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

本研究旨在阐明心脏-α-肾上腺素能受体在缺血再灌注性严重室性心律失常发生中的病理生理意义。作为第一步，我们评估了刺激大鼠乳头肌的电生理和变力作用，证实了电生理效应主要是动作电位时程的延长，并发现动作电位时程的延长与正性变力作用在时间上是一致的。此外，我们还发现肾上腺素能受体激动剂引起静息膜电位的超极化。最近的研究表明，氧自由基的产生和由此产生的膜脂过氧化参与了再灌注性心律失常的发生。因此，我们尝试用异丙苯氢氧化物…模拟氧自由基的直接脂质过氧化作用。更多的E和叔丁基氢过氧化氢，并发现用这些有机氢过氧化氢处理豚鼠乳头肌产生了有害的电生理变化，这些变化足以诱发在体心动过速。然而，刺激α-肾上腺素能受体并不能加重过氧化异丙苯引起的电生理变化。用[&lt；α&gt；]-哌唑嗪结合试验测定了豚鼠心脏缺血或缺血-再灌流后的肾上腺素能受体总数。这些步骤增加了[~3H&>]-哌唑嗪的总结合部位及其解离常数。综上所述，虽然缺血和再灌流似乎影响心脏α-肾上腺素能受体的动力学，但如果有的话，受影响的-α-肾上腺素能受体的病理生理学意义应该在缺血或缺血-再灌流引起的其他生化过程中寻找，而不是在膜脂过氧化和由此导致的膜功能丧失的过程中。较少

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