類鴉片藥物在臨床上，常被使用在嚴重疼痛及心血管疾病患者，當作鎮痛及麻醉劑。長期以來類鴉片藥物產生心血管作用，其作用機轉一直被認為是由於藥物作用在中樞系統所引起。然而，已有愈來愈多實驗證明，類鴉片藥物可藉由周邊系統來調節心血管功能，因此我們將研究類鴉片藥物直接作用在心臟收縮力之影響，並且判別在周邊自主神經系統上之類鴉片受體；更進一步文獻也顯示，類鴉片受體致效劑與拮抗劑，可以不藉和受體結合而產生藥物作用，所以另一方面我們也進一步去瞭解，這類藥物其非類鴉片藥物特性之藥理作用機轉。
　　 首先我們選用選擇性OP2 (kapa) 型類鴉片受體致效劑 "U-50488"，藉由監測天竺鼠心房及心室肌肉組織收縮反應，評估所具有的不同藥物反應。在受電刺激之左心房肌肉組織，U-50488在極低之濃度 (nanomolar範圍) 下，可產生抑制肌肉收縮力，而此作用可被具OP2 (kappa) 型類鴉片受體選擇性拮抗劑norbinaltorphimine (norBNI)，及百日咳菌毒素pertussis toxin (PTX) 所阻斷。然而此作用卻不會被atropine及propranolol前處理所影響。另外此作用也可以被給予norBNI後恢復。雖然U-50488具強的抑制左心房肌肉收縮力，但它卻不影響受電刺激之右心房及兩心室組織收縮力。另一方面U-50488對右心房自發性跳動頻率也不影響，由這些結果給予我們暗示，在左心房組織OP2型類鴉片受體被活化後，可藉由PTX敏感性之G protein，對左心房收縮力產生抑制作用。而在右心房及心室組織不具抑制作用，暗示在左心房組織有較多功能性之OP2型類鴉片受體來產生抑制反應，然而在右心房及心室則具較少OP2型類鴉片受體導致無法產生抑制性作用。
　　 另外我們也判別，在天竺鼠心房組織之自主神經之類鴉片受體類型，實驗方法是藉由監測選擇性類鴉片受體致效劑，對電場刺激 (field stimulation) 心房肌肉自主神經，所產生增強及減弱肌肉收縮雙向反應的影響。心肌因電場刺激所產生增強收縮力之反應，可被OP2型類鴉片受體致效劑，U-50488及U-69593抑制，且效果強。而此作用可被OP2型類鴉片受體拮抗劑norBNI恢復。然而OP1 (delta) 型及OP3 (mu) 型類鴉片受體致效劑（morphine及BW373U86）則不影響。另一方面因電場刺激所引起抑制收縮力反應，不被這些類鴉片受體致效劑影響。由這些結果可得到結論是，天竺鼠心臟交感神經之正腎腺素的釋放可被OP2型類鴉片受體調節，然而副交感神經之乙醯膽鹼的釋放則不受類鴉片受體調節。
　　 OP3 (mu) 型類鴉片受體致效劑嗎啡，對心臟膜電流之作用，在人類及大白鼠單一心臟細胞，使用全細胞膜電位鉗定法測試。嗎啡可隨濃度的增加，增強對心臟鈉電流的抑制作用。鈉電流若每5秒鐘被激發一次，嗎啡對鈉電流抑制一半的濃度 (IC50) 大約在30 microM左右，評估其作用機轉時發現，嗎啡10 microM可使鈉電流穩定不活化曲線向負電位方向移動約5 mV，並且對鈉電流從不活化狀態至恢復之時間有延遲作用。然而若改變激發鈉電流頻率從0.2 Hz至20 Hz，則未發現嗎啡對鈉電流有使用依賴性之抑制 (use-dependent INa block)，然而卻發現嗎啡 (30 microM) 對心臟之鈣電流 (ICa)，瞬時外流鉀電流 (Ito) 及內向整流鉀電流 (IK1) 不產生影響，而嗎啡抑制鈉電流作用，不被類鴉片受體拮抗劑naloxone所阻止或者恢復，所以此部分實驗結果顯示，嗎啡可不藉與類鴉片受體結合，產生抑制鈉電流，而它對鈉離子管道之阻斷機轉，是與不活化狀態之鈉管道結合。
　　 文獻記載，類鴉片受體拮抗劑naloxone在許多體內之實驗模式已證明具有抗心律不整作用，我們在離體大白鼠心臟實驗顯示，當給予naloxone (3∼10 microM) 後，可使缺血再灌流引發心律不整回復至正常之心律，因此更進一步的使用心臟單一細胞膜電流及膜電位鉗定法，研究naloxone抗心律不整作用機轉。在大白鼠心室細胞及天竺鼠、人類心房細胞中，naloxone以可逆性之作用方式延長動作電位期間，另外在大白鼠心室細胞中naloxone (1∼30 microM) 可以抑制鈉電流、瞬時外流鉀電流及鈣電流；相反的naloxone可增加內向整流鉀電流。對於鈉電流之作用，naloxone沒有移動鈉電流穩定不活化曲線，但會使鈉電流從不活化狀態恢復時間延長﹔而對於瞬時外流鉀電流之作用，naloxone可使瞬時外流鉀電流穩定不活化曲線向負電位方向移動，然而對於此電流從不活化狀態恢復時間不影響。在天竺鼠心房細胞實驗中發現，naloxone (10 microM) 可抑制遲發性外流鉀電流，由這些結果顯示naloxone對於心臟膜電流有不同程度之影響，而naloxone延長動作電位期間機轉是與naloxone對瞬時外流鉀電流及遲發性外流鉀電流抑制相關，而其抗心律不整作用是與naloxone直接抑制鈉電流與鉀電流有關，而與naloxone直接阻斷類鴉片受體之作用較不相關。
　　 綜合以上實驗我們發現，在天竺鼠心臟組織中，OP2型類鴉片受體只有在左心房組織可活化，產生抑制左心房收縮力之作用，而在右心房及心室未發現此作用，所以推論類鴉片受體在心臟之作用，可能會受到受體分佈不均而影響﹔在天竺鼠左心房組織自主神經中發現，只有OP2型類鴉片受體存在交感神經突觸之神經末梢，並且可抑制正腎上腺素釋放，而在左心房組織副交感神經則未發現有類鴉片受體存在，影響乙醯膽鹼之釋放。另外在類鴉片受體致效劑嗎啡之實驗也證實，嗎啡對鈉管道可產生阻斷之作用，並且作用在該管道不活化狀態，而此作用不透過嗎啡與類鴉片受體結合產生，而是嗎啡本身之直接作用。
另外在類鴉片受體拮抗劑naloxone實驗中發現，naloxone具有良好抗心律不整之作用，此作用是由於naloxone對鈉管道及鉀管道之直接作用，與類鴉片受體無關，在膜電流與膜電位鉗定實驗發現，其延長動作電位期間是由於naloxone對瞬時外流鉀電流及遲發性外流鉀電流抑制所產生。其抗心律不整作用與鈉電流及鉀電流抑制有關。

Opioids are widely used as analgesics or anesthetics in patients with intolerable pain, limited cardiovascular performace, or ischemic heart disease. It has long been recognized that opioids have potent actions on the cardiovascular system. The cardiovascular effects have been attributed to action central nervous system. Several lines of evidence, however, indicate that opioid can regulate the cardiovascular system by peripheral mechanism of action. Therefore, we investigated the direct effects of opioid on cardiac contractility and the opioid receptor subtype involved in regulation of autonomic nervous function. Furthermore, opioid receptor agonists and antagonist have "nonopioid'' action in heart. We also investigated the nonopioid actions of opioid receptor agonist and antagonist on heart.
