Received for publication July 12, 2005.
Revised September 14, 2005.
Accepted for publication September 14, 2005.

The amiodarone derivative, 2-Methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015) induces a Na⁺-dependent increase of [Ca²⁺] in ventricular myocytes

Abstract

2-Methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015; KB) 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. We therefore 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 nM vs. 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 nM vs. 346.4±52.6 nM at baseline, P<0.05). Though 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/Ca exchange was significantly decreased after KB application, but reverse-mode of the Na/Ca exchanger was significantly larger, suggesting an increase in [Na⁺]_i with KB. This was confirmed by a two-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.

Key words: L-type Ca2+ current, Na+ current, Na/Ca exchange, afterdepolarizations, arrhythmias, cardiac myocytes

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