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Weirich J.; Antoni, H.
Journal of Cardiovascular Pharmacology: June 1990
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The frequency-dependent block of cardiac sodium channels by class 1 antiarrhythmic drugs can be described by a periodical ligand binding process between drug molecules and channel binding sites. This predicts a linear relation between onset-rate constant of frequency-dependent block and diastolic interval as well as saturation of block with high stimulation rates. From both relationships, the binding kinetics (time constant, Ton) and saturation level of block (bdinf) can be estimated. This is examplified for the frequency-dependent block (reduction of the maximal upstroke velocity of action potentials) induced by prajmaline (10-6M). In the same way, the frequency-dependent effects of 11 other class I drugs reported in the literature were analyzed and compared with each other. When the drugs are ranked with respect to their binding kinetics (Ton), there is a close relationship to the subclasses (la, lb, lc), with lb drugs exhibiting the fastest and lc drugs the slowest kinetics. However, differences also exist in the saturation behavior of frequency-dependent block even within the same subclasses (la and lc). Thus, the class 1 drugs can also be subdivided in three other groups exhibiting clearly separated bands of block-frequency relations, with half-maximal saturation occurring at different stimulation rates. Our findings may have differential implications for the antiarrhythmic and proarrhythmic efficacy of class 1 drugs.

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