Amelioration of oxidative lung injury by antiarrhythmic agents

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dc.contributor.authorDas, Kumuda C.en
dc.contributor.committeechairMisra, Hara P.en
dc.contributor.committeememberWebb, Ryland E.en
dc.contributor.committeememberAhmed, S. Ansaren
dc.contributor.committeememberGregory, Eugene M.en
dc.contributor.committeememberKeith, James C. Jr.en
dc.contributor.departmentVeterinary Medical Sciencesen
dc.date.accessioned2014-03-14T21:21:09Zen
dc.date.adate2005-10-13en
dc.date.available2014-03-14T21:21:09Zen
dc.date.issued1992-10-15en
dc.date.rdate2005-10-13en
dc.date.sdate2005-10-13en
dc.description.abstractClass I antiarrhythmic drugs, such as lidocaine, quinidine and procainamide, are known to be effective membrane stabilizers. However, the mechanism of such "membrane stabilization" has not been elucidated. In the present study we found that all three drugs are powerful scavengers of hydroxyl! radical. In addition, lidocaine was found to be a quencher of singlet oxygen. These drugs are also found to inhibit NADPH-dependent lipid peroxidation in bovine lung microsomes in a dose dependent manner. Since oxyradicals are implicated in the lipid peroxidation process and antiarrhythmic drugs were found to scavenge/quench reactive oxygen species, we proposed that the membrane Stabilizing effects of antiarrhythmic drugs may, in part, be due to their antioxidant properties. Ischemia-reperfusion injury has been studied in many organs. Despite the evidence of functional, metabolic and structural abnormalities during reperfusion, the precise mechanism of reperfusion lung injury remains obscure. Data from the organ models suggest that toxic oxygen metabolites play an important role in the mechanism of reperfusion tissue injury. Lidocaine has also been shown to be clinically valuable for the treatment and prevention of ventricular arrhythmia occurring after surgical correction of myocardial infraction. We found that the class I antiarrhythmic drugs are effective in ameliorating post-ischemic lung reperfusion injury in an ex vivo perfused rat lung model exposed to both normoxic and hyperoxic conditions. Since phagocytes are known to generate reactive oxygen species and play an important role in causing irreversible oxidative tissue injury during reperfusion of organs, we examined the role of antiarrhythmic agents on macrophage function. We found that these drugs inhibit superoxide and hydrogen peroxide production in stimulated macrophages in a dose dependent manner. The diminished production of superoxide was found to be not due to the inactivation of superoxide generating NADPH-oxidase enzyme but by inhibition of the phagocytosis process by these drugs The results of these studies indicate that the antiarrhythmic drugs, such as, lidocaine, quinidine and procainamide, are effective antioxidants and can protect biomembranes against lipid peroxidation injury and post-ischemic reperfusion injury of the lung. We have investigated the mechanism(s) of action of these drugs in ameliorating oxidative tissue injury and found that these drugs are not only effective in removing reactive oxygen species but also cause inactivation of pulmonary macrophage from inappropriately generating reactive species of oxygen. The fundamental knowledge derived from these Studies could lead to enhanced functional improvement of patients following cardiopulmonary bypass, pulmonary arterial embolectomy and acute respiratory distress syndrome, all of which undergo a period of elective/induced ischemia and reperfusion or oxidative stress.en
dc.description.degreePh. D.en
dc.format.extentxiv, 188 leavesen
dc.format.mediumBTDen
dc.format.mimetypeapplication/pdfen
dc.identifier.otheretd-10132005-152552en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-10132005-152552/en
dc.identifier.urihttp://hdl.handle.net/10919/39844en
dc.language.isoenen
dc.publisherVirginia Techen
dc.relation.haspartLD5655.V856_1992.D37.pdfen
dc.relation.isformatofOCLC# 28529287en
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subject.lccLD5655.V856 1992.D37en
dc.subject.lcshLidocaineen
dc.subject.lcshLungs -- Diseasesen
dc.subject.lcshMyocardial depressants -- Physiological effecten
dc.subject.lcshProcainanideen
dc.subject.lcshQuinidineen
dc.titleAmelioration of oxidative lung injury by antiarrhythmic agentsen
dc.typeDissertationen
dc.type.dcmitypeTexten
thesis.degree.disciplineVeterinary Medical Sciencesen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.namePh. D.en

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