臺灣博碩士論文加值系統

Labedipinedilol-A, -B和-C是三個合成的二氫呲啶型衍生物，在結構上具有甲型、乙型腎上腺激素性受體阻斷與鈣離子通道阻斷作用的官能基團。在先前的研究中已證實，labedipinedilol-A, -B和-C在大白鼠身上，表現出具有甲型、乙型腎上腺激素性受體阻斷與鈣離子通道阻斷之三合一治療特性。然而，對於這些藥物在單一細胞層級的電生理學特性一直都還沒有去研究。本研究主要之目的是闡明labedipinedilol-A, -B和-C對於心臟細胞離子機轉的作用，並且評估labedipinedilol-A的抗心律不整活性。
在全細胞膜電位鉗定狀態下，對大白鼠單一心室細胞使用膜片鉗定技術來測定動作電位、鈉離子電流、L型鈣離子電流、瞬時外流鉀離子電流以及內向整流鉀離子電流。在從大白鼠心臟分離出的心室細胞中，labedipinedilol-A可以依濃度相關性地縮短動作電位期間與降低動作電位幅度，但是對於靜止膜電位並沒有明顯影響。
全細胞膜電位鉗定實驗顯示，於低鈉溶液中紀錄鈉離子電流時，labedipinedilol-A可以依濃度相關性地抑制鈉離子電流。在細胞外給予labedipinedilol-A可以明顯地降低L型鈣離子電流的振幅，且顯示濃度相關性的抑制現象。相反地，對於瞬時外流鉀離子電流與內向整流鉀離子電流，在給予labedipinedilol-A之後電流反而會增強。由此得知，labedipinedilol-A是一個鈉離子通道與L型鈣離子通道阻斷劑，卻也是瞬時外流鉀離子通道與內向整流鉀離子通道活化劑。
在拮抗乙型腎上腺激素性受體的實驗中發現，labedipinedilol-A可以競爭性地拮抗乙型腎上腺激素性受體作用劑(-)isoproterenol對於L型鈣離子電流的作用。
在研究labedipinedilol-A對強心配糖體ouabain誘發天竺鼠離體心房心律不整之保護作用的實驗中，結果顯示labedipinedilol-A能明顯延長ouabain誘發離體心房心律不整發作的時間。
在研究labedipinedilol-B和-C對大白鼠心室細胞的動作電位、鈉離子電流、L型鈣離子電流之影響的實驗中，labedipinedilol-B和-C具有類似labedipinedilol-A的作用，同樣能對單一心室細胞縮短其動作電位期間和降低動作電位幅度。依照藥物縮短動作電位期間的程度由強至弱排列，分別為labedipinedilol-A > labedipinedilol-C > labedipinedilol-B。
如同labedipinedilol-A的作用，labedipinedilol-B和-C也可以抑制心室細胞之鈉離子電流與L型鈣離子電流的尖峰振幅。對於鈉離子電流抑制作用的程度，由強至弱依序排列分別為labedipinedilol-A > labedipinedilol-B > labedipinedilol-C。而對於L型鈣離子電流的抑制作用，由強至弱排列分別為labedipinedilol-C > labedipinedilol-A > labedipinedilol-B。這些藥物對於大白鼠心室細胞L型鈣離子電流的抑制作用皆比nifedipine的作用強。Labedipinedilol-A, -B和-C對於鈉離子電流與L型鈣離子電流抑制作用強弱之差異，主要是來自於結構上官能基的不同。像是labedipinedilol-B在苯環上缺少一個methoxy moiety，不同於labedipinedilol-A和-C。此供電子基具有影響藥物生物活性的作用，能讓藥物與受體或離子通道有較高的結合活性。
總而言之，這些實驗結果能提供新型鈣離子通道阻斷劑labedipinedilol-A, -B和-C在心臟組織作用之離子機轉的些許解釋，以及在臨床藥物治療上新的方向。

Labedipinedilol-A, -B and -C are synthetic 1,4-dihydropyride derivatives with /-adrenoceptor and calcium channel blockading activities. As demonstrated previously, labedipinedilol-A, -B and -C have been described with triple blocking activities on /-adrenergic receptor and L-type calcium channel, functioning in a molecule displaying monotherapy properties on rats. However, a direct electrophysiological characterization of these drugs has not yet been documented at single cell level. The aim of present study is to elucidate the ionic mechanisms underlying the labedipinedilol-A, -B and -C actions on cardiac myocytes and to assess the antiarrhythmic activities.