The differential effects of a selective kappa (OP2)-opioid receptor agonist, U50488, were elucidated by monitoring the contraction of isolated guinea pig atrial and ventricular muscles. In electrically driven left atria, U50488 in nanomolar concentration range decreased the contractile force. Norbinaltorphimine (norBNI), a selective OP2-receptor antagonist, and pertussis toxin (PTX) pretreatment abolished the negative inotropic effect of U50488. In contrast, the inhibitory effect was not affected by the pretreatment of atropine and propranolol. The negative inotropic effect was also reversed by norBNI. Though U50488 exerted the negative inotropic effect in left atrium, it didn''t affect the contractile force of right atrium and both ventricles paced at 2 Hz. On the other hand, the beating rates in spontaneously beating right atria were also unchanged by U50488. These results suggest that activation of OP2-opioid receptor can produce negative inotropic effect only in left atria via activation of PTX-sensitive G protein. The absence of effects in right atria and ventricles indicate the greater distribution of functional OP2-opioid receptor in guinea pig left atria than in right atria and ventricles.
The opioid receptor subtypes of autonomic nerves of guinea pig atria were elucidated by monitoring the effects of selective opioid receptor agonists on the negative and positive inotropic responses respectively associated, with stimulation of the parasympathetic and sympathetic nerves. The positive inotropic effect, evoked by electrical field stimulation (2 Hz) was strongly reduced by the selective OP2-opioid receptor agonists U-50488 and U-69593. This effect was reversed by the selective OP2-opioid receptor antagonist nor-BNI. Whereas both OP1- and OP3-opioid receptor agonists, morphine and BW373U86, were ineffective. On the other hand, the negative inotropic response to electrical field stimulation was not affected by opioid receptor agonists. These results suggest that the noradrenaline release from cardiac sympathetic nerves of guinea pig could be modulated by OP2-opioid receptor, however, the acetylcholine release from cardiac parasympathetic nerves is not modulated by opioid receptors.
Direct effects of morphine, an mu (OP3)-opioid receptor agonist on various membrane ionic currents of rat ventricular and human atrial myocytes were examined by using patch-clamp techniques in whole-cell configuration. Morphine produced a concentration-dependent reduction in peak transient sodium current. When the sodium current (INa) was evoked at 5 s interval the estimated IC50 for morphine was about 30 microM. Morphine (10 mM) inhibited INa with a 5 mV shift in the potential-dependent inactivation curve to negative potentials and retarded the INa recovery rate from inactivation state. But use-dependent INa block was not observed when INa was elicited at frequency varied from 1 to 20 Hz. Morphine did not significantly affect the calcium inward current (ICa), transient outward current (Ito) and inwardly rectifying potassium current (IK1) at concentration of 30 microM. The inhibition effect of morphine on INa could not be prevented and reversed by treatment of the cells with opioid antagonist naloxone. According to these results, we suggest that morphine can directly inhibit the Na+ inward current and bind to the inactivated Na+ channels.
Naloxone, an opioid antagonist, was previously shown to have antiarrhythmic activity in vivo. In Langendorff perfused rat hearts, we found that ischemia/reperfusion-induced ventricular tachyarrhythmia reverted to normal sinus rhythm after the treatment with naloxone (3~10 microM). In this study, the underlying mechanism of its antiarrhythmic activity was investigated by method of voltage clamp or current clamp on isolated cardiac myocytes. In isolated rat ventricular and in guinea-pig and human atrial myocytes, naloxone prolonged the action potential duration reversibly. In rat ventricular myocytes, naloxone (1~30 microM) inhibited calcium current (ICa), transient outward potassium current (Ito), and sodium current (INa) concentration dependently. On the contrary, naloxone significantly increased inward rectifier potassium current (IK1). For the effect on INa, naloxone did not shift the inactivation curve of INa but retarded the INa recovery rate from inactivation state. Naloxone suppressed Ito with a significant left-shift of the inactivation curve, however, the time course of Ito recovery from inactivation was not affected. In human atrial myocytes, similar suppression of Ito by naloxone (3 microM) was also found. In guinea pig atrial myocytes, naloxone (10 microM) decreased the delayed rectifier K+ current (IK). These results show that naloxone exert various extent of inhibition on INa, Ito, IK and ICa. The prolongation of cardiac action potential is related to the inhibition of Ito and IK. The antiarrhythmic activity of naloxone is more closely related to the inhibition of Na+ and K+ currents rather than the blockade of myocardial opioid receptors.

縮寫表×××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××× 1
中文摘要×××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××× 3
英文摘要×××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××× 9
第一章 緒論××××××××××××××××××××××××××××××××××××××××××××××××××××××××××× 15
第二章 選擇性OP2型類鴉片受體致效劑U-50488在天竺鼠心臟組織之作用差異×× 49
第三章 判別天竺鼠心臟組織交感神經與副交感神經之類鴉片受體××××××××××××× 69
第四章 嗎啡對心臟單一細胞膜電流之影響?非類鴉片受體之作用×××××××××××××× 91
第五章 類鴉片受體拮抗劑naloxone在心臟組織中產生抗心律不整之作用機轉×× 121
第六章 綜合結論與展望××××××××××××××××××××××××××××××××××××××××××××××× 155
參考文獻×××××××××××××××××××××××××××××××××××××××××××××××××××××××××××× 159
論文相關著作×××××××××××××××××××××××××××××××××××××××××××××××××××××××× 190

Adler MW, Geller EB, Rosow CE, Cochin J. The opioid system and temperature regulation. Ann Rev Pharmacol Toxicol 1988; 18: 429-449.
Alarcon S, Hernandez J, Laorden ML. Effects of morphine: an electrophysiological study on guinea-pig papillary muscle. J Pharm Pharmacol 1992; 44: 275-277.
