Effects of Cyclopiazonic Acid on Triggered Activities in Ventricular Muscle and Cardiomyocytes Isolated from Hamster Hearts

Hwong-Ru Hwang；Yu-Fan Shen；Yao-Chang Chen；Chun-Peng Liu；Cheng-I Lin

action potential ； hamster ventricular muscle ； oscillatory transient inward currents ； post-rest potentiation ； SR Ca(superscript 2+)-pump inhibitor ； triggered arrhythmias

The Chinese Journal of Physiology

47卷3期（2004 / 09 / 30）

137 - 142

英文

The present experiments were performed to study the actions of cyclopiazonic acid on triggered activities generated in vitro in ventricular papillary muscle and cardiomyocytes isolated from the hearts of healthy male Syrian hamsters (Biobreeders F1B). Action potentials (APs) of ventricular muscle with a diameter around 1.5 mm were recorded using a microelectrode technique and force was recorded using a transducer. Ventricular preparations were driven at 2 Hz in high [Ca]0 (9 mM)-low [K]0 (1 mM) solution to induce delayed after depolarizations (DADs). Triggered activities were induced on resumption of electrical stimulation after a rest period of 20 sec. Effects of cyclopiazonic acid (3~10 μM) on steady-state rhythms and post-rest triggered activities were determined. Results revealed that cyclopiazonic acid initially enhanced the amplitude of DADs and induced post-rest triggered rhythms. However, after several minutes of cyclopiazonic acid exposure, AP duration (APD) was prolonged and DADs were significantly depressed. The effects on APP and DADs were reversible after washout of cyclopiazonic acid, but the diastolic potential during rest period oscillated and was able to generate high.frequency spontaneous APs at a reduced potential level. In ventricular myocytes isolated enzymatically, ionic currents were measured using of whole-cell patch-clamp techniques. In a high [Ca]0-low [K]0 solution, a series of oscillatory transient inward currents (I(subscript ti)) were obtained on repolarization to the holding potential (-45 mV) after a depolarizing pulse to the test potential of +20 mV for 1.2 sec. Cyclopiazonic acid (10 μM) reduced significantly the magnitude of I(subscript ti). The present results in hamster ventricular cells suggested that cyclopiazonic acid by inhibiting the sarcoplasmic reticulum (SR)-Ca(superscript 2+) pump would gradually deplete the amount of Ca(subscript 2+) within the SR. The consequent reduction in the amount of Ca(subscript 2+) released into the cytoplasm by cyclopiazonic acid might inhibit triggered arrhythmia through a reduction of DADs and I(subscript ti).