Under the whole-cell configuration, we investigate the effects of labedipinedilol-A on action potential, sodium current (INa), L-type calcium current (ICaL), transient outward potassium current (Ito), and inward rectifier potassium current (IK1) in single isolated ventricular myocytes from rats by using patch-clamp techniques. In single isolated ventricular myocytes form rats, labedipinedilol-A abbreviate markedly action potential duration (APD) and reduce in action potential amplitude (APA) in a concentration-dependent manner, but having no effect on the resting membrane potential (RMP).
Whole-cell voltage clamp study reveals that labedipinedilol-A produces a concentration-dependent reduction in sodium current (INa) amplitude, recorded in low [Na+]o solution. Extracellular application of labedipinedilol-A significantly reduces the peak amplitude of L-type calcium current (ICaL) with concentration-dependent inhibition. On the contrary, both the transient outward potassium current (Ito) and inward rectifier potassium currents (IK1) are enhanced by the addition of labedipinedilol-A. These results indicate that labedipinedilol-A acts as a inhibitor of the sodium and L-type calcium channel, but a activator of the transient outward and inward rectifier potassium channel.
In the experiment of antagonizing -adrenergic receptors, labedipinedilol-A can competitively antagonize the effect of β-adrenoceptor agonist, (-)isoproterenol, on L-type calcium current.
We investigate the protective effect of labedipinedilol-A on ouabain-induced arrhythmia in isolated whole atria from guinea-pigs. The results indicate that labedipinedilol-A significantly prolongs the onset time of extra-systole (arrhythmia) induced by ouabain in isolated atria.
We also investigate the effects of labedipinedilol-B and -C on action potential, sodium current and L-type calcium current in single isolated ventricular myocytes form rats. Similar to labedipinedilol-A, labedipinedilol-B and -C inhibit the action potential duration and action potential amplitude. According to the extent of shortening of action potential duration, the sequences are labedipinedilol-A > labedipinedilol-C > labedipinedilol-B in turn.
Similar to the actions of labedipinedilol-A, labedipinedilol-B and -C also inhibit the peak amplitude of sodium and L-type calcium current in ventricular myocytes isolated from rats. The degrees of inhibition of sodium current are labedipinedilol-A > labedipinedilol-B > labedipinedilol-C, respectively. The sequences of inhibitory effects for L-type calcium current are labedipinedilol-C > labedipinedilol-A > labedipinedilol-B, respectively. All of them are stronger than nifedipine for L-type calcium current in isolated rat ventricular myocytes. The different inhibitory capacity for sodium and L-type calcium current of labedipinedilol-A, -B, and -C are originated from the functional group in the structure. Such as the structure of labedipinedilol-B lacks a methoxy moiety on phenyl ring, differ from labedipinedilol-A and -C. The electron-donating substituent, i.e. methoxy, plays an important role in affecting biological activities. The methoxy moiety on phenyl ring is beneficial for receptor or channel binding.
These findings may provide some explanations of ionic mechanism for the effects of new-type calcium channel blockers, labedipinedilol-A, -B and -C, in the cardiac myocytes and a new aspect of their possible clinical therapeutic actions.

縮寫表...........................................1
中文摘要.........................................3
英文摘要.........................................6
第一章 緒論.....................................9
第二章 實驗材料與方法..........................18
第三章 實驗結果................................27
第四章 實驗討論................................47
第五章 實驗結論................................59
參考文獻........................................62
實驗圖表........................................71
附圖............................................99

Alam, R., Kataoka, S., Alam, S. and Yatsu, F., 1996, Inhibition of vascular smooth muscle cell proliferation by the calcium antagonist clentiazem: role of protein kinase C, Atherosclerosis 126, 207-219.
Anderson, J.L., Rodier, H.E. and Green, L.S., 1983, Comparative effects of beta-adrenergic blocking drugs on experimental ventricular fibrillation threshold, Am J Cardiol 51, 1196-1202.
Antonaccio, M.J. and Gomoll, A., 1993, Pharmacologic basis of the antiarrhythmic and hemodynamic effects of sotalol, Am J Cardiol 72, 27A-37A.
Apkon, M. and Nerbonne, J.M., 1988, Alpha 1-adrenergic agonists selectively suppress voltage-dependent K+ current in rat ventricular myocytes, Proc Natl Acad Sci U S A 85, 8756-8760.
