Abstract：
BACKGROUND AND PURPOSE:The electromechanical window (EMW), the interval between the end of the T-wave and the end of the left ventricular pressure (LVP) curve, has recently been proposed as a predictor of risk of Torsade de Pointes (TdP) in healthy animals, whereby a negative EMW (mechanical relaxation earlier than repolarization) after drug administration indicates an increased TdP risk. The aims of this study were to assess (i) the effect of the ventricular remodelling in the canine chronic, complete atrioventricular block (CAVB) model on EMW; (ii) the effect of the I(Kr) -blocker dofetilide on EMW; and (iii) the correlation of EMW with TdP inducibility. EXPERIMENTAL APPROACH:Our 11 year database of experiments of CAVB in dogs under general anaesthesia was reviewed and experiments included if ECG and LVP were recorded simultaneously at spontaneous rhythm. In total, 89 experiments in 44 dogs were appropriate and were analysed. KEY RESULTS:During normally conducted sinus rhythm or acute atrioventricular block, EMW was positive. During CAVB, EMW was decreased to negative values. Dofetilide further reduced EMW before inducing repetitive TdP in 82% of the experiments. However, subclassification into inducible and non-inducible dogs revealed no difference in EMW. Analysis of the components of EMW revealed that the observed changes in EMW were solely caused by QT prolongation. CONCLUSIONS AND IMPLICATIONS:In the canine CAVB model, ventricular remodelling and I(Kr) block by dofetilide are associated with negative EMW values, but this reflects QT prolongation, and implies that the EMW lacks specificity to predict dofetilide-induced TdP.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Stams TR,Bourgonje VJ,Beekman HD,Schoenmakers M,van der Nagel R,Oosterhoff P,van Opstal JM,Vos MAdoi
10.1111/bph.12483subject
Has Abstractpub_date
2014-02-01 00:00:00pages
714-22issue
3eissn
0007-1188issn
1476-5381journal_volume
171pub_type
杂志文章abstract：:The interaction between nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) was investigated in isolated circular smooth muscle cells and strips of the guinea-pig gastric fundus. VIP induced a concentration-dependent inhibition of carbachol-induced contraction in smooth muscle cells with a maximum at 10(-6) ...
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