Lean and Obese Coronary Perivascular Adipose Tissue Impairs Vasodilation via Differential Inhibition of Vascular Smooth Muscle K+ Channels

OBJECTIVE: The effects of coronary perivascular adipose tissue (PVAT) on vasomotor tone are influenced by an obese phenotype and are distinct from other adipose tissue depots. The purpose of this investigation was to examine the effects of lean and obese coronary PVAT on end-effector mechanisms of coronary vasodilation and to identify potential factors involved. APPROACH AND RESULTS: Hematoxylin and eosin staining revealed similarities in coronary perivascular adipocyte size between lean and obese Ossabaw swine. Isometric tension studies of isolated coronary arteries from Ossabaw swine revealed that factors derived from lean and obese coronary PVAT attenuated vasodilation to adenosine. Lean coronary PVAT inhibited K(Ca) and KV7, but not KATP channel-mediated dilation in lean arteries. In the absence of PVAT, vasodilation to K(Ca) and KV7 channel activation was impaired in obese arteries relative to lean arteries. Obese PVAT had no effect on K(Ca) or KV7 channel-mediated dilation in obese arteries. In contrast, obese PVAT inhibited KATP channel-mediated dilation in both lean and obese arteries. The differential effects of obese versus lean PVAT were not associated with changes in either coronary KV7 or K(ATP) channel expression. Incubation with calpastatin attenuated coronary vasodilation to adenosine in lean but not in obese arteries. CONCLUSIONS: These findings indicate that lean and obese coronary PVAT attenuates vasodilation via inhibitory effects on vascular smooth muscle K(+) channels and that alterations in specific factors such as calpastatin are capable of contributing to the initiation or progression of smooth muscle dysfunction in obesity

Contribution of hydrogen sulfide to the control of coronary blood flow

This study examined the mechanisms by which H2S modulates coronary microvascular resistance and myocardial perfusion at rest and in response to cardiac ischemia. Experiments were conducted in isolated coronary arteries and in open-chest anesthetized dogs. We found that the H2S substrate L-cysteine (1-10 mM) did not alter coronary tone of isolated arteries in vitro or coronary blood flow in vivo. In contrast, intracoronary (ic) H2S (0.1-3 mM) increased coronary flow from 0.49 ± 0.08 to 2.65 ± 0.13 ml/min/g (P□0.001). This increase in flow was unaffected by inhibition of Kv channels with 4-aminopyridine (P=0.127) but was attenuated (0.23 ± 0.02 to 1.13 ± 0.13 ml/min/g) by the KATP channel antagonist glibenclamide (P□0.001). Inhibition of NO synthesis (L-NAME) did not attenuate coronary responses to H2S. Immunohistochemistry revealed expression of cystathionine gamma-lyase (CSE), an endogenous H2S enzyme, in myocardium. Inhibition of CSE with β-cyano-L-alanine (10 µM) had no effect on baseline coronary flow or responses to a 15 sec coronary occlusion (P=0.82). These findings demonstrate that exogenous H2S induces potent, endothelial-independent dilation of the coronary microcirculation predominantly through the activation of KATP channels, however, our data do not support a functional role for endogenous H2S in the regulation of coronary microvascular resistance

Biphasic alterations in coronary smooth muscle Ca2+ regulation in a repeat cross-sectional study of coronary artery disease severity in metabolic syndrome

BACKGROUND AND AIMS: Coronary artery disease (CAD) is progressive, classified by stages of severity. Alterations in Ca(2+) regulation within coronary smooth muscle (CSM) cells in metabolic syndrome (MetS) have been observed, but there is a lack of data in relatively early (mild) and late (severe) stages of CAD. The current study examined alterations in CSM Ca(2+) regulation at several time points during CAD progression. METHODS: MetS was induced by feeding an excess calorie atherogenic diet for 6, 9, or 12 months and compared to age-matched lean controls. CAD was measured with intravascular ultrasound (IVUS). Intracellular Ca(2+) was assessed with fura-2. RESULTS: IVUS revealed that the extent of atherosclerotic CAD correlated with the duration on atherogenic diet. Fura-2 imaging of intracellular Ca(2+) in CSM cells revealed heightened Ca(2+) signaling at 9 months on diet, compared to 6 and 12 months, and to age-matched lean controls. Isolated coronary artery rings from swine fed for 9 months followed the same pattern, developing greater tension to depolarization, compared to 6 and 12 months (6 months = 1.8 ± 0.6 g, 9 months = 5.0 ± 1.0 g, 12 months = 0.7 ± 0.1 g). CSM in severe atherosclerotic plaques showed dampened Ca(2+) regulation and decreased proliferation compared to CSM from the wall. CONCLUSIONS: These CSM Ca(2+) regulation data from several time points in CAD progression and severity help to resolve the controversy regarding up-vs. down-regulation of CSM Ca(2+) regulation in previous reports. These data are consistent with the hypothesis that alterations in sarcoplasmic reticulum Ca(2+) contribute to progression of atherosclerotic CAD in MetS

Mechanisms underlying capsaicin effects in canine coronary artery: implications for coronary spasm