1. Bers, D.M.,Bassani, R. A.,Bassani, J. W. M.,Baudet, S.,Hryshko, L.V.(1993).Paradoxical twitch potentiation after rest in cardiac muscle.J. Mol. Cell. Cardiol.,25,1047-1057.
2. Chen, K.Y.,Lin, C.L.,Shih, T.C.,Lin, C.I.(1999).Differential electromechanical effects of cyclopiazonic acid on conducting and working myocardial tissues of the canine heart.Biomed. Eng. Appl. Basis Commun.,11,105-112.
3. Chen, Y. J.,Chen, S.A.,Chen, Y.C.,Yeh, H. I.,Chang, M.S.,Lin, C.I.(2002).Electrophysiology of single cardiomyocytes isolated from rabbit pulmonary veins: implication in initiation of focal atrial fibrillation.Basic Res. Cardiol.,97,26-34.
4. Chen, Y.J.,Chen, S.A.,Chen, Y.C.,Yeh, H.I.,Chan, P.,Chang, M.S.,Lin, C.I.(2001).Effects of rapid atrial pacing on the arrhythmogenic activity of single cardiomyocytes from pulmonary veins. Implication in initiation of atrial fibrillation.Circulation,104,2849-2854.
5. Chiesi, M.,Wrzosek, A.,Grueninger, S.(1994).The role of the sarcoplasmic reticulum in various types of cardiomyocytes.Mol. Cell. Biochem,130,159-171.
6. Hasegawa, J.,Satoh, H.,Vassalle, M.(1987).Induction of the oscillatory currents by low concentration of caffeine in sheep cardiac Purkinje fibres.N.S. Arch. Pharmacol.,335,310-320.
7. Hatem, S.N.,Sham, J.S.K.,Morad, M.(1994).Enhanced Na(superscript +)-Ca(superscript 2+) exchange activity in cardiomyopathic Syrian hamster.Circ. Res.,74,253-261.
8. He, H.,Giordano, F.J.,Hilal-Dandan, R.,Choi, D.J.,Rockman, H.A.,McDonough, P.M.,Bluhn, W.F.,Meyer, M.,Sayen, M.R.,Swanson, E.,Dillmann, W. H.(1997).Overexpression of the rat sarcoplasmic reticulum (SR) Ca(superscript 2+)ATPase gene in the heart of transgenic mice accelerates calcium transients and cardiac relaxation.J. Clin. Invest.,100,380-389.
9. Homburger, F.(1979).Myopathy of hamster dystrophy: History and morphologic aspects.Ann. N. Y. Acad. Sci.,317,2-17.
10. Iacono, G.,Vassalle, M.(1994).Effects of caffeine on intracellular sodium activity in cardiac Purkinje fibres: relation to force.Br. J. Pharmacol.,113,289-295.
11. Juhaszova, M.,Shimizu, H.,Bonn, M.L.,Yip, R.K.,Santiago, E.M.,Lindenmayer, G.E.,Blaustein, M.P.(1996).Localization of the Na(superscript +)-Ca(superscript 2+) exchanger in vascular smooth muscle, and in neurons and astrocytes.Ann. N. Y. Acad. Sci.,779,318-335.
12. Kass, R.S.,Tsien, R.W.,Weingart, R.(1978).Ionic basis of transient inward current induced by strophanthidin in cardiac Purkinje fibres.J. Physiol. (Lond),281,209-226.
13. Kim, E.M.,Choy, H.,Vassalle, M.(1997).Mechanisms of suppression and initiation of pacemaker activity in guinea pig sino-atrial node superfused in high [K]o.J. Mol. Cell. Cardiol.,29,1433-1445.
14. Kuo, T.H.,Tseng, W.,Wiener, J.(1987).Defective Ca(superscript 2+)-pumping ATPase of heart sarcolemma from cardiomyopathic hamster.Biochim. Biophys. Acta,900,10-16.
15. Lin, C.I.,Kotake, K.,Vassalle, M.(1986).On the mechanism underlying the oscillatory current in cardiac Purkinje fibers.J. Cardiovasc. Pharmacol.,8,906-914.
16. Lin, C.I.,Shen, Y.F.,Chen, Y.C.,Liebman J. (edited)(1997).Effects of thapsigargin on post-rest triggered activity in hamster ventricular muscles.Proceedings of the 23rd International Congress on Electrocardiology `96,Cleveland, Ohio:
17. Lin, C.I.,Yiu, M.Y.,Huang, H.R.,Lin, C.L.(1999).Reentrant tachyarrhythmias in right atria of cardiomyopathic versus healthy Syrian hamster.J. Biomed. Sci.,6,399-408.
18. Loh, S.H.,Lee, A.R.,Huang, W.H.,Lin, C.I.(1992).Ionic mechanisms responsible for the antiarrhythmic action of dehydroevodiamine in guinea-pig isolated cardiomyocytes.Br. J. Pharmacol.,106,517-523.
19. Vassalle, M.(2003).Mechanisms underlying cardiac pacemaker activity.J. Med. Sci.,23,249-264.
20. Vassalle, M.,DiGennaro, M.(1984).Caffeine actions on current induced by calcium-overload in Purkinje fibers.Eur. J. Pharmacol.,106,121-131.
21. Vassalle, M.,Lin, C.I.(1979).Effect of calcium on strophanthidin-induced electrical and mechanical toxicity in cardiac Purkinje fibers.Am. J. Physiol,236,689-697.
22. Waldo, A.L.,Wit, A.L.(1993).Mechanisms of cardiac arrhythmias.Lancet,341,1189-1193.
23. Wei, J.,Liu, H.C.,Lee, F.Y.,Lee, M.S.,Huang, C.Y.,Pan, H.P.,Lin, C.I.(2003).Role of the sarcoplasmic reticulum in altered action potential and contraction of myopathic human and hamster ventricle.Clin. Exp. Pharmacol. Physiol.,30,232-241.