CA 2 BLOCKERS AND CATECHOL REUPTAKE INHIBITORS

The specific aim is to investigate some of the mechanisms of action of the cardiac effects of catecholamine reuptake inhibitors: major psychostimulants as cocaine and amphetamines, tricyclic antidepressants as imipramine and amitriptyline. These compounds have produced in man lethal cardiac toxicity. Their interaction with different Ca2+ blockers (verapamil, diltiazem, nifedipine, nitrendipine and flunarizine) which have cardiac protective properties will be studied. In vitro and in vivo studies will be performed in acutely or chronically treated preparations. In vitro a new modified computerized Langendorff preparation for the study of the rodent heart will be assembled. On line recording, storage and analysis of heart rate, coronary flow, and supra aortic differential pressure are obtained. Timed administration of known amounts of catechol reuptake inhibitors are performed and dose response effects of these test substances are processed by the computer and expressed as a fraction of the preceding control measurement. The concentration of cold and tagged catechols will be sequentially measured in the effluent coronary fluid (Krebs Henseleit with .5% albumin). In other preparations perfused with suspended erthrocytes 47 Ca2+ influx will be measured in the presence of the different compounds under investigation. The effects of different catechol reuptake inhibitors on endogenous cardiac norepinephrine stores and Ca2+ influx may be clarified. In other preparations measurements of 125I Albumin transfer will be performed to define vascular bed under consideration and distribution of flow in this bed. In vivo, intact rats with a catheter inserted in the caudal artery will be studied in order to define and select, for possible clinical use, the most effective Ca2+ blocker which will neutralize the cardiac toxic effects of major psychostimulants or tricyclic antidepressants as already demonstrated in a similar model for cocaine which is neutralized by nitrendipine. Similar studies in vitro and in vivo will be performed on isolated hearts and animals after chronic treatment with the selected catechol reuptake inhibitors. These studies are aimed at determining the degree of functional (tissue) cardiac tolerance which may develop to the chronic administration of these compounds and possible cross tolerance between major psychostimulants and tricyclic antidepressants. Interactions of these chronically treated preparations with Ca2+ blockers will be evaluated.