Angiotensin receptors in GtoPdb v.2023.1

The actions of angiotensin II (Ang II) are mediated by AT1 and AT2 receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Angiotensin receptors [63, 155]), which have around 30% sequence similarity. The decapeptide angiotensin I, the octapeptide angiotensin II and the heptapeptide angiotensin III are endogenous ligands. losartan, candesartan, olmesartan, telmisartan, etc. are clinically used AT1 receptor blockers

Angiotensin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The actions of angiotensin II (Ang II) are mediated by AT1 and AT2 receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Angiotensin receptors [61, 152]), which have around 30% sequence similarity. The decapeptide angiotensin I, the octapeptide angiotensin II and the heptapeptide angiotensin III are endogenous ligands. losartan, candesartan, telmisartan, etc. are clinically used AT1 receptor blockers

Atrioventricular and interventricular delay optimization in cardiac resynchronization therapy: physiological principles and overview of available methods

In this review, the physiological rationale for atrioventricular and interventricular delay optimization of cardiac resynchronization therapy is discussed including the influence of exercise and long-term cardiac resynchronization therapy. The broad spectrum of both invasive and non-invasive optimization methods is reviewed with critical appraisal of the literature. Although the spectrum of both invasive and non-invasive optimization methods is broad, no single method can be recommend for standard practice as large-scale studies using hard endpoints are lacking. Current efforts mainly investigate optimization during resting conditions; however, there is a need to develop automated algorithms to implement dynamic optimization in order to adapt to physiological alterations during exercise and after anatomical remodeling

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate

[H-3]IVDE77, a novel radioligand with high affinity and selectivity for the insulin-regulated aminopeptidase

The hexapeptide angiotensin IV (Ang IV) induces diverse biological effects such as memory enhancement and protection against ischemic stroke. Studies on the mechanism of Ang IV however are hampered by its instability and its lack of selectivity. The high-affinity binding site for Ang IV is the insulin-regulated aminopeptidase (IRAP, EC 3.4.11.3), but Mg IV also acts as a weak agonist for the Ang II-receptor (AT(1)), implying the need for stable and highly selective Mg IV-analogues. Here we present the screening of novel Mg IV-analogues, selected on basis of high affinity for IRAP, high selectivity (compared to aminopeptidase N and the AT(1), receptor) and resistance against proteases. The selected compound IVDE77 possesses a number of advantages compared to Ang IV: (i) it has a 40 times higher affinity for IRAP (K-i 1.71 nM), (ii) it does not activate the AT(1), receptor, (iii) it is easily radiolabeled with tritium and (iv) it is resistant to proteolysis, even in human plasma. In addition, pre-treatment of intact CHO-K1 cells with IVDE77 led to a virtually complete inhibition of subsequent intracellular accumulation of [H-3]IVDE77-IRAP complexes. IVDE77 thus represents the first Ang IV-analogue able to abolish IRAP-availability completely at the cell surface in vitro. In summary, IVDE77 is a useful tool for the detection of IRAP under physiological conditions, and may contribute to elucidating the mechanism of Ang IV to ascertain which functions are IRAP-dependent. (C) 2013 Elsevier B.V. All rights reserved

Sustaining competitive advantage through effective knowledge management

Knowledge utilization to achieve competitive advantage is not only a source of creating critical success factors but nurturing core competencies as well. In order to stay, competitive organizations have to be fully aware of customer preference, trends and changing needs. This flexibility of any organization can help attain competitive advantage by adapting to changing environment and maintaining it. The real life example of marketing strategy by sportswear giants Adidas and Nike show how effective knowledge management can help achieve organization goals

Metal ion modulation of cystinyl aminopeptidase

Cystinyl aminopeptidase has one Zn(2+)-binding motif and is a member of the M1 aminopeptidase family. Ion modulation of its catalytic activity was studied in membranes of CHO-K1 cells (Chinese-hamster ovary K1 cells) using L-leucine-p-nitroanilide as substrate. The planar bidentate chelators 1,10-phenanthroline and 2,2′-bipyridine inhibited the activity in a concentration-dependent manner with Hill slopes of 3.32±1.78 and 2.10±0.26 respectively. The acetic acid-containing chelators EDTA, EGTA and DTPA (diethylenetriamine-N,N,N′,N″,N″-penta-acetic acid) weakly affected the activity, but they increased the potency of the planar chelators up to a limit, at which Hill slopes became close to unity. Moreover, competition between 1,10-phenanthroline and the substrate only took place in the presence of EDTA. These findings are compatible with a model in which the bidentate chelators inhibit enzyme activity by decreasing the free Zn(2+) concentration. By removing a modulatory ion from an allosteric site at the enzyme, the acetic acid-containing chelators facilitate the direct interaction between the bidentate chelators and the catalytic Zn(2+). The inhibitory effect of EDTA plus 1,10-phenanthroline could be completely reversed by Zn(2+). Ca(2+) and Mg(2+) increased the potency of Zn(2+) for this process. This is expected if they interact with the modulatory site to decrease the sensitivity of the enzyme towards 1,10-phenanthroline. Conversely, the bidendate chelators increased the high-affinity [(125)I]angiotensin IV binding to the membranes and this was potentiated by the acetic acid-containing chelators. These findings support the concept that high-affinity [(125)I]angiotensin IV binding, previously referred to as ‘AT(4) receptor binding’, only occurs for the cystinyl aminopeptidase apoenzyme

Effects of AV delay programming on ventricular resynchronisation: role of radionuclide ventriculography

PURPOSE: Optimal atrioventricular delay (AVD) setting for cardiac resynchronisation therapy, i.e. biventricular pacing in patients with heart failure, remains a formidable challenge. Thus, the purpose of this study was to evaluate the effects of different AVD on inter- and intra-ventricular resynchronisation using phase histograms of radionuclide ventriculography (RNV). METHODS: In 17 consecutive patients (mean age 64 +/- 6 years), RNV was performed 236 +/- 350 days after pacemaker implantation for cardiac resynchronisation therapy. Images were acquired during atrial pacing at 80 bpm and during biventricular pacing with AVD ranging from 80 to 160 ms. Inter-ventricular dyssynchrony was measured by the delay between the mean phase angles of the left and right ventricles. Intra-ventricular dyssynchrony was measured by the standard deviation (SD) of left ventricular phase histograms. RESULTS: Left ventricular (LV) ejection fraction (EF) was inversely correlated to LV dyssynchrony (SD of LV phase histogram, R = -0.82, p < 0.0001). However, the increase in LVEF by biventricular pacing (mean +4.4 +/- 4%) showed only modest correlation to the resulting resynchronisation effect (characterised by a -13 +/- 8 degrees decrease in LV phase histogram SD, R = -0.38, p < 0.0001). CONCLUSION: RNV is helpful in optimising pacing parameters for resynchronisation therapy. Varying AVD did not have a major impact on intra- or inter-ventricular resynchronisation. Thus, the benefit of AVD-based LVEF optimisation seems to result from atrioventricular resynchronisation