Apkon, M. and Nerbonne, J.M., 1991, Characterization of two distinct depolarization-activated K+ currents in isolated adult rat ventricular myocytes, J Gen Physiol 97, 973-1011.
Arnsdorf, M.F., 1989, Cardiac excitability and antiarrhythmic drugs: a different perspective, J Clin Pharmacol 29, 395-404.
Asano, M., Uchida, W., Shibasaki, K., Terai, M., Inagaki, O., Takenaka, T., Matsumoto, Y. and Fujikura, T., 1990, Pharmacological profiles of YM-16151-1 and its optical isomers: a novel calcium entry blocking and selective beta-1 adrenoceptor blocking agent, J Pharmacol Exp Ther 254, 204-211.
Bean, B.P., 1984, Nitrendipine block of cardiac calcium channels: high-affinity binding to the inactivated state, Proc Natl Acad Sci U S A 81, 6388-6392.
Bean, B.P., 1985, Two kinds of calcium channels in canine atrial cells. Differences in kinetics, selectivity, and pharmacology, J Gen Physiol 86, 1-30.
Belles, B., Malecot, C.O., Hescheler, J. and Trautwein, W., 1988, "Run-down" of the Ca current during long whole-cell recordings in guinea pig heart cells: role of phosphorylation and intracellular calcium, Pflugers Arch 411, 353-360.
Braunwald, E. and Colucci, W.S., 1984, Evaluating the efficacy of new inotropic agents, J Am Coll Cardiol 3, 1570-1574.
Brown, A.M. and Birnbaumer, L., 1988, Direct G protein gating of ion channels, Am J Physiol 254, H401-410.
Carmeliet, E., 1993, K+ channels and control of ventricular repolarization in the heart, Fundam Clin Pharmacol 7, 19-28.
Chakko, C.S. and Gheorghiade, M., 1985, Ventricular arrhythmias in severe heart failure: incidence, significance, and effectiveness of antiarrhythmic therapy, Am Heart J 109, 497-504.
Colatsky, J.J. and Tsien, R.W., 1979, Sodium channels in rabbit cardiac Purkinje fibres, Nature 278, 265-268.
Colatsky, T.J., 1980, Voltage clamp measurements of sodium channel properties in rabbit cardiac Purkinje fibres, J Physiol 305, 215-234.
Colatsky, T.J., Follmer, C.H. and Starmer, C.F., 1990, Channel specificity in antiarrhythmic drug action. Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias, Circulation 82, 2235-2242.
Doerr, T. and Trautwein, W., 1990, On the mechanism of the "specific bradycardic action" of the verapamil derivative UL-FS 49, Naunyn Schmiedebergs Arch Pharmacol 341, 331-340.
Eisner, D.A., Lederer, W.J. and Vaughan-Jones, R.D., 1983, The control of tonic tension by membrane potential and intracellular sodium activity in the sheep cardiac Purkinje fibre, J Physiol 335, 723-743.
Ellrodt, G., Chew, C.Y. and Singh, B.N., 1980, Therapeutic implications of slow-channel blockade in cardiocirculatory disorders, Circulation 62, 669-679.
Fabiato, A., 1983, Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum, Am J Physiol 245, C1-14.
Fabiato, A., 1985, Time and calcium dependence of activation and inactivation of calcium-induced release of calcium from the sarcoplasmic reticulum of a skinned canine cardiac Purkinje cell, J Gen Physiol 85, 247-289.
Fedida, D., Shimoni, Y. and Giles, W.R., 1989, A novel effect of norepinephrine on cardiac cells is mediated by alpha 1-adrenoceptors, Am J Physiol 256, H1500-1504.
Fedida, D., Shimoni, Y. and Giles, W.R., 1990, Alpha-adrenergic modulation of the transient outward current in rabbit atrial myocytes, J Physiol 423, 257-277.
Fish, F.A., Prakash, C. and Roden, D.M., 1990, Suppression of repolarization-related arrhythmias in vitro and in vivo by low-dose potassium channel activators, Circulation 82, 1362-1369.
Franciosa, J.A., Wilen, M., Ziesche, S. and Cohn, J.N., 1983, Survival in men with severe chronic left ventricular failure due to either coronary heart disease or idiopathic dilated cardiomyopathy, Am J Cardiol 51, 831-836.
Giles, W.R. and Imaizumi, Y., 1988, Comparison of potassium currents in rabbit atrial and ventricular cells, J Physiol 405, 123-145.
