Abstract
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 INa inactivation, KB130015 leads to an increase in [Na+]i and consequently in cellular Ca2+ load. This effect is partially offset by a decrease in ICaL resulting in a mild inotropic effect without the signs of Ca2+ overload and related arrhythmias usually associated with Na+ channel openers.
Footnotes
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This work was supported by grants from the FWO, the Flanders Fund for Scientific Research (to K.R.S. and K.M.).
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doi:10.1124/jpet.105.092221.
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ABBREVIATIONS: ICD, implantable cardiac defibrillator; KB130015 (KB), 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran; DHO, dihydroouabain; SR, sarcoplasmic reticulum; CTRL, control; DPI 201-106, (±)-4-[3-(4-diphenylmethyl-1-piperazinyl)-2-hydroxy propoxy]-1H-indole-2-carbonitrile; BDF 9148, (±)-4-[3-[[1-(diphenylmethyl)-3-azetidinyl]oxy]-2-hydroxypropoxy]-1H-indole-2-carbonitrile; EAD, early after-depolarization.
- Received July 12, 2005.
- Accepted September 14, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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