BLOCK OF MYOCARDIAL ION CHANNELS BY ANTIMALARIAL DRUGS

疟疾仍然是世界上最重要和最广泛的疾病之一。氯喹是治疗疟疾的首选药物。恶性疟原虫对氯喹的抗药性增加，这使得发现替代疗法成为当务之急。这些努力导致了氟苯三胺作为抗疟疾药物的开发。然而，氯喹和氟苯三胺减慢了室性传导速度，延长了QT间期。这些不良反应的机制尚不清楚，但我们的初步数据表明，传导障碍是由于阻断了Na+电流，而QTC间期延长是由于阻断了介导心室复极的特定K+电流。甲氟喹是另一种新的抗疟疾药物，尚未得到广泛研究，但也可能有类似的不良副作用。我们建议定义这些抗疟疾药物的心脏效应的细胞机制。本研究的具体目的是：1)研究抗疟疾药物对猫心室肌细胞动作电位的影响；2)研究抗疟疾药物对猫心室肌细胞内向钠电流和外向钾电流的影响；3)确定抗疟药物阻断非洲爪哇卵母细胞表达的克隆人K+通道(HERG、KvLQT1/mink、HIRK1)的机制。这些研究将确定这些广泛使用的药物导致传导减慢和QTC间期延长的细胞和分子机制，并为评估新的抗疟疾药物的潜在心脏副作用提供基线数据。

Malaria remains one of the most important and widespread diseases in the world. Chloroquine is the drug of choice for treatment of malaria. Increased resistance of P. falciparum to chloroquine has made the discovery of alternative therapies a high priority. These efforts have resulted in the development of halofantrine as an antimalarial drug. However, chloroquine and halofantrine slow ventricular conduction velocity and prolong the QTc interval. The mechanisms of these adverse effects are unknown, but our preliminary data suggest that impaired conduction results from block of Na+ current, whereas the prolonged QTc interval is caused by block of specific K+ currents that mediate ventricular repolarization. Mefloquine is another new antimalarial drug that has not been extensively studied, but may also have similar unwanted side effects. We propose to define the cellular mechanisms responsible for the cardiac effects of these antimalarial drugs. The specific aims are to: 1) characterize the effects of antimalarial drugs on action potentials in feline ventricular myocytes; 2) characterize the effects of antimalarial drugs on inward sodium current and outward K+ currents in feline ventricular myocytes; and 3) determine the mechanism of block by antimalarial drugs of cloned human K+ channels (HERG, KvLQT1/minK, HIRK1) expressed in Xenopus oocytes. These studies will define the cellular and molecular mechanisms of slowed conduction and prolonged QTc interval by these widely used drugs, and provide baseline data to evaluate the potential adverse cardiac effects of new antimalarial drugs.