Showing papers by "David A. Eisner published in 2019"

Calcium Buffering in the Heart in Health and Disease

Abstract: Changes of intracellular Ca2+ concentration regulate many aspects of cardiac myocyte function. About 99% of the cytoplasmic calcium in cardiac myocytes is bound to buffers, and their properties will therefore have a major influence on Ca2+ signaling. This article considers the fundamental properties and identities of the buffers and how to measure them. It reviews the effects of buffering on the systolic Ca2+ transient and how this may change physiologically, and in heart failure and both atrial and ventricular arrhythmias, as well. It is concluded that the consequences of this strong buffering may be more significant than currently appreciated, and a fuller understanding is needed for proper understanding of cardiac calcium cycling and contractility.

Phosphodiesterase 5 inhibition improves contractile function and restores transverse tubule loss and catecholamine responsiveness in heart failure.

Abstract: Heart failure (HF) is characterized by poor survival, a loss of catecholamine reserve and cellular structural remodeling in the form of disorganization and loss of the transverse tubule network. Indeed, survival rates for HF are worse than many common cancers and have not improved over time. Tadalafil is a clinically relevant drug that blocks phosphodiesterase 5 with high specificity and is used to treat erectile dysfunction. Using a sheep model of advanced HF, we show that tadalafil treatment improves contractile function, reverses transverse tubule loss, restores calcium transient amplitude and the heart’s response to catecholamines. Accompanying these effects, tadalafil treatment normalized BNP mRNA and prevented development of subjective signs of HF. These effects were independent of changes in myocardial cGMP content and were associated with upregulation of both monomeric and dimerized forms of protein kinase G and of the cGMP hydrolyzing phosphodiesterases 2 and 3. We propose that the molecular switch for the loss of transverse tubules in HF and their restoration following tadalafil treatment involves the BAR domain protein Amphiphysin II (BIN1) and the restoration of catecholamine sensitivity is through reductions in G-protein receptor kinase 2, protein phosphatase 1 and protein phosphatase 2 A abundance following phosphodiesterase 5 inhibition.

Phosphodiesterase 5 inhibition improves contractile function and restores transverse tubule loss and catecholamine responsiveness in heart failure

Abstract: Heart failure (HF) is characterized by poor survival, a loss of catecholamine reserve and cellular structural remodeling in the form of disorganization and loss of the transverse tubule network. Indeed, survival rates for HF are worse than many common cancers and have not improved over time. Tadalafil is a clinically relevant drug that blocks phosphodiesterase 5 with high specificity and is used to treat erectile dysfunction. Using a sheep model of advanced HF, we show that tadalafil treatment improves contractile function, reverses transverse tubule loss and restores calcium transient amplitude and the hearts response to catecholamines. Accompanying these effects tadalafil treatment normalized BNP mRNA and prevented development of subjective signs of HF. These effects are independent of changes in myocardial cGMP content and are associated with upregulation of both monomeric and dimerized forms of protein kinase G and of the cGMP hydrolyzing phosphodiesterase 2 and 3. We propose that the molecular switch for the loss of transverse tubules in HF and their restoration following tadalafil treatment involves the BAR domain protein Amphiphysin II (BIN1) and the restoration of catecholamine sensitivity is through reductions in G-protein receptor kinase 2, protein phosphatase 1 and protein phosphatase 2A abundance following phosphodiesterase 5 inhibition.

Misleading with citation statistics

Abstract: Citation analysis is now big business, to the point of supporting ‘impact factor mania’ (Casadevall & Fang, 2014). As a consequence of this exaggerated importance being placed on citations as discussed in detail below, many reputable scientific organisations have endorsed the San Francisco declaration (DORA) (2012) to improve the ways in which the output of scientific research is evaluated. Originally Garfield and Sher simply wanted to select the most significant journals to list in Current

Electro-physics-iology Clarified? No Spooky Action Required

Abstract: The letter by Mark Noble (2019) suggests that conventional understanding of electrophysiological phenomena in terms of transmembrane ionmovements is incorrect. He contends that electrons are the true current carriers. Here, we argue that it is his approach that is fundamentally flawed and internally inconsistent. We are surprised that it was accepted for publication in Experimental Physiology. Essentially, Noble was addressing the question, ‘what comprises electric current in bioelectric phenomena?’ Our definitive criticism is that significant free-electron movement in an aqueous ionic medium cannot occur (details below). Noble asserts that ‘electricity is now defined as electrons moving’; not so, because an electric current is no more than the movement of charged particles. Such particles need not be electrons; ions are also charged particles, and movement of either constitutes ‘an electric current’. Electron flow (as conventionally understood current) is restricted to solids, such as metals and semiconductors. Electrophysiological events and phenomena occur at a supramolecular scale, above that of those bio-phenomena of possible quantum relevance that Noble invokes. For the present specific case, standard electrochemistry reveals that the probabilities of free electronpaths between theelements in an aqueous solutionof electrolytes are vanishingly small. Noble argues that the depolarization phase of the action potential is not attributable to cation (Na+) entry but rather results from an outward flow of electrons. This conclusion is counter to an enormous literature. For example, an influx of radioactive Na+ accompanies the action potential in the squid axon and, importantly, the number of ions that enter precisely match the inward current (Bezanilla, Rojas, & Taylor, 1970). Injection of mRNA for the sodium channel into Xenopus oocytes results in a current similar to that seen in native cells (Noda et al., 1986). Finally, the ability of blockers, such as tetrodotoxin, to abolish the action potential is readily explained by the channel theory but not by the ‘electronic’ hypothesis. Noble suggests that repolarization (in the specific instance of cardiac sinus node cells), could result from electrons emerging from mitochondria. Taking this at face value, an obvious problem is that no trans-cell membrane repolarizing current would be observed. The proposed increase in ‘cytoplasmic negativity’ (by mitochondrially derived electrons) would not be the result of either the egress of cations or the ingress of anions through the cell membrane. Such a process would comprise a unique example in electrophysiology where the transmembrane potential would alter with no