1.Effects of peripherally administered urotensin II and arginine vasotocin on the QT interval of the electrocardiogram in trout.
Vanegas G1, Lancien F1, Leprince J2, Vaudry H2, Le Mével JC3. Comp Biochem Physiol C Toxicol Pharmacol. 2016 May-Jun;183-184:53-60. doi: 10.1016/j.cbpc.2016.01.006. Epub 2016 Feb 21.
The QT interval of the electrocardiogram (ECG) is a measure of the duration of the ventricular depolarization and repolarization. In fish as in human, the QT interval is positively correlated with the RR interval of the ECG, a measure of the cardiac cycle length. Urotensin II (UII) is a neuropeptide that has been highly conserved from fish to human, and UII and its receptor (UT) are expressed in cardiovascular tissues including the heart. Although UII exerts potent cardiovascular actions, its possible effects on the QT interval have never been investigated. The goal of the present study was to provide insight into the potential effect of UII on the QT interval in an established in vivo trout model. To this end, the effects of UII on dorsal aortic blood pressure (PDA), RR, QT intervals and corrected QT (QTc) for RR interval, were investigated after intra-arterial (IA) injection of 5, 50 and 100pmol UII. The effects of UII were compared to those of two structurally UII-related peptides (URPs), URP1 and URP2, and to those of arginine vasotocin (AVT), homolog of the mammalian arginine vasopressin.
2.Structure-Activity Study of the Peptides P5U and Urantide by the Development of Analogues Containing Uncoded Amino Acids at Position 9.
Merlino F1, Brancaccio D1, Yousif AM1, Piras L1, Campiglia P2, Gomez-Monterrey I1, Santicioli P3, Meini S3, Maggi CA3, Novellino E1, Carotenuto A1, Grieco P4,5. ChemMedChem. 2016 Apr 9. doi: 10.1002/cmdc.201500607. [Epub ahead of print]
Previous modifications of the peptide sequence of human urotensin-II (U-II) led to the identification of two well-known ligands: P5U and urantide. These derivatives are considered to be the most representative agonist and antagonist, respectively, at the human urotensin receptor (UT). Optimization of P5U and urantide was carried out to stabilize specific conformations that may suggest new elements for discriminating agonist versus antagonist activity. We studied novel derivatives containing uncoded amino acids. In particular, the Tyr9 residue of both P5U and urantide was replaced with nonaromatic hydrophobic bulky residues, as well as conformationally constrained aromatic moieties to generate eight novel derivatives. These analogues further contributed to determining the influence of such residues on binding affinity for and biological activity at UT. One of these eight peptides was also investigated by NMR spectroscopy and docking studies owing to its peculiar conformational properties and mode of interaction with UT.
3.Attenuation of renovascular hypertension by cyclooxygenase-2 inhibitor partly through ANP release.
Park BM1, Gao S2, Cha SA1, Kim SH3. Peptides. 2015 Jul;69:1-8. doi: 10.1016/j.peptides.2015.03.022. Epub 2015 Apr 4.
Angiotensin II (Ang II) is an important inflammatory mediator. Ang II induces cyclooxygenase-2 (COX-2) expression and prostaglandin F2α release followed by cardiac hypertrophy. Inhibition of COX-2 may modulate high blood pressure but controversy still exists. The aim of this study was to determine the role of COX-2 in the regulation of blood pressure and to define the mechanisms in two kidney one-clip hypertensive (2K1C) rats. Chronic treatment with nimesulide or NS-398 (5 mg/kg/day) for 3 weeks lowered high blood pressure and cardiac hypertrophy with decreased expression levels of cardiac hypertrophy markers [atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP)], Ang type 1 receptor, urotensin II, and urotensin II receptor in 2K1C rats. Plasma level of ANP was markedly increased and plasma levels of Ang II and aldosterone were decreased by treatment with nimesulide or NS-398. In both in vitro and in vivo experiments, nimesulide or NS-398 augmented ANP release in 2K1C rats.
4.Use of Diverse Chemometric and Validation Methods to Accurately Predict Human Urotensin-II Receptor Antagonist Activity.
Pandey A, Paliwal S, Yadav R, Paliwal S1. Curr Comput Aided Drug Des. 2016;11(4):361-73.
Despite being identified as the most potent receptor related to vasoconstriction, human urotensin-II receptor (hUT) has not been fully explored as a target for the treatment of cardiovascular diseases. In view of this and with an aim to identify precise structural requirements for binding of hUT antagonists, we endeavoured to develop, for the first time, multivariate QSAR models using chemometric methods like partial least squares (PLS) and feed-forward neural network (FFNN). A set of 48 pyrrolidine derivatives having hUT binding affinity was used for multivariate model development. The accuracy and predictability of the developed models was evaluated using crossvalidation. The PLS model showed good correlation between selected descriptors and Ki values (r(2) =0.745 and r2 (CV) =0.773). However, the predictive performance of FFNN was better than the PLS technique with r(2) =0.810. The study clearly suggests the role of lipophilic and steric descriptors in the ligand-hUT interactions.