Apkon M, Nerbonne JM, Characterization of two distinct depolarization-activated K+ currents in isolated adult rat ventricular myocytes. J Gen Physiol 1991; 97: 973-1011.
Atweth SF, Kuhar MJ. Autoradiographic localization of opiate receptors in rat brain. I. Spinal cord and lower medulla. Brain Res 1977; 124: 53-67.
Barron BA, Gu H, Gaugl JF, Caffrey JL. Screening for opioids in dog heart. J Mol Cell Cardiol 1992; 24: 67-77.
Bean BP. Two kinds of calcium channels in canine atrial cells: Differences in kinetics, selectivity and pharmacology. J Gen Physiol 1985; 86: 1-31.
Bell C. Differential effects of tetrodotoxin on sympathomimetic actions of nicotine and tyramine. Br J Pharmacol 1968; 32: 96-103.
Benthuysen JL, Smith NT, Sanford TJ, Head N, Dec-Silver H. Physiology of alfentanil-induced rigidly. Anesthesiology 1986; 64: 440-446.
Bergey JL, Beil ME. Antiarrhythmic evaluation of naloxone against acute coronary occlusion-induced arrhythmias in pig. Eur J Pharmacol 1983; 90: 427-431.
Bian JS, Zhang WM, Xia Q, Wong TM. Phospholipase C inhibitors attenuate arrhythmias induced by k-receptor stimulation in isolated ret heart. J Mol Cell Cardiol 1998; 30: 2103-2110.
Blinks JR. Field stimulation as a means of effecting the graded release of autonomic transmitters in isolated heart muscle. J Pharmacol Exp Ther 1966; 151: 221-235.
Bollolli R. Mechanism of myocardial "stunning". Circulation 1990; 82: 723-738.
Boluyt MO, Younes A, Caffrey JL, O''Neill L, Barron BA, Crow MT, Lakatta EG. Age-associated increase in rat cardiac opioid production. Am J Physiol 1993; 265: H212-H218.
Brasch H. Influence of the optical isomers (+)- and (-)-naloxone on beating frequency, contractile force and action potentials of guinea-pig isolated cardiac preparations. Br J Pharmacol 1986; 88: 733-740.
Braunwald E, Kloner RA. The stunned myocardium-prolonged post-ischemic ventricular dysfunction. Circulation 1982; 66: 1146-1149.
Caffrey JL, Boluyt MO, Younes A, Barron BA, O''Neill L, Crow MT, Lakatta EG. Aging, cardiac proenkephalin mRNA and enkephalin peptides in the fisher 344 rat. J Mol Cell Cardiol 1994; 26: 701-711.
Callahan P, Pasternak GW. Opiates, opioid peptides and their receptors. J Cardiothorac Anesth 1987; 1: 569-576.
Carmeliet E, Saikawa T. Shortening of the action potential and reduction of pacemaker activity by lidocaine, quinidine, and procainamide in sheep cardiac purkinje fibers. Circ Res 1982; 50: 257-272.
Carmeliet E. Voltage- and time-dependent block of the delayed K+ current in cardiac myocytes by dofetilide. J Pharmacol Exp Ther 1992; 262: 809-817.
Carratu, MR, Mitolo-Chieppa D. Inhibition of ionic currents in frog node of Ranvier treated with naloxone. Br J Pharmacol 1982; 77: 115-119.
Cerbai E, Cavalcabo PDB, Masini I, Porciatti F, Mugelli A. Antiarrhythmic properties of naloxone : an electrophysiological study on sheep cardiac Purkinje fibers. Eur J Pharmacol 1989; 162: 491-500.
Chi JF, Chu SH, Lee CS, Chou NK, Su MJ. Mechanical and electrophysiological effects of 8-oxoberberine (JKL 1073A) on atrial tissue. Br J Pharmacol 1996; 118: 503-512.
Clarkson CW, Follmer CH, Ten Eick RE, Hondeghem LM, Yeh JZ. Evidence for two component of sodium channel block by lidocaine in isolated cardiac myocytes. Circ Res 1988; 63: 869-878.
Cohen CJ, Bean BP, Tsien RW. Maximal upstroke velocity as an index of available sodium conductance. Comparison of maximal upstroke velocity and voltage clamp measurements of sodium current in rabbit Purkinje fibers. Circ Res 1984; 54: 636-651.
Colatsky TJ, Follmer CH, Starmer CF. Channel specificity in antiarrhythmic drug action. Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias. Circulation 1990; 82: 2235-2242.
Colatsky TJ. Mechanisms of action of lidocaine and quinidine on action potential duration in rabbit cardiac Purkinje fibers. An effect on steady state sodium currents? Circ Res 1982; 50: 17-27.
Cooper DMF, Mons M, Karpen JW. Adenylyl cyclases and the interaction between calcium and cAMP signaling. Nature 1995; 373: 421-424.
Coraboeuf E, and Carmeliet E. Existence of two transient outward currents in sheep Purkinje fibers. Pflugers Arch 1982; 392: 352-359.
Curtis MJ, Hearse DJ. Ischemia-induced and reperfusion-induced arrhythmias differ in their sensitivity to potassium: implications for mechanisms of initiation and maintenance of ventricular fibrillation. J Mol Cell Cardiol 1989; 21: 21-40.
DiFrancesco DA, Ferroni M, Mazzanti M, Tromba C. Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol 1993; 55, 455-472.
Dirksen R, Otten, MH, Wood GJ, Verbaan CJ, Haalebos MM, Verdouw PV, Nijhuis GMN. Naloxone in shock . Lancet 1980; 2: 1360.
Du XY, Schoemaker RG, Bos E, Saxena PR. Different pharmacological responses of atrium and ventricle: studies with human cardiac tissue. Eur J Pharmacol 1994; 259: 173-180.
Dukes ID, Cleemann L, Morad M. Tedisamil blocks the transient and delayed rectifier K+ currents in mammalian cardiac and glial cell. J Pharmacol Exp Ther 1990; 254: 560-569.
Dukes ID, Morad M. Tedisamil inactivates transient and delayed rectifier K+ currents in rat ventricular myocytes. Am J Physiol 1989; 257: H1746-H1749.
Dumont M, Oullette M, Brakier-Gingras L, Lemaire S. Circadian regulation of the biosynthesis of cardiac Met-enkephalin and precursors in normotensive and spontaneously hypertensive rat. Life Sci 1991; 48: 1895-1902.
Eisner DA, Lederer WT. Na-Ca exchange: Stoichiometry and electrogenicity. Am J Physiol 1985; 248:Cl89-C202.
Escande D, Coulombe A, Faivre, JF, Deroubaix E, Coraboeuf E. Two types of transient outward currents in adult human atrial cells. Am J Physiol 1987; 252: H142-H148.
