Antiarrhythmic and Inotropic Effects of Selective Na+/Ca2+ Exchanger Inhibition: What Can We Learn from the Pharmacological Studies?

Life-long stable heart function requires a critical balance of intracellular Ca2+. Several ion channels and pumps cooperate in a complex machinery that controls the influx, release, and efflux of Ca2+. Probably one of the most interesting and most complex players of this crosstalk is the Na+/Ca2+ exchanger, which represents the main Ca2+ efflux mechanism; however, under some circumstances, it can also bring Ca2+ into the cell. Therefore, the inhibition of the Na+/Ca2+ exchanger has emerged as one of the most promising possible pharmacological targets to increase Ca2+ levels, to decrease arrhythmogenic depolarizations, and to reduce excessive Ca2+ influx. In line with this, as a response to increasing demand, several more or less selective Na+/Ca2+ exchanger inhibitor compounds have been developed. In the past 20 years, several results have been published regarding the effect of Na+/Ca2+ exchanger inhibition under various circumstances, e.g., species, inhibitor compounds, and experimental conditions; however, the results are often controversial. Does selective Na+/Ca2+ exchanger inhibition have any future in clinical pharmacological practice? In this review, the experimental results of Na+/Ca2+ exchanger inhibition are summarized focusing on the data obtained by novel highly selective inhibitors

Entropy and Hausdorff Dimension in Random Growing Trees

We investigate the limiting behavior of random tree growth in preferential attachment models. The tree stems from a root, and we add vertices to the system one-by-one at random, according to a rule which depends on the degree distribution of the already existing tree. The so-called weight function, in terms of which the rule of attachment is formulated, is such that each vertex in the tree can have at most K children. We define the concept of a certain random measure mu on the leaves of the limiting tree, which captures a global property of the tree growth in a natural way. We prove that the Hausdorff and the packing dimension of this limiting measure is equal and constant with probability one. Moreover, the local dimension of mu equals the Hausdorff dimension at mu-almost every point. We give an explicit formula for the dimension, given the rule of attachment

Laminar analysis of the slow wave activity in the somatosensory cortex of anesthetized rats.

Rhythmic slow waves characterize brain electrical activity during natural deep sleep and under anesthesia, reflecting the synchronous membrane potential fluctuations of neurons in the thalamocortical network. Strong evidence indicates that the neocortex plays an important role in the generation of slow wave activity (SWA), however, contributions of individual cortical layers to the SWA generation are still unclear. The anatomically correct laminar profiles of SWA were revealed under ketamine/xylazine anesthesia, with combined local field potential recordings, multiple-unit activity (MUA), current source density (CSD) and time-frequency analyses precisely co-registered with histology. The up-state related negative field potential wave showed the largest amplitude in layer IV, the CSD was largest in layers I and III, while MUA was maximal in layer V, suggesting spatially dissociated firing and synaptic/transmembrane processes in the rat somatosensory cortex. Up-state related firing could start in virtually any layers (III-VI) of the cortex, but were most frequently initiated in layer V. However, in a subset of experiments, layer IV was considerably active in initiating up-state related MUA even in the absence of somatosensory stimulation. Somatosensory stimulation further strengthened up-state initiation in layer IV. Our results confirm that cortical layer V firing may have a major contribution to the up-state generation of ketamine/xylazine-induced SWA, however, thalamic influence through the thalamorecipient layer IV can also play an initiating role, even in the absence of sensory stimulation. This article is protected by copyright. All rights reserved

Herpesvirus-mediated delivery of a genetically encoded fluorescent Ca2+ sensor to canine cardiomyocytes

We report the development and application of a pseudorabies virus-based system for delivery of troponeon, a fluorescent Ca2+ sensor to adult canine cardiomyocytes. The efficacy of transduction was assessed by calculating the ratio of fluorescently labelled and nonlabelled cells in cell culture. Interaction of the virus vector with electrophysiological properties of cardiomyocytes was evaluated by the analysis of transient outward current (Ito), kinetics of the intracellular Ca2+ transients, and cell shortening. Functionality of transferred troponeon was verified by FRET analysis. We demonstrated that the transfer efficiency of troponeon to cultured adult cardiac myocytes was virtually 100%. We showed that even after four days neither the amplitude nor the kinetics of the Ito current was significantly changed and no major shifts occurred in parameters of [Ca2+]i transients. Furthermore, we demonstrated that infection of cardiomyocytes with the virus did not affect the morphology, viability, and physiological attributes of cells

