Détails sur le projet
Description
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.
Statut | Terminé |
---|---|
Date de début/de fin réelle | 12/1/86 → 3/31/90 |
Financement
- National Institute on Drug Abuse
Keywords
- Cardiología y medicina cardiovascular
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