Giles, W.R. and Shibata, E.F., 1985, Voltage clamp of bull-frog cardiac pace-maker cells: a quantitative analysis of potassium currents, J Physiol 368, 265-292.
Glossmann, H. and Striessnig, J., 1990, Molecular properties of calcium channels, Rev Physiol Biochem Pharmacol 114, 1-105.
Hagiwara, N., Irisawa, H. and Kameyama, M., 1988, Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino-atrial node cells, J Physiol 395, 233-253.
Hamill, O.P., Marty, A., Neher, E., Sakmann, B. and Sigworth, F.J., 1981, Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches, Pflugers Arch 391, 85-100.
Hand, H., 2002, Common cardiac arrhythmias, Nurs Stand 16, 43-52.
Harrison, D.C., 1985, Antiarrhythmic drug classification: new science and practical applications, Am J Cardiol 56, 185-187.
Harvey, R.D. and Ten Eick, R.E., 1988, Characterization of the inward-rectifying potassium current in cat ventricular myocytes, J Gen Physiol 91, 593-615.
Hilgemann, D.W., 1990, Regulation and deregulation of cardiac Na+-Ca2+ exchange in giant excised sarcolemmal membrane patches, Nature 344, 242-245.
Josephson, I.R., Sanchez-Chapula, J. and Brown, A.M., 1984a, A comparison of calcium currents in rat and guinea pig single ventricular cells, Circ Res 54, 144-156.
Josephson, I.R., Sanchez-Chapula, J. and Brown, A.M., 1984b, Early outward current in rat single ventricular cells, Circ Res 54, 157-162.
Kass, R.S., Lederer, W.J., Tsien, R.W. and Weingart, R., 1978, Role of calcium ions in transient inward currents and aftercontractions induced by strophanthidin in cardiac Purkinje fibres, J Physiol 281, 187-208.
Khatter, J.C., Agbanyo, M., Hoeschen, R.J., Navaratnam, S. and Bains, R., 1986, Digitalis-induced mechanical toxicity: protection by slow Ca2+ channel blockers, J Pharmacol Exp Ther 239, 206-210.
Kjekshus, J., 1990, Arrhythmias and mortality in congestive heart failure, Am J Cardiol 65, 42I-48I.
Alam, R., Kataoka, S., Alam, S. and Yatsu, F., 1996, Inhibition of vascular smooth muscle cell proliferation by the calcium antagonist clentiazem: role of protein kinase C, Atherosclerosis 126, 207-219.
Anderson, J.L., Rodier, H.E. and Green, L.S., 1983, Comparative effects of beta-adrenergic blocking drugs on experimental ventricular fibrillation threshold, Am J Cardiol 51, 1196-1202.
Antonaccio, M.J. and Gomoll, A., 1993, Pharmacologic basis of the antiarrhythmic and hemodynamic effects of sotalol, Am J Cardiol 72, 27A-37A.
Apkon, M. and Nerbonne, J.M., 1988, Alpha 1-adrenergic agonists selectively suppress voltage-dependent K+ current in rat ventricular myocytes, Proc Natl Acad Sci U S A 85, 8756-8760.
Apkon, M. and Nerbonne, J.M., 1991, Characterization of two distinct depolarization-activated K+ currents in isolated adult rat ventricular myocytes, J Gen Physiol 97, 973-1011.
Arnsdorf, M.F., 1989, Cardiac excitability and antiarrhythmic drugs: a different perspective, J Clin Pharmacol 29, 395-404.
Asano, M., Uchida, W., Shibasaki, K., Terai, M., Inagaki, O., Takenaka, T., Matsumoto, Y. and Fujikura, T., 1990, Pharmacological profiles of YM-16151-1 and its optical isomers: a novel calcium entry blocking and selective beta-1 adrenoceptor blocking agent, J Pharmacol Exp Ther 254, 204-211.
Bean, B.P., 1984, Nitrendipine block of cardiac calcium channels: high-affinity binding to the inactivated state, Proc Natl Acad Sci U S A 81, 6388-6392.
Bean, B.P., 1985, Two kinds of calcium channels in canine atrial cells. Differences in kinetics, selectivity, and pharmacology, J Gen Physiol 86, 1-30.
Belles, B., Malecot, C.O., Hescheler, J. and Trautwein, W., 1988, "Run-down" of the Ca current during long whole-cell recordings in guinea pig heart cells: role of phosphorylation and intracellular calcium, Pflugers Arch 411, 353-360.
