CARDIOVASCULAR AND MOLECULAR PROPERTIES OF IONOPHORES

本提案的主要目标是了解 携带阳离子穿过生物膜的羧基离子载体 与细胞的固有调节过程相互作用， 导致生物反应。 离子载体对心脏的影响 将在三个层次上进行审查：（1） 清醒犬通过分析主动脉压力波和血液 化学;（2）灌注的代谢和收缩反应 这可能会让我们更深入地了解 在该制剂中，离子载体诱导的工作效率也增加 （3）离体培养心脏搏动的收缩反应 细胞及其与细胞内钙活性的相关性 被荧光探针Quin-2检测到 心脏细胞的反应将是 与红细胞的被动反应和培养的 淋巴瘤细胞被钙相关的抗原诱导形成“帽”， 离子载体增强过程。 一般的假设是， 其中离子载体影响代谢和生理行为， 细胞是通过直接增加细胞内钠的活性， 促进细胞内活性的二次升高。 观察到的离子载体与磷脂的相互作用， 极大地影响它们在生物膜中的行为， 表征了 离子载体的分子特性是其能力的基础， 转运阳离子，即形成脂溶性阳离子复合物， 通过圆二色谱（CD）、HPLC色谱行为和 与荧光阳离子铊（T1+）相互作用。 总的来说， 收集的信息将有助于确定治疗潜力 用于心力衰竭和休克的离子载体，以及它们的潜在毒性 由于广泛使用离子载体作为饲料， 用于饲养家禽和牛的补充剂。 后一种考虑将 也可以通过改进用于离子载体的新的灵敏测定来进行， 组织直接基于它们络合阳离子的能力。

The broad objective of this proposal is to understand how the ability of carboxylic ionophores to carry cations across biological membranes interacts with the inherent regulatory processes of cells to produce the resulting biological responses. The effects of ionophores on the heart will be examined at three levels of integration: (1) the responses of conscious dogs deduced from analysis of the aortic pressure wave and blood chemistry; (2) the metabolic and contract-tile responses of the perfused rabbit heart which might provide insight into the remarkable inonophore-induced increased in work efficiency in this preparation as well as intact animals; (3) the contractile responses of culture beating heart cells and their correlation with intracellular calcium activity as reported by the fluorescent probe Quin-2. The responses of heart cells will be compared to the passive responses of RBCs and the responses of cultured lymphoma cells which are induced to "cap" by antigens in a calcium related, ionophore-enhanced process. The general hypothesis that the mechanism by which ionophores influence the metabolic and physiological behavior of cells is by directly increasing intracellular sodium activity thereby promoting a secondary rise in intracellular activity, will be evaluated. The observed interaction of ionophores with phospholipids, which may greatly affect their behavior in biological membranes, will also be characterized. The molecular properties of ionophores underlying their ability to transport cations, i.e. formation of lipid soluble cation complexes, will be studied by circular dichroism (CD), HPLC chromatographic behavior and interaction with the fluorescent cation thallous (T1+). In toto, the information gathered will help determine the therapeutic potential of ionophores for heart failure and shock, as well as their toxic potential for man and animals resulting from the widespread use of ionophores as feed supplements for raising poultry and cattle. This latter consideration will also be pursued by refinement of a novel sensitive assay for ionophores in tissues based directly on their ability to complex cations.