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CARDIOVASCULAR

The Amiodarone Derivative KB130015 [2-Methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran] Induces an Na⁺-Dependent Increase of [Ca²⁺] in Ventricular Myocytes

Laboratory of Experimental Cardiology, Catholic University Leuven, Leuven, Belgium (V.B., D.D., K.R.S.); Interdisciplinary Research Center, Catholic University Leuven Kortrijk, Kortrijk, Belgium (F.V.); and Center for Experimental Surgery and Anesthesiology, Leuven, Leuven, Belgium (K.M.)

KB130015 [KB; 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran] is a novel amiodarone derivative designed to retain the antiarrhythmic effects without the side effects. Unlike amiodarone, KB slows Na⁺ current inactivation and could, via an increase in [Na⁺]_i, potentially lead to Ca²⁺ overload. Therefore, we studied the effects of KB on Na⁺ and Ca²⁺ handling in single pig ventricular myocytes using the whole-cell ruptured patch-clamp technique and K₅fluo-3 as [Ca²⁺]_i indicator. KB at 10 µM did not prolong action potential duration but slightly increased the early plateau; spontaneous afterdepolarizations were not observed. The amplitude of the [Ca²⁺]_i transient was larger (434.9 ± 37.2 versus 326.8 ± 39.8 nM at baseline, n = 13, P < 0.05), and the time to peak [Ca²⁺]_i was prolonged. During voltage-clamp pulses, [Ca²⁺]_i transient peak was also larger (578.1 ± 98.9 versus 346.4 ± 52.6 nM at baseline, P < 0.05). Although L-type Ca²⁺ current was reduced (by 21.9% at +10 mV, n = 9, P < 0.05), sarcoplasmic reticulum Ca²⁺ content was significantly enhanced with KB. Forward Na⁺/Ca²⁺ exchange was significantly decreased after KB application, but reverse mode of the Na⁺/Ca²⁺ exchanger was significantly larger, suggesting an increase in [Na⁺]_i with KB. This was confirmed by a 2-fold increase of the [Na⁺]-dependent current generated by the Na/K-ATPase (from 0.17 ± 0.02 to 0.38 ± 0.06 pA/pF, P < 0.05). In conclusion, as predicted from the slowing of I_Na inactivation, KB130015 leads to an increase in [Na⁺]_i and consequently in cellular Ca²⁺ load. This effect is partially offset by a decrease in I_CaL resulting in a mild inotropic effect without the signs of Ca²⁺ overload and related arrhythmias usually associated with Na⁺ channel openers.

Address correspondence to: Dr. Karin R. Sipido, Laboratory of Experimental Cardiology, KUL, Campus Gasthuisberg O/N 7th Floor, Herestraat 49, B-3000 Leuven, Belgium. E-mail: karin.sipido{at}med.kuleuven.be

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