Evans CJ, Keith DE, Morrison H, Magendzo K, Edwards RH. Cloning of a delta opioid receptor by functional expression. Science (Wash. DC) 1992; 258: 1039-1044.
Faden AI. Role of endogenous opioids in central cardiaovascular regulation and dysregulation. In: A Herz (ed.) Opioid II (Handbook of experimental pharmacology series, vol 104). Springer, Berlin Heidelberg New York, 1993, pp. 191-204.
Faden, AI, Holaday JW. Opiate antagonists a role in the treatment of hypovolemic shock. Science 1979; 250: 317-318.
Fagbemi O, Lepran I, Parratt JR, Szekeres L. Naloxone inhibits early arrhythmias resulting from acute coronary ligation. Br J Pharmacol 1982; 76: 504-506.
Fermini B, Wang Z, Duan DY, Nattlel S. Differences in the rate dependence of the transient outward current in rabbit and human atrium. Am J Physiol 1992; 263: H1747-H1745.
Ferrier GR, Moffat MP, Lukas A. Possible mechanisms of ventricular arrhythmias elicited by ischemia followed by reperfusion: studies on isolated canine ventricular tissues. Circ Res 1985; 56: 184-194.
Feuertein G, Siren A-L. The opioid system in cardiac and vascular regulation of normal and hypertensive states. Circulation 1987; 75 Suppl I: 1125-1129.
Flacke JW, Flacke WE, Bloor BC, Van Etten AP, Kripke BJ. Histamine release by four narcotics: a double-blind study in humans. Anesth Analg 1987; 66: 723-730.
Frame LH, Argentieri TM. Naloxone has local anesthetic effects on canine cardiac Purkinje fibers. Circulation 1985; 72 Suppl III: 234.
Frazier DT, Ohta M, Marahashi T. Nature of the morphine receptor present in the squid axon. Proc Soc Exp Biol Med 1973; 142: 1209-1214.
Fryer RM, Hsu AK, Eells JT, Nagase H, Gross GJ. Opioid-induced second window of cardioprotection: potential role of mitochondrial KATP channels. Circ Res 1999; 84: 846-851.
Fuder H, Buder M, Riers HD, Rothacher G. On the opioid receptor subtype inhibiting the evoked release of 3H-noradrenaline from guinea-pig atria in vitro. Naunyn-Schmiedeberg''s Arch Pharmacol 1986; 322: 148-155.
Gautret B. Schmitt H. Multiple sites for the cardiovascular actions of fentanyl in rats. J Cardiovasc Pharmacol 1985; 7: 649-652.
Giles WR. Imaizumi Y. Comparison of potassium currents in rabbit atrial and ventricular cells. J Physiol (Lond) 1988; 405:123-145.
Gurney AM. Molecular pharmacology of ion channels using the patch clamp. In EC Hulme (eds.): Receptor-Effector Coupling. A Practical Approach, IRL Press, 1990, pp. 155-179.
Gwathmey JK, Haijjar RJ. Effect of protein kinase C activation on sarcoplasmic reticulum function and apparent myofibrillar Ca2+ sensitivity in intact and skinned muscles from normal and diease human myocardium. Circ Res 1990; 67: 744-752.
Hagiwara NH, Irisawa H, Kameyama M. Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino-atrial node cells. J Phsiol (Lond) 1988; 395: 233-253.
Hagiwara NH, Irisawa H, Kasanuki H, Hosoda S. Background current in sino-atrial node cells of the rabbit heart. J Physiol (Lond) 1992; 448: 53-72.
Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ. Improved patch clamp techniques for high resolution current recording from cells and cell-free membrane patchs. Pflugers Arch 1981; 391: 85-100.
Hantson P, Evenepoel M, Ziade D, Hassoun A, Mahieu P. Adverse cardiac manifestations following dextropropoxyphene overdose: Can naloxone be helpful? Ann Emerg Med 1995; 25: 263-266.
Harrison C, Smart D, Lambert DG. Stimulatory effects of opioids. Br J Anaesth 1998; 81: 20-28.
Harrison DC. Is there a relational basis for the modified classification of antiarrhythmic drugs? In J Morganroth, EN Moore (eds.): New Drugs and Devises. Boston, MA, Martinus Nijhoff, 1985, pp. 36-40.
Hirano Y, Hiraoka M. Barium-induced automatic activity in isolated ventricular myocytes from guinea pig hearts. J Physiol (Lond) 1988; 395: 455-472
Hiraoka M, Kawano S. Calcium-sensitive and insensitive transient outward current in rabbit ventricular myocytes. J Physiol (Lond) 1989; 410: 187-212.
Holaday JW, Faden AI. Naloxone acts at central opiate receptors to reverse hypotension, hypothermia and hypoventilation in spinal shock. Brain Res 1980; 189: 295-299.
Holaday JW, Faden AI. Naloxone reversal of endotoxin hypotension suggests role of endorphins in shock. Nature 1978; 275: 450-451.
Holaday JW. Cardiovascular effects of endogenous opiate systems. Ann Rev Pharmacol Toxicol 1983; 23: 541-594.
Holubarsch C, Hasenfuss G, Schmidt-Schweda S, Knorr A, Pieske B, Ruf T, Fasol R, Just H: Angiotensin I and II exert inotropic effects in atrial but not in ventricular human myocardium. An in vitro study under physiological experimental conditions. Circulation 1993; 88: 1228-1237.
Hong SJ, Chang CC. Calcium channel subtypes for the sympathetic and parasympathetic nerves of guinea-pig atria. Br J Pharmacol 1995; 116 : 1577-1582.
Howells RD, Kilpatrick DL, Bailey LC, Noe M, Udenfriend S. Preproenkephalin mRNA in rat heart. Proc Natl Acad Sci USA 1986; 83: 1960-1963.
Huang XD, Lee AYS, Wong TM, Zhan CY, Zhao YY. Naloxone inhibits arrhythmias induced by coronary artery occlusion and reperfusion in anaesthetized dogs. Br J Pharmacol 1986; 87: 475-477.
Hughes J, Kosterlitz HW, Smith TW. Distribution of methionine-enkephalin and leucine enkephalin in the brain and peripheral tissues, Br J Pharmacol 1977; 62: 639-647.
Hughes J. Peripheral opiate receptor mechanisms. Trends Pharmacol Sci 1981; 2: 21-24.
Hume JR, Uehara A. Ionic basis of the different action potential configurations of single guinea pig atrial and ventricular myocytes. J Physiol 1985; 368: 525-544.
Hurle MA, Mediavillo A, Florez J. Differential respiratory patterns induced by opiois applied to the ventral medullary and dorsal pontine surfaces of cats. Neuropharmacology 1985; 24: 597-606.
Hutter OF, Noble D. Rectifying properties of heart muscle. Nature 1960; 188: 495.
