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.
| Lattanzio Jr, F A; Pressman, B C (1986) Alterations in intracellular calcium activity and contractility of isolated perfused rabbit hearts by ionophores and adrenergic agents. Biochem Biophys Res Commun 139:816-21 |
| Fahim, M; Pressman, B C (1986) Improvement of cardiac performance by carboxylic ionophore monensin in greyhound and mongrel dogs. Naunyn Schmiedebergs Arch Pharmacol 333:412-20 |
