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

本课题旨在阐明心脏肾上腺素能受体<alpha>在缺血再灌注所致严重室性心律失常发生中的病理生理意义。本文首先研究了β-肾上腺素受体激动剂对大鼠乳头肌的电生理和变力作用<alpha>，证实了其主要的电生理作用是延长动作电位时程，并发现动作电位时程延长与正性变力作用在时间上有很好的对应关系。此外，我们还发现<alpha>刺激肾上腺素受体可引起静息膜电位的超极化。近年来的研究表明，氧自由基的产生和膜脂过氧化参与了再灌注心律失常的发生。因此，我们试图用过氧化氢直接过氧化脂质来模拟氧自由基的影响 ...更多信息 E和叔丁基过氧化氢，并发现这些有机过氧化氢处理在豚鼠乳头肌中产生了缓慢的电生理变化，这些变化足以诱发原位心脏的心律失常。然而，肾上腺素能受体的兴奋<alpha>并不加剧过氧化二氢所引起的电生理变化。在<alpha>经受缺血或缺血-再灌注的豚鼠离体心脏中，通过[ &lt;^3H&gt; ]-哌唑嗪结合试验测定β-肾上腺素受体的总数。这些步骤增加了[ &lt;^3H&gt; ]-哌唑嗪的总结合位点及其解离常数。结论：尽管缺血和再灌注似乎影响心脏肾上腺素受体的功能<alpha>，但<alpha>如果有的话，受影响的肾上腺素受体的病理生理学意义应在缺血或缺血-再灌注引起的其他生化疾病中寻找，而不是在膜脂过氧化和防止膜功能丧失的过程中。少

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