Inhibition of calmodulin and protein kinase C by amiodarone and other class III antiarrhythmic agents
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Class III antiarrhythmic agents may prolong refractoriness via modulation of ion channels, which may be sensitive to Ca2+ regulatory proteins or enzymes. Accordingly, the purpose of this study was to quantitate the effects of several structurally diverse class III antiarrhythmic agents on calmodulin-regulated enzymes and protein kinase C activity, and to evaluate the ability of these agents and known calmodulin antagonists to prolong cardiac refractoriness in vivo. The rank order of potency (IC50;μM) of selected class III antiarrhythmic agents and reference calmodulin antagonists as inhibitors of calmodulin-regulated phosphodiesterase activity were: calmidazolium (0.12 μM)>amiodarone (0.62 μM)>desethylamiodarone (1.5 μM)>trifluoperazine (4.3 μM), bepridil (5 μM)>W-7 (7.5 μM), clofilium (13 μM). Similar concentration-related inhibition was evident in a second calmodulin-regulated system, inhibition of myosin light-chain phosphorylation and superprecipitation light-chain phosphorylation and superprecipitation of arterial actomyosin. Sotalol and tetraethylammonium were inactive at 100 μM. Protein kinase C activity was also inhibited by some of these agents; desethylamiodarone (IC50=11 μM) was more potent than the reference agent, H-7 (IC50=79 μM), or amiodarone (38% inhibition at 100 μM) and clofilium (32% inhibition at 100 μM). In vivo, the minimally effective doses required to increase ventricular effective refractory doses required to increase ventricular effective refractory periods in paced guinea pigs were (in mg/kg) bepridil, sotalol >clofilium >amiodarone >W-7, desethylamiodarone . No changes in refractory period were noted with maximum testable doses of calmidazolium or trifluoperazine. These studies show that some, but not all, class III antiarrhythmic agents are effective and potent calmodulin antagonists or protein kinase C inhibitors. Moreover, some calmodulin antagonists are effective at prolonging refractoriness in vivo. However, a lack of correlation between these agents suggests that these mechanisms are not solely responsible for the prolongation of refractoriness of all class III agents.
Key Wordscalmodulin protein kinase C antiarrhythmic drugs
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- 1.Kikkawa U, Nishizuka Y. Protein kinase C.The Enzymes 1986;17:167–189.Google Scholar
- 3.Roufogalis BD. Calmodulin antagonism. In: Marme D (ed).Calcium and Cell Physiology. Berlin: Springer-Verlag, 1985:148–168.Google Scholar
- 4.Silver PJ. Pharmacological modulation of cardiac and vascular contractile protein function.J Cardiovasc Pharmacol 1986;8 (Suppl 9):S34-S46.Google Scholar
- 5.Levitan IB. Phosphorylation of ion channels.J Membrane Biol 1985;87:177–190.Google Scholar
- 9.Cohen IS, Datyner NB, Gintant GA, et al. Time dependent outward currents in the heart. In: Fozzard HA, et al. (eds).The Heart and Cardiovascular System. New York: Raven Press, 1986:637–669.Google Scholar
- 10.Weishaar RE, Burrows JD, Kobylarz DC, et al. Multiple molecular forms of cyclic nucleotide phosphodiesterase in cardiac and smooth muscle and in platelets: Isolation, characterization and effects on various reference phosphodiesterase inhibitors and cardiotonic agents.Biochem Pharmacol 1986;35:787–800.PubMedGoogle Scholar
- 13.Tallarida RJ, Murray RB (eds).Manual of Pharmacologic Calculations with Computer Programs, 2nd ed. New York: Springer-Verlag, 1986.Google Scholar
- 23.Kuo CS, Reddy CP, Munakata K, et al. Arrhythmias dependent predominantly on dispersion or repolarization. In: Zipes DP, Jalife J (eds).Cardiac Electrophysiology Arrhythmias. New York: Grune and Stratton, 1985:277–286.Google Scholar
- 24.DiFrancesco D, McNaughton PA. The effects of calcium on outward membrane current in the cardiac Purkinje fibre.J Physiol (Lond) 1979;289:347–373.Google Scholar