Isenberg G, Klockner. Calcium tolerant ventricular myocytes prepared by preincubation in a KB-medium. Pflugers Arch 1982; 394: 6-18.
Isenberg G. Cardiac Purkinje fibers: cesium as a tool to block inward rectifying potassium currents. Pflugers Arch 1976; 365: 99-106.
Jahnel U, Klemm, P, Nawrath H. Different mechanisms of the inhibition of the transient outward current in rat ventricular myocytes. Naunyn-Schmiedeberg''s Arch Pharmacol 1994; 349: 87-94.
Jahnel U, Rupp J, Ertl R, Nawrath H. Positive inotropic response to 5-HT in human atrial but not in ventricular heart muscle. Naunyn-Schmiedeberg''s Arch Pharmacol 1992; 346: 482-485.
Jakob H, Nawrath H. Tetrodotoxin slightly shortens action potential duration in ventricular but not in atrial heart muscle. Experientia 1988; 44: 16-17.
Jia H, Furukawa T, Singer DH, Sakakibara Y, Eager S, Backer C. Characteristics of lidocaine block of sodium channels in single human atrial cells. J Pharmacol Exp Ther 1993; 264: 1275-1284.
Josephson IR, Sanchez-Chapula J, Brown AM. Early outward current in rat single ventricular cells. Circ Res 1984; 54: 157-162.
Ju YK, Saint DA, Gage PW. Effects of lignocaine and quinidine on the persistent sodium current in rat ventricular myocytes. Br J Pharmacol 1992; 107: 311-316.
Kanemasa T, Asakura K, Ninomiya M. k-opioid agonist U50488 inhibits P-type Ca2+ channels by two mechanisms. Brain Res 1995; 702: 207-212.
Kaschube M., Brasch H. Negative chronotropic but no antiarrhythmic effect of (+)- and (-)- naloxone in rats and guinea pigs. Cardiovasc Res 1991; 25: 230-234.
Kass RS, Sanguinetti MC. Inactivation of calcium channel current in calf cardiac Purkinje fiber. Evidence for voltage- and calcium-mediated mechanisms. J Gen Physiol 1984; 84: 705-726.
Katz RI, Kopin IJ. Electrical field-stimulated release of epinephrine-H3 from rat atrium: effects of ions and drugs, J Pharmacol Exp Ther 1969; 169: 229-236.
Kenyon JL, Gibbons WR. Influence of chloride, potassium, and tetraethylamonium on the early outward current of sheep cardiac Purkinje fibers. J Gen Physiol 1979; 73: 117-138.
Kieffer B, Befort K, Gaveriaux-Ruff C, Hirth CG. The delta opioid receptor: isolation of a cDNA by expression clonining and pharmacological characterization. Proc Natl Acad Sci USA 1992; 89: 12048-12052.
Kieffer BL. Molecular aspect of opioid receptors. In: A Dickenson, JM Besson (eds.): The Pharmacology of Pain. Berlin Heidelberg: Springer-Verlag, 1997, pp. 281-304.
Kieffer BL. Opioids: first lessons from knockout mice. Trend Pharmacol Sci 1999; 20: 19-26.
Kieffer BL. Recent advances in molecular recognition and signal transduction of active peptides: receptors for opioid peptides. Cell Mol Neurobiol 1995; 15: 615-635.
Kojima M, Hamamoto T, Ban T. Sodium channel-blocking properties of flecainide, a class Ic antiarrhythmic drug in guinea pig papillary muscles. An open channel blocker or an inactivated channel blocker. Naunyn-Schmiedeberg''s Arch Pharmacol 1989; 399: 441-447.
Kosterlitz HW, Taylor DW. The effect of morphine on vagal inhibition of the heart. Br J Pharmacol 1959; 14: 209-214.
Koumi S, Sato R, Katori R, Hisatome I, Nagasawa K, Hajakawa H. Sodium channel states control binding and unbinding behavior of antiarrhythmic drugs in cardiac myocytes from the guinea pig. Cardiovasc Res 1992; 26: 1199-1205
Koumi SK, Backer CL, Arentzen CE. Characterization of inwardly rectifying K+ channel in human cardiac myocytes. Circulation 1995; 92: 164-174.
Lambert DG. Recent advances in opioid pharmacology. Br J Anaesth 1998; 81: 3-7.
Lang RE, Hermann K, Dietz R, Gaida W, Ganten D, Kraft K, Unger T. Evidence for the presence oof enkephalins in the heart. Life Sci 1983; 32: 399-406.
Langenfeld H, Weirich J, Kohler C, Kochsiek K. Comparative analysis of the action of class I antiarrhythmic drugs (lidocaine, quinidine, and prajmaline) in rabbit atrial and ventricular myocardium. J Cardiovasc Pharmacol 1990; 15: 338-345.
Laorden ML, Hernandez J, Caceles MD, Miralles FS, Puig MM. Interaction between halothane and morphine on isolated heart muscle. Eur J Pharmacol 1990; 175: 285-290.
Laubie M, Schmitt H Drouillat M. Central sites and mechanisms of hypotensive and bradycardic effects of the narcotic analgesic agent fentanyl. Naunyn-Schmiedeberg''s Arch Pharmacol 1977a; 296: 255-261.
Laubie M, Schmitt H, Vincent M, Remond G. Central cardiovascular effects of morphinomimetic peptides in dogs. Eur J Pharmacol 1977b; 46: 67-71.
Ledda F, Mantelli L, Corti V, Fantozzi R. Inhibition of the cardiac response to sympathetic nerve stimulation by opioid peptides and its potentiation by morphine and methadone. Eur J Pharmacol 1984; 102: 443-450.
Lee KS, Hume JR, Giles W, Brown AM. Sodium current depression by lidocaine and quinidine in isolated ventricular cells. Nature 1981; 291: 325-327.
Litovsky SH, Antzelevitch C. Transient outward current prominent in canine ventricular epicardium but not endocardium. Circ Res 1988; 62: 116-126.
Llobel F, Laorden ML. Effects of morphine on atrial preparations obtained from non-failing and failing human hearts. Br J Anaesth 1996; 76: 106-110.
Lubbe WF, Bricknell OL, Marzagao C. Ventricular arrhythmias associated with coronary artery occlusion and reperfusion in the isolated perfused rat heart: A mode for assessment of antifibrillatory action of antiarrhythmic agents. Cardiovasc Res 1978; 12: 212-220.
Manson JW, Hondeghem LM, Katzung BC. Amiodarone blocks inactivated cardiac sodium channels. Pflugers Arch 1983; 396: 79-81.
Markiewicz K, Kus W, Cholewa M, Bubinski R. Electrophysiologic effects of blocking and stimulating the opioid system in patients with unexplained heart palpitations. Clin Cardiol 1991; 14: 813.
