Sildenafil therapy for Fetal Cardiovascular Dysfunction during Hypoxic Development: Studies in the chick embryo

Abstract

There is a need for developing clinically translatable therapy for preventing fetal origins of cardiovascular disease in pregnancy complicated by chronic fetal hypoxia. Evidence shows that sildenafil protects placental perfusion and fetal growth. However, whether beneficial effects of sildenafil transcend onto the fetal heart and circulation in complicated development is unknown. We isolated the direct effects of sildenafil on the fetus using the chick embryo and hypothesised that sildenafil also protects fetal cardiovascular function in hypoxic development. Chick embryos (n = 11 per group) were incubated in normoxia or hypoxia (14% O₂) from day 1 and treated with sildenafil (4 mg/kg/day) from day 13 of the 21-day incubation. Hypoxic incubation increased oxidative stress (4-hydroxynoneal, 141.1 ± 17.6% of normoxic control), reduced superoxide dismutase (60.7 ± 6.3%), increased phosphodiesterase type 5 expression (167 ± 13.7%) and decreased nitric oxide bioavailability (54.7 ± 6.1%) in the fetal heart, and promoted peripheral endothelial dysfunction (70.9 ± 5.6 AUC of normoxic control; all P < 0.05). Sildenafil treatment after onset of chronic hypoxia prevented the increase in phosphodiesterase expression (72.5 ± 22.4), protected against oxidative stress (94.7 ± 6.2) and normalised nitric oxide bioavailability (115.6 ± 22.3) in the fetal heart, and restored endothelial function in the peripheral circulation (89.8 ± 2.9). Sildenafil protects the fetal heart and circulation directly in hypoxic development via mechanisms including decreased oxidative stress and enhanced nitric oxide bioavailability. Sildenafil may be a good translational candidate for human antioxidant therapy to prevent fetal origins of cardiovascular dysfunction in adverse pregnancy.

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Differences in TRPC3 and TRPC6 channels assembly in mesenteric vascular smooth muscle cells in essential hypertension

Abstract

Increased vascular tone in essential hypertension involves a sustained rise in total peripheral resistance. A model has been proposed in which the combination of membrane depolarization and higher L-type Ca²⁺ channel activity generates augmented Ca²⁺ influx into vascular smooth muscle cells (VSMCs), contraction and vasoconstriction. The search for culprit ion channels responsible of membrane depolarization has provided several candidates, including members of the TRPC family. TRPC3 and TRPC6 are DAG–activated, non-selective cationic channels contributing to stretch- or agonist-induced depolarization. Conflicting information exists regarding changes in TRPC3/TRPC6 functional expression in hypertension. However, although TRPC3-TRPC6 channels can heteromultimerize, the possibility that differences in their association pattern may change their functional contribution to vascular tone is largely unexplored. We probe this hypothesis using a model of essential hypertension (BPH mice) and its normotensive control (BPN mice). First, non-selective cationic currents through homo and heterotetramers recorded from transfected CHO cells indicated that TRPC currents were sensitive to the selective antagonist Pyr10 only when TRPC6 was present, while intracellular anti-TRPC3 antibody selectively blocked TRPC3-mediated currents. In mesenteric VSMCs, basal and agonist-induced currents were more sensitive to Pyr3 and Pyr10 in BPN cells. Consistently, myography studies showed a larger Pyr3/10-induced vasodilation in BPN mesenteric arteries. mRNA and protein expression data supported changes in TRPC3 and TRPC6 proportion and assembly, with a higher TRPC3 channel contribution in BPH VSMCs which could favour cell depolarization. These differences in functional and pharmacological properties of TRPC3 and TRPC6 channels depending on their assembly could represent novel therapeutical opportunities.

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A unifying hypothesis for M1 muscarinic receptor signalling in pyramidal neurons

Abstract

G_q-coupled muscarinic acetylcholine (ACh) receptors (mAChRs) mediate two distinct electrophysiological responses in cortical pyramidal neurons: transient inhibition driven by calcium-dependent small conductance potassium ("SK") channels, and longer-lasting and voltage-dependent excitation involving non-specific cation channels. Here we examine the interaction of these two cholinergic responses with respect to their contributions to intracellular calcium dynamics, testing the unifying hypothesis that rundown of inhibitory SK responses at resting membrane potentials (RMPs) reflects depletion of intracellular calcium stores, while mAChR-driven excitation acts to refill those stores by promoting voltage-dependent entry of extracellular calcium. We report that fidelity of cholinergic SK responses requires the continued presence of extracellular calcium. Inhibitory responses that diminished after repetitive ACh application at RMPs were immediately rescued by pairing mAChR stimulation with subthreshold depolarization (∼10 mV from RMPs) initiated with variable delay (up to 500 ms) after ACh application, but not by subthreshold depolarization preceding mAChR stimulation. Further, rescued SK responses were time-locked to ACh application, rather than to the timing of subsequent depolarizing steps, suggesting that cholinergic signal transduction itself is not voltage-sensitive, but that depolarization facilitates rapid cycling of extracellular calcium through the endoplasmic reticulum to activate SK channels. Consistent with this prediction, rescue of SK responses by subthreshold depolarization required the presence of extracellular calcium. Our results demonstrate that, in addition to gating calcium-release from intracellular stores, mAChR activation facilitates voltage-dependent refilling of calcium stores, thereby maintaining the ongoing fidelity of SK-mediated inhibition in response to phasic release of ACh.

