TM1-1對心臟缺血-再灌流之保護與血管藥理作用評估

Abstract

(+)-Thaliporphine是一種結構為phenolic aporphine的生物鹼，來自樟科植物，經實驗證明可經由抑制鈉電流 (INa)、瞬間外流鉀電流 (Ito)、抗氧化及提高血中NO含量等途徑，進而降低心臟缺血或缺血再灌流之傷害。TM1是(+)-Thaliporphine的類似物，研究結果顯示TM1能夠抑制鈉電流 (INa)、L型鈣電流 (ICa, L) 和瞬間外流鉀電流 (Ito)，因此屬於非選擇性之抗心律不整藥物。TM1-1、Laurolitsine、Norglaucine與Glaucinone四種化合物則為TM1之衍生物，本篇主要是在比較這四種類似物與TM1的心血管作用，並評估是否與Thaliporphine、TM1一樣，具有抗心律不整之潛力。 離體大白鼠心臟組織張力實驗中，四種衍生物均顯著抑制右心房自發性心跳，而在組織收縮力方面，TM1-1於1~30 uM即可使右心房收縮力明顯增加，Laurolitsine、Norglaucine在高劑量下亦可提高收縮力，但Glaucinone則反而是降低右心房收縮力；對左心房組織收縮力的影響與右心房類似；不過在右心室組織中，四者均會使收縮力顯著降低。比較之前的實驗結果，TM1-1對心臟組織收縮力的影響與TM1最類似。除此之外，TM1-1、Laurolitsine與Norglaucine可降低左心房及右心室的興奮性，使閾值 (threshold) 提高，其中又以TM1-1的抑制性最大。 離體血管實驗結果則顯示TM1與四種衍生物具有非內皮依賴性的血管放鬆作用，相較下TM1-1的作用最強，TM1次之，推測可能是因為TM1-1對甲型腎上腺素受體之阻斷作用較強。不過於較高濃度時，二者應有類似的鈣離子管道阻斷作用，故可使高鉀刺激收縮之血管放鬆。 比較四種衍生物的心血管藥理作用後，選擇TM1-1進行療效評估。結果顯示在離體天竺鼠的心臟組織中，TM1-1可有效抑制ouabain誘發之心律不整。而當觀察活體大白鼠實驗模式，發現靜脈注射TM1-1 (0.1~1 umole/kg) 可改善五分鐘缺血三十分鐘再灌流所引起的心律不整，降低動物的死亡率，亦可顯著改善長時間缺血再灌流所引起之心肌壞死現象。 綜合以上結果推測TM1-1之作用機轉與TM1最為類似，可能同樣經由抑制鈉電流、鈣電流及瞬間外流鉀電流而產生抗心律不整作用，詳細反應機轉尚待電生理實驗進一步證明。 值得注意的是TM1-1在離體大鼠右心室組織，可使isoproterenol之劑量反應曲線顯著左移，其作用機轉尚須深入研究。至於TM1-1促進乙型腎上腺素受體以及阻斷甲型腎上腺素受體之特性，對其抗心律不整作用的影響，抑或是否具有治療其他及病的潛力，仍須深入研究探討。

(+)-Thaliporphine isolated from the plants of Neolitsea Konishii K is a phenolic aporphine alkaloid. (+)-Thaliporphine has been reported to inhibit sodium current (INa), and transient potassium outward current (Ito). It also inhibits LDL peroxidation, scavenges superoxide, and increases serum NO level. Consequently, (+)-thaliporphine exerts cardioprotective action in ischemic or ischemia-reperfusion rats. TM1, a (+)-thaliporphine derivative, inhibits sodium current (INa), calcium current (ICa, L) and transient potassium outward current (Ito). Those effects make it have antiarrhythmic potential, too. In this study, we compared the cardiovascular effects of TM1 and other four derivatives, TM1-1, laurolitsine, norglaucine and glaucinone. Besides, we planned to investigate whether TM1-1 had the same efficacy as TM1 to decrease ischemia-reperfusion injury. In isolated rat right atria, all of the derivatives significantly decreased spontaneous beating rate. The contractile force of TM1-1 was increased at concentration ranging from 1 to 30 uM, and the contractile force of laurolitsine, norglaucine was slightly increased at 30 uM. On the contrary, glaucinone significantly suppressed the contractility of right atria. The effects on contractile force of the derivatives in left and right atria were the same. However, all of them exerted negative inotropic effects in right ventricular strips. When compared with the results studied before, TM1-1 had the most similar effects with TM1. Besides, TM1-1, laurolitsine, and norglaucine increased the excitation threshold in the left atria and right ventricular strips, and TM1-1 was the most potent one. TM1 and the four derivatives had endothelium-independent vasorelaxant effects on isolated rat aortic rings. TM1-1 provided better alpha-adrenoceptor blocking ability than TM1. However, TM1 and TM1-1 induced relaxation in high potassium-precontracted rings with similar efficacy. These results suggested that they had the same calcium channel blocking ability. Furthermore, we investigated the cardioprotective effects of TM1-1. In guinea pig heart, ouabain-induced arrhythmia could be converted to normal rhythm by TM1-1. In vivo study, TM1-1 (0.1 to 1 umole/kg) significantly decreased the incident of coronary occlusion (5 min)–reperfusion (30 min) induced arrhythmia and mortality. Myocardial infarction induced by coronary occlusion (1 hr)–reperfusion (2 hr) was also significant reduced by TM1-1. To summarize, we suggested that TM1-1, like TM1, might exert cardioprotective activity through INa, ICa, L and Ito blocking ability. The mechanisms remain to be clarified by further study. It’s notable that TM1-1 significantly shifted the dose-response curve of isoproterenol to left. It needs more study to clarify whether alpha-adrenoceptor blocking activity or beta-adrenoceptor enhancing activity can modulate the cardioprotective efficacy of TM1-1.