BIOLOGY OF INOPHORES: A STRUCTURE/REACTIVITY STUDY

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It is proposed to study the effect of a series of naturally occurring and synthetic ionophores upon the spontaneous beating of the right atrial pacemaker region of White New Zealand rabbits. Both classes of ionophore have been shown to have potential as antihypertensive drugs and also as vasodilators to enhance blood flow and hence, for example, impaired cardiac muscle contractility. Despite this potential, there are only very limited studies on the effect that these ion carriers have upon the ionic transport mechanisms that are responsible for the development of muscle tension and activity. The research proposed involves a detailed use of ionophores of known metal ion specificity to modify both the muscle tension and beating rate of the atrial region. By observing the effect of ion selective species it will be possible to help in the design of ionophoric materials, since to date the features that control any physiologic activity are not even marginally recognized as compared to our knowledge of their laboratory physical chemical properties, including transport of metal ions across hydrophobic liquid membranes. Preliminary data from the proposed system has illustrated the feasibility of the planned research. Initial studies will be with the use of such ion specific ionophores as monensin (Na), valinomycin (K) and X-537A (Ca) to ascertain the effect of disturbing the flux of these ions upon the atrial region. Some of these compounds have been previously studied in other laboratories, but initial repetition in our laboratory, coupled with the other ionophores will provide a better procedure for evaluating our results. Other ionophores to be studied include various crowns and crypts, and also the new series of compounds, the silacrowns, which have been shown to possess ionophoric character, without some of potentially nasty side effects reported for regular crown and crypt ionophores. In parallel with our studies, ionophore samples will be provided other research groups for testing on vascular smooth muscle preparations.