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A survey of the dose of inhalational agents used to maintain anaesthesia in infants.

BACKGROUND: Various animal studies suggest that currently used anaesthetics are toxic to the developing brain. Many reviews advise that the total anaesthetic drug exposure should be reduced but the dose usually used in clinical practice has not been clearly elucidated. OBJECTIVES: To provide an overview of the dose ranges currently used in clinical practice during the maintenance phase of anaesthesia in infants undergoing anaesthesia for noncardiac surgery and diagnostic procedures. DESIGN: A two-centre mixed prospective (London) and retrospective (Utrecht) observational cohort study. SETTING: Two independent tertiary paediatric referral centres in March and November 2013; Great Ormond Street Hospital (GOSH), London, United Kingdom and Wilhelmina Children's Hospital, University Medical Center Utrecht (UMCU), The Netherlands. PATIENTS: A total of 76 infants were included in the analysis, 38 infants from each hospital. METHODS: Patients from GOSH were matched by procedure, age and weight with patients from the UMCU. The end-tidal concentrations of the inhalational agents were investigated from anaesthetic charts during the maintenance phase and corrected for the age-specific minimal alveolar concentration (MAC), expressed as a percentage from the MAC (%MAC). RESULTS: Three different types of inhalational anaesthetics were used: sevoflurane, desflurane, isoflurane. The mean %MAC was 0.85. No significant differences in %MAC were found between GOSH and the UMCU (P = 0.329); the mean %MAC in GOSH was 0.87 and in the UMCU was 0.82. There was a significant increase in the %MAC in relation to age (slope = 0.036 MAC month-1, P

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A Longitudinal Study of Pre-pregnancy and Pregnancy Risk Factors Associated with Antenatal and Postnatal Symptoms of Depression: Evidence from Growing Up in New Zealand

Abstract

Objectives Antenatal and postnatal depression can lead to poor outcomes for women and their children. The aim of this study was to explore whether risk factors differ for depression symptoms that are present during pregnancy and/or after childbirth. Methods An ethnically and socioeconomically diverse sample of 5301 women completed interviews during the third trimester of pregnancy and 9 months after childbirth. Depression symptoms were measured using the Edinburgh Postnatal Depression Scale (EPDS). Depression symptoms (defined as EPDS >12) among participants and associations with pre-pregnancy and pregnancy maternal characteristics were explored using logistic regression. Results The rate of antenatal depression symptoms (ADS) only was 8.5, 5% of women had depression symptoms at 9 months postpartum (PDS) only and 3% experienced depression symptoms at both time points. Perceived stress and Pacific or Asian ethnicity were risk factors for ADS and PDS. Anxiety during and before pregnancy was a risk factor for ADS only while having a pre-pregnancy diagnosis of depression was a risk factor for PDS only. Having ADS increased the odds ratio of PDS by 1.5 (95% CI 1.01–2.30). Conclusions The results supported evidence from previous longitudinal studies that depression symptoms appear to be higher during pregnancy than in the first year following childbirth. The study found that PDS may often be a continuation or recurrence of ADS.

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Dissociating retrieval interference and reanalysis in the P600 during sentence comprehension

Abstract

We investigated the relative independence of two key processes in language comprehension, as reflected in the P600 ERP component. Numerous studies have linked the P600 to sentence- or message-level reanalysis; however, much research has shown that skilled, cue-based memory retrieval operations are also important to successful language processing. Our goal was to identify whether these cue-based retrieval operations are part of the reanalysis processes indexed by the P600. To this end, participants read sentences that were either grammatical or ungrammatical via subject-verb agreement violations, and in which there was either no possibility for retrieval interference or there was an attractor noun interfering with the computation of subject-verb agreement (e.g., "The slogan on the political poster(s) was/were …"). A stimulus onset asynchrony manipulation (fast, medium, or slow presentation rate) was designed to modulate participants' ability to engage in reanalysis processes. Results showed a reliable attraction interference effect, indexed by reduced behavioral sensitivity to ungrammaticalities and P600 amplitudes when there was an opportunity for retrieval interference, as well as an effect of presentation rate, with reduced behavioral sensitivity and smaller P600 effects at faster presentation rates. Importantly, there was no interaction between the two, suggesting that retrieval interference and sentence-level reanalysis processes indexed by the P600 can be neurocognitively distinct processes.

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I can't wait! Neural reward signals in impulsive individuals exaggerate the difference between immediate and future rewards

Abstract

Waiting for rewards is difficult, and highly impulsive individuals with low self-control have an especially hard time with it. Here, we investigated whether neural responses to rewards in a delayed gratification task predict impulsivity and self-control. The EEG was recorded from participants engaged in a guessing game in which on each trial they could win either a large or small reward, paid either now or after 6 months. Ratings confirmed that participants preferred immediate, large rewards over small, delayed rewards. Electrophysiological reward signals reflecting the difference between immediate and future rewards predicted self-report measures of impulsivity and self-control. Further, these signals were highly reliable across two sessions over a 1-week interval, showing high temporal stability like stable personality traits. These results suggest that greater valuation of immediate rewards causes impulsive individuals to redirect control away from delayed rewards, indicating why it is so hard for them to wait.

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