臺灣博碩士論文加值系統

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.

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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

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