleus regulates neurohumoral outflow to the circulation. Moreover, an exacerbated angiotensin II action within the paraventricular nucleus contributes to neurohumoral activation in hypertension. While angiotensin II effects involve changes in paraventricular nucleus neuronal activity, the precise underlying mechanisms, cellular targets, and distribution of angiotensin II receptors within the paraventricular nucleus remain largely unknown. Thus, whether angiotensin II effects involve direct actions on paraventricular neurons, or whether it acts via intermediary cells, such as astrocytes, is still controversial. To address this important gap in our knowledge, we used a multidisciplinary approach combining patch-clamp electrophysiology in presympathetic paraventricular neurons and astrocytes, along with in vivo sympathetic nerve recordings and astrocyte-targeted gene manipulations. We present evidence for a novel mechanism underlying central angiotensin II actions, which involves astrocytes as major intermediary cellular targets. We found that angiotensin II AT1 receptor mRNA is expressed in paraventricular astrocytes. Moreover, we report that AngII inhibited glutamate transporter function, increasing in turn extracellular glutamate levels. This resulted in the activation of neuronal extrasynaptic NMDA-receptors, increased presympathetic neuronal activity, enhanced sympathoexcitatory outflow, and increased blood pressure. Together, our studies support astrocytes as critical intermediary cell types underlying brain angiotensin II regulation of the circulation, and indicate that angiotensin II-mediated neuronal and sympathoexcitatory effects are dependent on a unique neuro-glial signaling modality involving non-synaptic glutamate transmission.

The inhibitory neurotransmitter GABA plays a key role in the modulation of paraventricular nucleus (PVN) neuronal excitability and sympathoexcitatory outflow, under both physiological and pathological conditions. In addition to mediating conventional synaptic transmission (phasic inhibition), GABA A receptors of distinct biophysical, molecular and pharmacological properties have been recently found to underlie a slower, persistent form of inhibition (tonic inhibition). Whether the 'tonic' inhibitory modality is present in presympathetic PVN neurons, and what its role is in modulating their activity is at present unknown. Here, we combined tract-tracing techniques with patch-clamp electrophysiology to address these questions. Recordings obtained from PVN-RVLM (rostral ventrolateral medulla) projecting neurons show that besides blocking GABA A -mediated inhibitory postsynaptic currents (IPSCs, I phasic ), the GABA A receptor blockers bicuculline and picrotoxin caused an outward shift in the holding current (I tonic ). Conversely, the high affinity GABA A blocker gabazine blocked I phasic without affecting I tonic . THIP, a GABA A receptor agonist that preferentially activates δ-over γ-containing receptors, enhanced the magnitude of I tonic . Our results also indicate that during conditions of strong and/or synchronous synaptic activity, I tonic may be activated by spillover of synaptically released GABA. Blockade of I tonic induced membrane depolarization, increased firing activity, and enhanced the input-output function of PVN-RVLM neurons. Altogether, our results support the presence of a persistent GABA A -mediated inhibitory modality in presympathetic PVN neurons, which plays a major role in modulating their excitability and firing activity.

Abstract. Although scrub typhus is uncommon in pregnant women, when present, it can have serious repercussions for the mother and developing fetus. Since it is uncommon, the clinical impact of scrub typhus on pregnancy has not been elucidated and an effective and safe therapeutic regimen has not been validated. The medical records of pregnant women whose scrub typhus were treated at Chungnam National University Hospital were reviewed and their clinical outcomes were evaluated. A review of the literature was also performed on pregnant women with scrub typhus and their clinical outcomes. Eight pregnant women with scrub typhus were treated successfully with a single 500-mg dose of azithromycin, and no relapses were reported. They all delivered healthy babies at term, without congenital or neonatal complications. In the reviews, azithromycin was effective against scrub typhus and had favorable pregnancy outcomes. Ciprofloxacin and cefuroxime failed to treat scrub typhus and fetal loss resulted. A single 500-mg dose of azithromycin may be a reasonable treatment regimen for pregnant women with scrub typhus. Ciprofloxacin might not be advisable for the treatment of scrub typhus during pregnancy. Scrub typhus itself seems to have serious adverse effects on pregnancy if not appropriately controlled.

Neurohumoral activation, a hallmark in heart failure (HF), is linked to the progression and mortality of HF patients. Thus, elucidating its precise underlying mechanisms is of critical importance. Besides its classical peripheral vasodilatory actions, the gas nitric oxide (NO) is a pivotal neurotransmitter in the central nervous system (CNS) control of the circulation. While accumulating evidence supports a contribution of blunted NO function to neurohumoral activation in HF, the precise cellular sources, and NO synthase (NOS) isoforms involved, remain unknown. Here, we used a multidisciplinary approach to study the expression, cellular distribution and functional relevance of the endothelial NOS isoform (eNOS) within the hypothalamic paraventricular (PVN) nucleus in Sham and HF rats. Our results show high expression of eNOS in the PVN (mostly confined to astroglial cells), which contributes to constitutive NO bioavailability, as well as tonic inhibition of presympathetic neuronal activity and sympathoexcitatory outflow from the PVN. A diminished eNOS expression and eNOS-derived NO availability was found in the PVN of HF rats, resulting in turn in blunted NO inhibitory actions on neuronal activity and sympathoexcitatory outflow. Taken together, our study supports blunted CNS eNOS-derived NO as a pathophysiological mechanism underlying neurohumoral activation in HF.

These data provide evidence that APE1/ref-1 in endothelial cells mitigates TNF-alpha-induced monocyte adhesion and expression of vascular cell adhesion molecules, and this anti-adhesive property of APE1/ref-1 is primarily mediated by a NOS-dependent mechanism. Furthermore, APE1/ref-1 may inhibit VCAM-1 expression by inhibiting superoxide production and p38 MAPK activation.

These results suggest that midazolam has an antiinflammatory action by inhibiting inducible nitric oxide synthase and cyclooxygenase-2 expression, possibly through suppression of NF-kappaB and p38 mitogen-activated protein kinase activation.