Braunwald, E. and Colucci, W.S., 1984, Evaluating the efficacy of new inotropic agents, J Am Coll Cardiol 3, 1570-1574.
Brown, A.M. and Birnbaumer, L., 1988, Direct G protein gating of ion channels, Am J Physiol 254, H401-410.
Carmeliet, E., 1993, K+ channels and control of ventricular repolarization in the heart, Fundam Clin Pharmacol 7, 19-28.
Chakko, C.S. and Gheorghiade, M., 1985, Ventricular arrhythmias in severe heart failure: incidence, significance, and effectiveness of antiarrhythmic therapy, Am Heart J 109, 497-504.
Colatsky, J.J. and Tsien, R.W., 1979, Sodium channels in rabbit cardiac Purkinje fibres, Nature 278, 265-268.
Colatsky, T.J., 1980, Voltage clamp measurements of sodium channel properties in rabbit cardiac Purkinje fibres, J Physiol 305, 215-234.
Colatsky, T.J., Follmer, C.H. and Starmer, C.F., 1990, Channel specificity in antiarrhythmic drug action. Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias, Circulation 82, 2235-2242.
Doerr, T. and Trautwein, W., 1990, On the mechanism of the "specific bradycardic action" of the verapamil derivative UL-FS 49, Naunyn Schmiedebergs Arch Pharmacol 341, 331-340.
Eisner, D.A., Lederer, W.J. and Vaughan-Jones, R.D., 1983, The control of tonic tension by membrane potential and intracellular sodium activity in the sheep cardiac Purkinje fibre, J Physiol 335, 723-743.
Ellrodt, G., Chew, C.Y. and Singh, B.N., 1980, Therapeutic implications of slow-channel blockade in cardiocirculatory disorders, Circulation 62, 669-679.
Fabiato, A., 1983, Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum, Am J Physiol 245, C1-14.
Fabiato, A., 1985, Time and calcium dependence of activation and inactivation of calcium-induced release of calcium from the sarcoplasmic reticulum of a skinned canine cardiac Purkinje cell, J Gen Physiol 85, 247-289.
Fedida, D., Shimoni, Y. and Giles, W.R., 1989, A novel effect of norepinephrine on cardiac cells is mediated by alpha 1-adrenoceptors, Am J Physiol 256, H1500-1504.
Fedida, D., Shimoni, Y. and Giles, W.R., 1990, Alpha-adrenergic modulation of the transient outward current in rabbit atrial myocytes, J Physiol 423, 257-277.
Fish, F.A., Prakash, C. and Roden, D.M., 1990, Suppression of repolarization-related arrhythmias in vitro and in vivo by low-dose potassium channel activators, Circulation 82, 1362-1369.
Franciosa, J.A., Wilen, M., Ziesche, S. and Cohn, J.N., 1983, Survival in men with severe chronic left ventricular failure due to either coronary heart disease or idiopathic dilated cardiomyopathy, Am J Cardiol 51, 831-836.
Giles, W.R. and Imaizumi, Y., 1988, Comparison of potassium currents in rabbit atrial and ventricular cells, J Physiol 405, 123-145.
Giles, W.R. and Shibata, E.F., 1985, Voltage clamp of bull-frog cardiac pace-maker cells: a quantitative analysis of potassium currents, J Physiol 368, 265-292.
Glossmann, H. and Striessnig, J., 1990, Molecular properties of calcium channels, Rev Physiol Biochem Pharmacol 114, 1-105.
Hagiwara, N., Irisawa, H. and Kameyama, M., 1988, Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino-atrial node cells, J Physiol 395, 233-253.
Hamill, O.P., Marty, A., Neher, E., Sakmann, B. and Sigworth, F.J., 1981, Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches, Pflugers Arch 391, 85-100.
Hand, H., 2002, Common cardiac arrhythmias, Nurs Stand 16, 43-52.
Harrison, D.C., 1985, Antiarrhythmic drug classification: new science and practical applications, Am J Cardiol 56, 185-187.
Harvey, R.D. and Ten Eick, R.E., 1988, Characterization of the inward-rectifying potassium current in cat ventricular myocytes, J Gen Physiol 91, 593-615.
Hilgemann, D.W., 1990, Regulation and deregulation of cardiac Na+-Ca2+ exchange in giant excised sarcolemmal membrane patches, Nature 344, 242-245.