Matuda H. Open state substructure of inwardly rectifying potassium channels revealed by magnesium block in guinea pig heart cells. J Physiol (LOND) 1988; 397: 237-258.
Maxwell RJ, Lip YH. Reperfusion injury: a review of the pathophysiology, clinical manifestations and therapeutic options. Int J Cardiol 1997; 58: 95-117.
Medgett IC, McCulloch MW, Rand MJ. Partial agonist action of clonidine on prejunctional and postjunctional a-adrenoceptors. Naunyn-Schmiedeberg''s Arch Pharmacol 1978; 304: 215-221.
Micol JA, Laorden ML. Effects of m-, d- and k-agonists on isolated right atria of the rat. Neuropeptides 1994; 26: 365-370.
Micol JA, Laorden ML. Interaction between halothane and mu, delta and kappa opioid agonists on the isolated right atria of the rat. Br J Anaesth 1992; 69: 487-491.
Micol JA, Laorden ML. Involvement of catecholamines in the effect of U-50,488H on isolated left atria of the rat. Gen Pharmacol 1993; 24: 873-875.
Miki T, Cohen MV, Downey JM. Opioid receptor contributes to ischemic preconditioning through protein kinase C activation in rabbits. Mol Cell Biochem 1998; 186: 3-12.
Mitra R, Morad M. A reliable method for dissociation of myocytes from heart and stomach of vertebrates. Am J Physiol 1985; 18: H1056-H1060.
Mohrman DE, Heller LJ. Charcteristics of cardiac cells. In DE Mohrman, LJ Heller (eds.): Cardiovascular physiology. McGraw-Hill Press, 1997, pp. 21-46.
Moote CA, Knill RL, Skinner RN, Rose EA. Morphine produces a dose dependent respiratory depression which is potentiated by nonREM sleep. Anesth Analg 1989; 68: S201.
Morad M, Goldman Y. Excitation-contraction coupling in heart muscle: membrane control of development of tension. Prog Biophys Mol Biol 1973; 27: 257-313.
Murat I, Levron JC, Berg A, Saint-Maurice C. Effects of fentanyl on baroreceptor reflex control of heart rate in newborn infants. Anesthesiology 1988; 68: 717-722.
Musha T, Satoh E, Koyanagawa H, Kimura T, Satoh S. Effects opioid agonists on sympathetic and parasympathetic transmission to the dog heart. J Pharmacol Exp Ther 1989; 250: 1087-1091.
Neer EJ. Heterotrimeric G-proteins-organizers of transmembrane signals. Cell 1995; 80: 249-257.
Nilius B, Hess P, Lansman JB, Tsien RW. A novel type of cardiac calcium channel in ventricular cells. Nature (Lond) 1985; 316: 443-446.
Niroomand F, Mura RA, Piacentini L, Kubler W. Opioid receptor agonists activate pertussis toxin-sensitive G proteins and inhibit adenylyl cyclase in canine cardiac sarcolemma. Naunyn-Schmiedeberg''s Arch Pharmacol 1996; 354: 643-649.
Noble D, Tsien RW. The kinetics and rectifier properties of slow potassium current in cardiac Purkinje fibers. J Physiol (Lond) 1968; 195: 185-214.
Oldroyd KG, Hicks MN, Cobbe SM. Influence of hyperkalaemia and ischemia on non-receptor-mediated cardiac electrophysiological effects of naloxone. Cardiovasc Res 1993; 27: 296-303.
Pancrazio JJ, Frazer MJ, Lynch C. Barbiturate anesthetics depress the resting K+ conductance of myocardium. J Pharmacol Exp Ther.1993; 265: 358-365.
Parratt JR, Sitsapesan R. Stereospecific antiarrhythmic effect of opioid receptor antagonists in myocardial ischemia. Br J Pharmacol 1986; 87: 621-622.
Pasqualucc V, Moricca G, Solinas P. Intrathecal morphine for the control of the pain of myocardial infarction. Anaesthesia 1981; 36: 68-69.
Patel S, Patel U, Vithalani D, Verma SC. Regulation of catecholamine release by presynaptic receptor system. Gen Pharmacol 1981; 12: 405-422.
Paterson SJ, Robson LE, Kasterlitz HW. Classification of opioid receptors. Br Med Bull 1983; 39: 31-36.
Pepe S, Xiao RP, Hohl C, Altschuld R, Lakatta EG. '' Cross talk'' between opioid peptide and adrenergic receptor signaling in isolated rat heart. Circulation 1997; 95: 2122-2129.
Peters WP, Johnson MW, Friedman PA, Mitch WE. Pressor effect of naloxone in septic shock. Lancet 1981; 1: 529-532.
Pogwizd S, Corr PB. Electrophysiological mechanisms underlying arrhythmias due to reperfusion of ischemic myocardium. Circulation 1987; 56: 184-194.
Pugsley MK, Penz, WP, Walker MJA, Wong TM. Cardiovascular actions of k-agonist, U-50,488H in the absence and presence of opioid receptor blockade. Br J Pharmacol 1992; 105: 521-526.
Pugsley MK, Saint DA, Penz MP, Walker MJ. Elecrophysiological and antiarrhythmic actions of the kappa agonist PD 129290, and its R, R (+)-enantiomer, PD 129289. Br J Pharmacol 1993; 110: 1579-1585.
Pugsley MK, Saint DA, Walker MJA. An electrophysiological basis for the antiarrhythmic actions of the k-opioid receptor agonist U-50,488H. Eur J Pharmacol 1994; 261: 303-309.
Rabkin SW. Morphine and morphicetin increase the threshold for epinephrine-induced cardiac arrhythmias in the rat through mu opioid receptors. Clin Exp Physiol 1993; 20: 95-102.
Rees S, Pabla R, Pugsley MK, Banner K, Curtis MJ. Drugs and the cardiovascular system. In CP Page, MJ Curtis, MC Sutter, MJA Walker, BB Hoffman (eds.): Integrated Pharmacology. Mosby Press, 1997, pp. 158-164.
Reisine T, Bell GL. Molecular biology of opioid receptors. Trends Neurosci 1993; 16: 506-510.
Roden DM, George ALJr. The cardiac ion channels: relevance to management of arrhythmias. Annu Rev Med 1996; 47: 135-148.
Rogers TB, Gaa ST, Massey C. Dosemeci A. Protein kinase C inhibits Ca2+ accumulation in cardiac sarcoplasmic reticulum. J Biol Chem 1990; 265: 4302-4308.
Rosow CE, Philbin DM, Keegan CR, Moss J. hemodynamics and histamine release during induction with sufentanil or fentanyl. Anesthesiology 1984; 60: 489-491.
Saeki T, Nishimura M, Sato N, Fujinami T, Watanabe Y. Electrophysiological demonstration and activation of m-opioid receptors in the rabbit sinoatrial node. J Cardiovasc Pharmacol 1995; 26: 160-168.
