Validation of a guinea pig Langendorff heart model for assessing potential cardiovascular liability of drug candidates

Torsades de Pointes in the Guinea-Pig Heart

“…Complete block of I Kr in guinea-pig cardiomyocytes required 1000 nM dofetilide in early reports [11], yet the data presented by Dr Osadchii in this issue confirms the findings of two previous studies showing that neither 10 nor 1000 nM dofetilide is able to reproducibly induce TdP in perfused, guinea-pig hearts [12,13]. In addition, Guo et al who used the guinea-pig model to analyze cardiovascular risk of 15 reference compounds, including dofetilide, reported arrhythmias for only 3 drugs, namely aconitine, ouabain and pinacidil [13]. Interestingly, none of these drugs are associated with considerable I Kr block.…”

“…The low incidence of arrhythmias in guinea-pig hearts appears to be at odds with data obtained from rabbit hearts, where a much higher sensitivity for proarrhythmic drugs is reported [3,13]. What is the underlying mechanism?…”

Accurate detection of drug-induced delayed ventricular repolarization with a suitable correction formula in Langendorff guinea pig heart

“…Hence, a hERG assay using the patch-clamp method (Guth et al, 2004;Kirsch et al, 2004) has been widely performed in early-stage development when only small amounts of test drugs are available, but the assay is known to sometimes show false positive signals (Redfern et al, 2003). Recently, an isolated perfused guinea pig heart model using the Langendorff method was proposed for early screening of QT risk because of its expected high reliability (Hamlin et al, 2004;Guo et al, 2009) and small amount of test drug required.…”

“…Concerning guinea pigs, the general correction formula proposed by Bazett (1920) or Fridericia (1920) has been used for correcting QT intervals against RR intervals in isolated hearts (Hamlin et al, 2004;Guo et al, 2009) and in anesthetized (Hamlin et al, 2003a;Testai et al, 2004;Hauser et al, 2005;Tabo et al, 2007) or conscious animals (Hamlin et al, 2003a). However, there is inadequate information about which equation corrects the QT interval appropriately for the RR interval in isolated guinea pig hearts.…”

Investigations of diterpene alkaloids isolated from Aconitum anthora L. and A. moldavicum L., and of aconitine-derived lipo-alkaloids

“…176,177 Only one previous study has been reported the hERG channel inhibitory effect of the most commonly available DA, aconitine (5). 92 Our data suggest that some structurally and functionally unrelated diterpene and NDAs may block the hERG K + channel, and may therefore act in cardiac action potential repolarisation, with prolongation of the QT interval, and increase of the risk of potentially fatal ventricular arrhythmias. 161 The toxic plasma concentration of aconitine (5) is 30-1000 times lower than its IC 50 value on hERG channels, and its serious cardiac side effects are generally believed to be a result of Na + channel modulation.…”