Josephson, I.R., Sanchez-Chapula, J. and Brown, A.M., 1984a, A comparison of calcium currents in rat and guinea pig single ventricular cells, Circ Res 54, 144-156.
Josephson, I.R., Sanchez-Chapula, J. and Brown, A.M., 1984b, Early outward current in rat single ventricular cells, Circ Res 54, 157-162.
Kass, R.S., Lederer, W.J., Tsien, R.W. and Weingart, R., 1978, Role of calcium ions in transient inward currents and aftercontractions induced by strophanthidin in cardiac Purkinje fibres, J Physiol 281, 187-208.
Khatter, J.C., Agbanyo, M., Hoeschen, R.J., Navaratnam, S. and Bains, R., 1986, Digitalis-induced mechanical toxicity: protection by slow Ca2+ channel blockers, J Pharmacol Exp Ther 239, 206-210.
Kjekshus, J., 1990, Arrhythmias and mortality in congestive heart failure, Am J Cardiol 65, 42I-48I.
Lee, C.O. and Dagostino, M., 1982, Effect of strophanthidin on intracellular Na+ ion activity and twitch tension of constantly driven canine cardiac Purkinje fibers, Biophys J 40, 185-198.
Lefevre, I.A., Coulombe, A. and Coraboeuf, E., 1991, The calcium antagonist D600 inhibits calcium-independent transient outward current in isolated rat ventricular myocytes, J Physiol 432, 65-80.
Liang, J.C., Yeh, J.L., Chiang, L.C., Yang, Y.C., Sheu, S.H., Lai, W.T., and Chen, I.J., 2000, Labedipinedilol-A: A vanilloid-based α/β-adrenoceptor blocker with calcium entry blocking and long-acting antihypertensive properties, Drug Dev Res 49, 94-108.
McDonald, T.F., Pelzer, S., Trautwein, W. and Pelzer, D.J., 1994, Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells, Physiol Rev 74, 365-507.
Meinertz, T., Hofmann, T., Kasper, W., Treese, N., Bechtold, H., Stienen, U., Pop, T., Leitner, E.R., Andresen, D. and Meyer, J., 1984, Significance of ventricular arrhythmias in idiopathic dilated cardiomyopathy, Am J Cardiol 53, 902-907.
Mitra, R. and Morad, M., 1985, A uniform enzymatic method for dissociation of myocytes from hearts and stomachs of vertebrates, Am J Physiol 249, H1056-1060.
Mitra, R. and Morad, M., 1986, Two types of calcium channels in guinea pig ventricular myocytes, Proc Natl Acad Sci U S A 83, 5340-5344.
Nayler, W.G., Thompson, J.E. and Jarrott, B., 1982, The interaction of calcium antagonists (slow channel blockers) with myocardial alpha adrenoceptors, J Mol Cell Cardiol 14, 185-188.
Neher, E. and Sakmann, B., 1976, Single-channel currents recorded from membrane of denervated frog muscle fibres, Nature 260, 799-802.
Nilius, B., Hess, P., Lansman, J.B. and Tsien, R.W., 1985, A novel type of cardiac calcium channel in ventricular cells, Nature 316, 443-446.
Pfisterer, M., 1991, Negative inotropic effects of antiarrhythmic drugs: a clinical point of view, J Cardiovasc Pharmacol 17 Suppl 6, S44-47.
Reuter, H., 1967, The dependence of slow inward current in Purkinje fibres on the extracellular calcium-concentration, J Physiol 192, 479-492.
Rose, H., Ionescu, I., Popping, S., Fischer, Y. and Kammermeier, H., 1992, Negative inotropic effects of the new class I antiarrhythmic agents berlafenone and alprafenone on electrically stimulated isolated cardiomyocytes, Arzneimittelforschung 42, 289-291.
Rosen, M.R., Gelband, H., Merker, C. and Hoffman, B.F., 1973, Mechanisms of digitalis toxicity. Effects of ouabain on phase four of canine Purkinje fiber transmembrane potentials, Circulation 47, 681-689.
Sanguinetti, M.C., Scott, A.L., Zingaro, G.J. and Siegl, P.K., 1988, BRL 34915 (cromakalim) activates ATP-sensitive K+ current in cardiac muscle, Proc Natl Acad Sci U S A 85, 8360-8364.