Sagy, M, Shavit G, Oron Y,Vidne BA, Gitter S, Sarne Y. Nonopiate effect of naloxone on cardiac muscle contractility. J Cardiaovasc Pharmacol 1987; 9: 682-685.
Sanchez-Chapula J, Tsuda Y, Joephson IR. Voltage and use-dependent effect of lidocaine on sodium current in single ventricular cell. Circ Res 1983; 52: 557-565.
Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K+ current. J Gen Physiol 1990; 96: 195-215.
Sanguinetti MC, Siegl PKS. Control of cardiac contractility by K+ channel modulators; in JK Gwathmey (ed.): Heart Failure: Basic Science and Clinical Aspects. New York, Marcel Dekker, 1993, pp. 613-627.
Sarne Y, Flitstein A, Oppenheimer E. Anti-arrhythmic activities of opioid agonists and antagonists and their stereoisomers. Br J Pharmacol 1991; 102: 696-698.
Sarne Y, Hochman I, Eshed, M, Oppenheimer E. Antiarrhythmic action of naloxone: direct, non-opiate effect on the rat heart. Life Sci 1988 43: 859-864.
Satoh M, Minami M. Molecular pharmacology of the opioid receptors. Pharmacol Ther 1995; 68: 343-364.
Saxena PR, Villalon CM, Dhasmana KM, Verdouw PD. 5-hydroxytryptamine-induced increase in left ventricular dP/dtmax does not suggest the presence of ventricular 5-HT4 receptors in the pig. Naunyn-Schmiedeberg''s Arch Pharmacol 1992; 346: 629-636.
Schoemaker RG, Du XY, Bax WA, Bos E, Saxena PR. 5-hydroxytryptamine stimulates human isolated atrium but not ventricle. Eur J Pharmacol 1993; 230: 103-105.
Schoemaker RG, Du XY, Bax WA, Saxena PR. 5-hydroxytryptamine increases contractile force in porcine right atrium but not in left ventricle. Naunyn-Schmiedeberg''s Arch Pharmacol 1992; 346: 486-489.
Schultz JE, Hsu AK, Cross GJ. Ischemic preconditioning in the intact rat heart is mediated by delta1- but not mu- or kappa-opioid receptors. Circulation 1998; 97: 1282-1289.
Schultz JE, Hsu AK, Gross GJ. Morphine mimics the cardioprotective effect of ischemic preconditioning via the glibenclamide-sensitive mechanism in the rat heart. Circ Res 1996; 78: 1100-1104.
Schultz JE, Rose E, Yao Z, Gross GJ. Evidence for involvement of opioid receptors in ischemic preconditioning in rat hearts. Am J Physiol 1995; 268: H2157-H2161.
Schultz JJ, Hsu AK, Gross GJ. Ischemic preconditioning and morphine-induced cardioprotection involve the delta-opioid receptor in the intact rat heart. J Mol Cell Cardiol 1997a; 29: 2187-2195.
Schultz JJ, Hsu AK, Gross GJ. Ischemic preconditioning is mediated by a peripheral opioid receptor mechanism in the intact rat heart. J Mol Cell Cardiol 1997b; 29: 1355-1362.
Scott BH. Opioids in cardiac surgery: Cardiopulmonary bypass and inflammatory response. Int J Cardiol 1998; 64 Suppl. 1: S35-S41.
Sheng JZ, Wong TM. Chronic U50,488H abolishes inositol 1,4,5-triphosphate and intracellular Ca2+ elevations evoked by k-opioid receptor in rat myocytes. Eur J Pharmacol 1996; 307: 323-329.
Sheu SS, Fozzard HA. Transmembrane Na+ and Ca2+ electrochemical gradients in cardiac muscle and their relationship to force development. J Gen Physiol 1982; 80: 325-351.
Sheu SS, Lederer WJ. Lidocaine''s negative inotropic and antiarrhythmic action. Circ Res 1985; 57: 578-590.
Singh BN, Hauswirth O. Comparative mechanisms of action of antiarrhythmic drug. Am Heart J 1974; 87: 367-382.
Singh BN, Vaughan Williams EM. Effect of altering potassium concentration on the action of lidocaine and diphenylhydantoin on rabbit atrial and ventricular muscle. Circ Res 1971; 29: 286-295.
Sitsapesan R, Parrat JR. The effects of drugs interacting with opioid receptors on the early ventricular arrhythmias arising from myocardial ischaemia. Br J Pharmacol 1989; 97: 795-800.
Slawsky MT, Castle NA. K+ channel blocking actions of flecainide compared with those of propafenone and quinidine in adult rat ventricular myocytes. J Pharmacol Exp Ther 1994; 269: 66-74.
Springhorn JP, Clay WC. Preproenkephalin mRNA expression in developing rat heart and in cultured ventricular cardiac muscle cells. Biochem J 1989; 258: 73-78.
Stark K, Schoffel E, Illes P. The sympathetic axons innervating the sinus node of the rabbit possess presynaptic opioid k- but not m- or d- receptors. Naunyn-Schmiedeberg''s Arch Pharmacol 1985; 329: 206-209.
Starke K. Presynaptic receptors. Ann Rev Pharmacol Toxicol 1981; 21: 7-30.
Stefano GB, Hartman A, Bilfinger TV, Magazine HI, Liu Y, Casares F, Goligorsky MS. Presence of m3 opiate receptor in endothelial cell: coupling to nitric oxide production and vasodilation. J Biol Chem 1995; 270: 30290-30293.
Su MJ, Chang YM, Chi JF, Lee SS. Thaliporphine, a positive inotropic agent with a negative chronotropic action. Eur J Pharmacol 1994; 254: 141-150.
Su MJ, Lin SO, Wang CH, Tseng YZ, Tseng CD. Comparison of the electrophysiological effect of amiodarone, lidocaine and quinidne on rat ventricular cells. Proc Natl Sci Counc (ROC) 1990; 14: 105-113.
Tai KK, Bian CF, Wong TM. k-opioid receptor stimulation increases intracellular free calcium in isolated rat ventricular myocytes. Life Sci 1992; 51: 909-913.
Tai KK, Jin WQ, Chan TKY, Wong TM. Characterization of [3H]U69593 binding sites in the rat heart by receptor binding assays. J Mol Cell Cardiol 1991; 23: 1297-1302.
Tang J, Yang HYT, Costa E. Distribution of met-enkephalin-arg6-phe7 in various tissues of rats and guinea pigs. Neuropharmacology 1982; 21: 595-600
Tseng G-N, Hoffman BF. Two components of transient outward current in canine ventricular myocytes. Circ Res 1989; 64:633-647.