AIMS: The TRPV1, transient receptor potential vanilloid type 1, agonist capsaicin is considered to be beneficial for cardiovascular health because it dilates coronary arteries through an endothelial-dependent mechanism and may slow atheroma progression. However, recent reports indicate that high doses of capsaicin may constrict coronary arterioles and even provoke myocardial infarction. Thus far, the mechanisms by which TRPV1 activation modulates coronary vascular tone remain poorly understood. This investigation examined whether there is a synergistic interplay between locally acting vasoconstrictive pro-inflammatory hormones (autacoids) and capsaicin effects in the coronary circulation. METHODS AND RESULTS: Experiments were performed in canine conduit coronary artery rings and isolated smooth muscle cells (CASMCs). Isometric tension measurements revealed that 1-10 μM capsaicin alone did not affect resting tension of coronary artery rings. In contrast, in endothelium-intact rings pre-contracted with a Gq/11-coupled FP/TP (prostaglandin F/thromboxane) receptor agonist, prostaglandin F2α (PGF2α; 10 μM), capsaicin first induced transient dilation that was followed by sustained contraction. In endothelium-denuded rings pre-contracted with PGF2α or thromboxane analogue U46619 (1 μM, a TP receptor agonist), capsaicin induced only sustained contraction. Blockers of the TP receptor or TRPV1 significantly inhibited capsaicin effects, but these were still observed in the presence of 50 μM nifedipine and 70 mM KCl. Capsaicin also potentiated 20 mM KCl-induced contractions. Fluorescence imaging experiments in CASMCs revealed that the Gq/11-phospholipase C (PLC)-protein kinase C (PKC) and Ca(2+)-PLC-PKC pathways are likely involved in sensitizing CASMC TRPV1 channels. CONCLUSION: Capsaicin alone does not cause contractions in conduit canine coronary artery; however, pre-treatment with pro-inflammatory prostaglandin-thromboxane agonists may unmask capsaicin's vasoconstrictive potential

The read-across hypothesis and environmental risk assessment of pharmaceuticals

This article is made available through the Brunel Open Access Publishing Fund. Copyright © 2013 American Chemical Society.Pharmaceuticals in the environment have received increased attention over the past decade, as they are ubiquitous in rivers and waterways. Concentrations are in sub-ng to low μg/L, well below acute toxic levels, but there are uncertainties regarding the effects of chronic exposures and there is a need to prioritise which pharmaceuticals may be of concern. The read-across hypothesis stipulates that a drug will have an effect in non-target organisms only if the molecular targets such as receptors and enzymes have been conserved, resulting in a (specific) pharmacological effect only if plasma concentrations are similar to human therapeutic concentrations. If this holds true for different classes of pharmaceuticals, it should be possible to predict the potential environmental impact from information obtained during the drug development process. This paper critically reviews the evidence for read-across, and finds that few studies include plasma concentrations and mode of action based effects. Thus, despite a large number of apparently relevant papers and a general acceptance of the hypothesis, there is an absence of documented evidence. There is a need for large-scale studies to generate robust data for testing the read-across hypothesis and developing predictive models, the only feasible approach to protecting the environment.BBSRC Industrial Partnership Award BB/ I00646X/1 and BBSRC Industrial CASE Partnership Studentship BB/I53257X/1 with AstraZeneca Safety Health and Environment Research Programme

The Astropy Problem

The Astropy Project (http://astropy.org) is, in its own words, "a community effort to develop a single core package for Astronomy in Python and foster interoperability between Python astronomy packages." For five years this project has been managed, written, and operated as a grassroots, self-organized, almost entirely volunteer effort while the software is used by the majority of the astronomical community. Despite this, the project has always been and remains to this day effectively unfunded. Further, contributors receive little or no formal recognition for creating and supporting what is now critical software. This paper explores the problem in detail, outlines possible solutions to correct this, and presents a few suggestions on how to address the sustainability of general purpose astronomical software

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

The Role of Transporters in the Pharmacokinetics of Orally Administered Drugs

Drug transporters are recognized as key players in the processes of drug absorption, distribution, metabolism, and elimination. The localization of uptake and efflux transporters in organs responsible for drug biotransformation and excretion gives transporter proteins a unique gatekeeper function in controlling drug access to metabolizing enzymes and excretory pathways. This review seeks to discuss the influence intestinal and hepatic drug transporters have on pharmacokinetic parameters, including bioavailability, exposure, clearance, volume of distribution, and half-life, for orally dosed drugs. This review also describes in detail the Biopharmaceutics Drug Disposition Classification System (BDDCS) and explains how many of the effects drug transporters exert on oral drug pharmacokinetic parameters can be predicted by this classification scheme

A mitogenomic timetree for Darwin’s enigmatic South American mammal Macrauchenia patachonica

The unusual mix of morphological traits displayed by extinct South American native ungulates (SANUs) confounded both Charles Darwin, who first discovered them, and Richard Owen, who tried to resolve their relationships. Here we report an almost complete mitochondrial genome for the litoptern Macrauchenia. Our dated phylogenetic tree places Macrauchenia as sister to Perissodactyla, but close to the radiation of major lineages within Laurasiatheria. This position is consistent with a divergence estimate of B66 Ma (95% credibility interval, 56.64–77.83 Ma) obtained for the split between Macrauchenia and other Panperissodactyla. Combined with their morphological distinctiveness, this evidence supports the positioning of Litopterna (possibly in company with other SANU groups) as a separate order within Laurasiatheria. We also show that, when using strict criteria, extinct taxa marked by deep divergence times and a lack of close living relatives may still be amenable to palaeogenomic analysis through iterative mapping against more distant relatives