Schocken, D.D., Arrieta, M.I., Leaverton, P.E. and Ross, E.A., 1992, Prevalence and mortality rate of congestive heart failure in the United States, J Am Coll Cardiol 20, 301-306.
Schwartz, A. and Taira, N., 1983, Calcium channel-blocking drugs: a novel intervention for the treatment of cardiac disease. Introduction, Circ Res 52, I1-2.
Schwartz, A. and Triggle, D.J., 1984, Cellular action of calcium channel blocking drugs, Annu Rev Med 35, 325-339.
Sheu, S.S. and Lederer, W.J., 1985, Lidocaine's negative inotropic and antiarrhythmic actions. Dependence on shortening of action potential duration and reduction of intracellular sodium activity, Circ Res 57, 578-590.
Shibasaki, K., Arai, Y., Uchida, W., Okazaki, T., Asano, M. and Takenaka, T., 1997, Antianginal effects of YM430, a novel calcium entry-blocking and beta-adrenoceptor-blocking agent in several experimental angina models, Gen Pharmacol 29, 545-550.
Shibasaki, K., Uchida, W., Shirai, Y., Inagaki, O., Asano, M. and Takenaka, T., 1994, Pharmacological properties of YM-15430-1, a 1,4-dihydropyridine derivative with beta 1-adrenoceptor-blocking activity, Arch Int Pharmacodyn Ther 328, 213-224.
Shibata, E.F. and Giles, W.R., 1985, Ionic currents that generate the spontaneous diastolic depolarization in individual cardiac pacemaker cells, Proc Natl Acad Sci U S A 82, 7796-7800.
Singh, B.N., 1990, Advantages of beta blockers versus antiarrhythmic agents and calcium antagonists in secondary prevention after myocardial infarction, Am J Cardiol 66, 9C-20C.
Vaughan, E.M. and Williams, D.M., 1975, Classification of antidysrhythmic drugs, Pharmacol Ther [B] 1, 115-138.
Vaughan Williams, E.M., 1984, A classification of antiarrhythmic actions reassessed after a decade of new drugs, J Clin Pharmacol 24, 129-147.
Ver Donck, L., Borgers, M. and Verdonck, F., 1993, Inhibition of sodium and calcium overload pathology in the myocardium: a new cytoprotective principle, Cardiovasc Res 27, 349-357.
Watano, T., Harada, Y., Harada, K. and Nishimura, N., 1999, Effect of Na+/Ca2+ exchange inhibitor, KB-R7943 on ouabain-induced arrhythmias in guinea-pigs, Br J Pharmacol 127, 1846-1850.
Wilson, J.R., Schwartz, J.S., Sutton, M.S., Ferraro, N., Horowitz, L.N., Reichek, N. and Josephson, M.E., 1983, Prognosis in severe heart failure: relation to hemodynamic measurements and ventricular ectopic activity, J Am Coll Cardiol 2, 403-410.
Wit, A.L. and Rosen, M.R., 1983, Pathophysiologic mechanisms of cardiac arrhythmias, Am Heart J 106, 798-811.
Yamamoto, N., Nomura, M., Okubo, K., Maeda, K. and Goto, T., 1999, Pharmacologic characterization of FR172516: a new combined calcium channel-blocking and beta-adrenoceptor-blocking agent, J Cardiovasc Pharmacol 33, 587-594.
Yeh, J.L., Liou, S.F., Liang, J.C., Huang, Y.C., Chiang, L.C., Wu, J.R., Lin, Y.T. and Chen, I.J., 2000, Vanidipinedilol: a vanilloid-based beta-adrenoceptor blocker displaying calcium entry blocking and vasorelaxant activities, J Cardiovasc Pharmacol 35, 51-63.
Yeh, J.L., Tsai, C.H., Liang, J.C., Wu, J.R., Huang, Y.C., and Chen, I.J., 2001, Third-generation dihydropyridine-type calcium channel blocker labedipinedilol-B displays α/β-adrenoceptor blocking activities, Drug Dev Res 52, 462-474.
梁至中, Synthesis and pharmacology of new-type calcium channel blocker Labedipinedilol-A. 高雄醫學大學博士論文, 2001年.
蔡玠和, Pharmacological study of a dihydropyridine derivative with α/β adrenergic blocking activities. 高雄醫學大學碩士論文, 2000年.
李誌雄, A new dihydropyridine type calcium channel blocker displaying potassium channel opening and adrenoceptor blocking activities. 高雄醫學大學碩士論文, 2001年.