Tsuchida A, Miura T, Tanno M, Nozawa Y, Kita H, Shimamoto K. Time window for the contribution of the delta-opioid receptor to cardioprotection by ischemic preconditioning in the rat heart. Cardiovasc Drugs Ther 1998; 12: 365-373.
Ulett GA, Han S, Han JS. Electoacupuncture: mechanisms and clinical application. Biol Psychiatry 1998; 44:129-138.
Utz J, Eckert R, Trautwein W. Inhibition of L-type calcium currents in guinea pig ventricular myocytes by the k-opioid agonist U50488H does not involve binding to opiate receptor. J Pharmacol Exp Ther 1995; 274: 627-633.
Vahlensieck U, Boknik P, Gombosova I, Huke S, Knapp J, Linck B, Lub H, Muller FU, Neumann J, Neng MC, Scheld HH, Jankowski H, Schluter H, Zimmermann N, Schmitz W. Inotropic effects of diadenosine tetraphosphate (AP4A) in human and animal cardiac preparations. J Pharmacol Exp Ther 1999; 288: 805-813.
Vargish T, Reynolds DG, Gurll NJ, Lechner RB, Holaday JW, Faden AI. Naloxone reversal of hypovolemic shock in dogs. Circ Shock 1980; 7: 31-38.
Varon J, Duncan SR. Naloxone reversal of hypotension due to captopril overdose. Ann Emerg Med 1991; 20: 1125-1127.
Vaughan Williams EM. Classification of antiarrhythmic drugs. In E Sandoe. E Flensted-Jensen, EH Olsen (eds.): Symposium on Cardiac Arrhythmias. Denmark: Astra, 1970, pp. 449-501.
Ventura C, Bastagli L, Bernardi P, Caldarera CM, Guarnieri C. Opioid receptors in rat cardiac sarcolemma: effect of phenylephrine and isoproterenol. Biochim Biophys Acta 1989; 987: 69-74.
Ventura C, Capogrossi MC. k-opioid peptide receptor stimulation increase cytosolic pH and myofilament responsiveness to Ca2+ in cardiac myocytes. Am J Physiol 1991; 261: H1671-1674.
Ventura C, Guarnieri C, Vaona I, Campana G, Pintus G, Spampinato S. Dynorphin gene express and release in the myocardial cell. J Biol Chem 1994; 269: 5384-5386.
Ventura C, Spurgeon H, Lakatta EG, Guarnieri C, Capogrossi MC. k and d opioid receptor stimulation affects cardiac myocyte function and Ca2+ release from an intracellular pool in myocytes and neurons. Circ Res 1992; 70: 66-81.
Vismara LA, Leaman DL, Zelis R. The effects of morphine on venous tone in patients with acute pulmonary edema. Circulation 1976; 54: 335-337.
Wang Z, Fermini B, Nattel S. Delayed rectifier outward current and repolarization in human atrial myocytes. Circ Res 1993; 73: 276-285.
Wang Z, Fermini B, Nattel S. Mechanism of flecainides rate-dependent actions on action potential duration in canine atrial tissues. J Pharmacol Exp Ther 1993; 267, 575-581.
Wasserstrom JA, Salata JJ. Basis for tetrodotoxin and lidocaine effects on action potentials in dog ventricular myocytes. Am J Physiol 1988; 254: H1157-Hll66.
Weihe E, McKnight AT, Corbett AD, Kosterlitz HW. Proenkephalin- and prodynorphin-deived opioid peptides in guinea-pig heart and skin. Neuropeptides 1985; 5: 453-456.
Weitzellet R, Illes P, Starke K. Inhibition via opioid m- and d-receptors of vagal transmission in rabbit isolated heart. Naunyn-Schmiedeberg''s Arch Pharmacol 1984; 328: 186-190.
Wenzlaff H, Weil G, Stein B, Teschemacher H. Negative inotropic effects of opioid receptor agonists in isolated rat ventricular cardiomyocytes mediated via k opioid receptors are sensitive to pertussis toxin, Naunyn-Schmiedeberg''s Arch Pharmacol 1998; 358: 360-366.
Wettwer E, Amos G, Gath J, Zerkowski HR, Reidemeister JC, Ravens U. Transient outward current in human and rat ventricular myocytes. Cardiovasc Res 1993; 27: 1662-1669.
Winslow E. Methods for the detection and assessment of antiarrhythmic activity. Pharmacol Ther 1984; 124: 401-433.
Wong TM, Lee AYS, Tai KK. Effects of drugs interacting with opioid receptors during normal perfusion or ischemia and reperfusion in the isolated rat heart-an attempt to identify cardiac opioid receptor subtype(s) involved in arrhythmogenesis. J Mol Cell Cardiol 1990; 22: 1167-1175.
Wong TM, Sheng JZ, Wong NS, Tai KK. Signal transduction in the cardiac k-receptor. Biol Signals 1995; 4: 174-178.
Wong-Dusting H K, Rand MJ. Effect of [D-Ala2, Met5]enkephalinamide and [D-Ala2,D-Leu5]enkephalin on cholinergic and noradrenergic neurotransmission in isolated atria. Eur J Pharmacol 1985; 111: 65-72.
Wong-Dusting H K, Rand MJ. Effects of the opioid peptides [Met5]enkephalin-Arg6-Gly7-Leu8 on cholinergic neurotransmission in the rabbit isolated atria. Clin Exp Pharmacol Physiol 1987; 14: 725-730.
Wu MH, Su MJ, Lee SS, Young ML. The electrophysiological effects of antiarrhythmic potential of a secoaporphine, N-allylsecoboldine. Br J Pharmacol 1994; 113: 221-227.
Xia Q, Sheng JZ, Tai KK, Wong TM. Effects of chronic U50,488H treatment on binding and mechanical responses of the rat hearts. J Pharmacol Exp Ther 1994; 268: 930-934.
Xiao RP, Pepe S, Spurgeon HA, Capogrossi MC, Lakatta EG. Opioid peptide receptor stimulation reverses beta-adrenergic effects in rat heart cells. Am J Physiol 1997; 272: H797-805.
Xiao RP, Spurgeon HA, Capogrossi, MC, and Lakatta, EG. Stimulation of opioid receptors on cardiac ventricular myocytes reduces L type Ca2+ channel current. J Mol Cell Cardiol 1993; 25: 661-666.
Yu XC, Li HY, Wong HX, Wong TM. U50,488H inhibits effects of norepinephrine in rat cardiomyocytes?cross-talk between k-opioid and b-adrenergic receptors. J Mol Cell Cardiol 1998; 30: 405-413.
Yue DT, Marban E. A novel cardiac potassium channel that is active and conductive at depolarized potentials. Pflugers Arch 1988; 413:127-133.
Zygmunt AC, Gibbons WR. Calcium-activated chloride current in rabbit ventricular myocytes. Circ Res 1991; 68:424-437.