The potential use of the Penicillium chrysogenum antifungal protein PAF, the designed variant PAFopt and its γ-core peptide Pγopt in plant protection

The prevention of enormous crop losses caused by pesticide-resistant fungi is a serious challenge in agriculture. Application of alternative fungicides, such as antifungal proteins and peptides, provides a promising basis to overcome this problem; however, their direct use in fields suffers limitations, such as high cost of production, low stability, narrow antifungal spectrum and toxicity on plant or mammalian cells. Recently, we demonstrated that a Penicillium chrysogenum-based expression system provides a feasible tool for economic production of P. chrysogenum antifungal protein (PAF) and a rational designed variant (PAFopt ), in which the evolutionary conserved γ-core motif was modified to increase antifungal activity. In the present study, we report for the first time that γ-core modulation influences the antifungal spectrum and efficacy of PAF against important plant pathogenic ascomycetes, and the synthetic γ-core peptide Pγopt , a derivative of PAFopt , is antifungal active against these pathogens in vitro. Finally, we proved the protective potential of PAF against Botrytis cinerea infection in tomato plant leaves. The lack of any toxic effects on mammalian cells and plant seedlings, as well as the high tolerance to harsh environmental conditions and proteolytic degradation further strengthen our concept for applicability of these proteins and peptide in agriculture

Effect of Apabetalone on Cardiovascular Events in Diabetes, CKD, and Recent Acute Coronary Syndrome: Results from the BETonMACE Randomized Controlled Trial

CKD and type 2 diabetes mellitus interact to increase the risk of major adverse cardiovascular events (i.e., cardiovascular death, nonfatal myocardial infarction, or stroke) and congestive heart failure. A maladaptive epigenetic response may be a cardiovascular risk driver and amenable to modification with apabetalone, a selective modulator of the bromodomain and extraterminal domain transcription system. We examined this question in a prespecified analysis of BETonMACE, a phase 3 trial.BETonMACE was an event-driven, randomized, double-blind, placebo-controlled trial comparing effects of apabetalone versus placebo on major adverse cardiovascular events and heart failure hospitalizations in 2425 participants with type 2 diabetes and a recent acute coronary syndrome, including 288 participants with CKD with eGFR <60 ml/min per 1.73 m2 at baseline. The primary end point in BETonMACE was the time to the first major adverse cardiovascular event, with a secondary end point of time to hospitalization for heart failure.Median follow-up was 27 months (interquartile range, 20-32 months). In participants with CKD, apabetalone compared with placebo was associated with fewer major adverse cardiovascular events (13 events in 124 patients [11%] versus 35 events in 164 patients [21%]; hazard ratio, 0.50; 95% confidence interval, 0.26 to 0.96) and fewer heart failure-related hospitalizations (three hospitalizations in 124 patients [3%] versus 14 hospitalizations in 164 patients [9%]; hazard ratio, 0.48; 95% confidence interval, 0.26 to 0.86). In the non-CKD group, the corresponding hazard ratio values were 0.96 (95% confidence interval, 0.74 to 1.24) for major adverse cardiovascular events, and 0.76 (95% confidence interval, 0.46 to 1.27) for heart failure-related hospitalization. Interaction of CKD on treatment effect was P=0.03 for major adverse cardiovascular events, and P=0.12 for heart failure-related hospitalization. Participants with CKD showed similar numbers of adverse events, regardless of randomization to apabetalone or placebo (119 [73%] versus 88 [71%] patients), and there were fewer serious adverse events (29% versus 43%; P=0.02) in the apabetalone group.Apabetalone may reduce the incidence of major adverse cardiovascular events in patients with CKD and type 2 diabetes who have a high burden of cardiovascular disease