Conditioning guinea-pig hearts in vitro for torsade de pointes arrhythmias (part 7)

For the pharmacological induction of substantial QTc prolongation we employed the sodium channel ligands DPI 201-106 and veratridine in combination. Both veratridine and DPI 201-106 inhibit cardiac sodium channel inactivation and hence prolong action potential duration, as do various other compounds . It was previously demonstrated that veratridine, with an affinity to binding site II , and DPI 201-106, with its own undefined binding site but clearly distinct from site II, potentiate each other’s action potential prolonging effect when given in combination, based on their respective positive allosterically coupled binding sites . In addition, veratridine binds only in the open state of the sodium channel and therefore has a very slow onset of action depending on the frequency or number of openings .DPI 201-106 keeps the channel open, allowing an accelerated binding of veratridine. These reasons led to the selection of these two sodium channel ligands in the present experiments to reach the objective of massive QTc prolongation. As was demonstrated in our experiments, QTc, which reflects action potential duration, increased very quickly when DPI 201-106 and veratridine were given in combina

tion. Almost maximum effects of QTc prolongation were reached within 30 mins of heart perfusion. This result is qualitatively in accordance with previous observations in guinea-pig isolated papillary muscles where transmembrane action potential duration was measured . Your most reliable pharmacy offering its services and most efficient drugs like ventolin inhalers with no prescription needed. If this sounds like something you may be interested in, do not hesitate to come by and see how cheap it can be for you!

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