PHARMACOLOGICAL STUDY ON CARDIAC <alpha> -ADRENOCEPTORS AS A FACTOR OF POTENTIATING CARDIAC ARRHYTHMIAS INDUCED BY ISCHEMIA

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THE AIM OF THE PRESENT RESEARCH PROJECT IS TO CLARIFY THE PATHOPHYSIOLOGICAL SIGNIFICANCE OF CARDIAC <alpha> -ADRENOCEPTORS IN GENESIS OF SEVERE VENTRICULAR ARRHYTHMIAS INDUCED BY ISCHEMIA AND REPERFUSION. AS THE FIRST STEP, WE EVALUATED THE ELECTROPHYSIOLOGICAL AND INOTROPIC EFFECTS OF <alpha> -ADRENOCEPTOR STIMULATION IN RAT PAPILLARY MUSCLES, AND CONFIRMED THAT THE MAJOR ELECTROPHYSIOLOGICAL EFFECT IS THE PROLONGATION OF ACTION POTENTIAL DURATION AS ALREADY REPORTED, AND FOUND THAT THE APD PROLONGATION WAS TEMPORALLY WELL CORRESPONDED TO THE POSITIVE INOTROPIC EFFECT. IN ADDITION, WE FOUND THAT STIMUALTION OF <alpha> -ADRENOCEPTORS PRODUCED HYPERPOLARIZATION OF THE RESTING MEMBRANE POTENTIAL. RECENT STUDIES PROVIDE EVIDENCE THAT THE GENERATION OF OXYGEN FREE RADICALS AND THE RESULTING MEMBRANE-LIPID PEROXYDATION ARE INVOLVED IN GENESIS OF REPERFUSION-ARRHYTHMIAS. THUS, WE ATTEMPTED TO IMITATE THE INFLUENCE OF OXYGEN FREE RADICALS WITH DIRECT LIPID-PEROXYDATION BY CUMENE HYDROPEROXID … More E AND t-BUTYL HYDROPEROXIDE AND FOUND THAT TREATMENT WITH THESE ORGANIC HYDROPEROXIDES PRODUCED DELETERIOUS ELECTROPHYSIOLOGICAL CHANGES IN GUINEA-PIG PAPILLARY MUSCLES, THE CHANGES BEING SUFFICIENT FOR INDUCING ARRHYTHMIAS IN IN SITU HEARTS. HOWEVER, STIMULATION OF <alpha> -ADRENOCEPTORS DID NOT EXACERBATE THE ELECTROPHYSIOLOGICAL CHANGES INDUCED BY CUMENE HYDROPEROXIDE. TOTAL NUMBER OF <alpha> -ADRENOCEPTORS WAS DETERMINED BY [ <^3H> ]-PRAZOSIN BINDING ASSAY IN GUINEA-PIG ISOLATED HEARTS WHICH WERE SUBJECTED TO ISCHEMIA OR ISCHEMIA-REPERFUSION. THESE PROCEDURES INCREASED THE TOTAL BINDING SITE OF[ <^3H> ]-PRAZOSIN AND ITS DISSOCIATION CONSTANTS. IN CONCLUSION, ALTHOUGH ISCHEMIA AND REPERFUSION APPEAR TO AFFECT THE DYNAMICS OF CARDIAC <alpha> -ADRENOCEPTORS, THE PATHOPHYSIOLOGICAL SIGNIFICANCE OF THE AFFECTED <alpha> -ADRENOCEPTORS, IF ANY, SHOULD BE SEEKED IN OTHER BIOCHEMICAL PROCESSES INDUCED ISCHEMIA OR ISCHEMIA-REPERFUSION THAN IN THE PROCESS OF MEMBRANE-LIPID PEROXYDATION AND RESULTING LOSS OF THE MEMBRANE FUNCTION. Less