Persad S, Dhalla N S
St. Boniface General Hospital Research Centre, and Department of Physiology, Faculty of Medicine, The University of Manitoba, Winnipeg, Canada.
Can J Physiol Pharmacol. 1998 Oct-Nov;76(10-11):961-6. doi: 10.1139/cjpp-76-10-11-961.
It is now well known that the signal transduction pathway involving beta-adrenoceptors and adenylyl cyclase is altered in ischemic heart disease. Since leukocytes accumulate in the ischemic heart and produce hypochlorous acid (HOCl), we investigated the effects of HOCl upon beta-adrenoceptors and adenylyl cyclase activities by perfusing rat hearts with 0.1 mM HOCl for 10 min and isolating cardiac membranes. Marked depressions in both the density and affinity of beta1-adrenoceptors were observed, whereas no significant change in the affinity or density of beta2-adrenoceptors was seen in hearts perfused with HOCl. After treatment of hearts with HOCl, competition curves using isoproterenol, a beta-adrenoceptor agonist, revealed a decrease in the proportion of high affinity binding sites. The adenylyl cyclase activities in the absence and presence of forskolin, NaF, Gpp(NH)p, or isoproterenol were depressed in hearts perfused with HOCl; however, the stimulatory effects of these agents on adenylyl cyclase were either unaltered or augmented. The presence of methionine in the perfusion medium prevented the HOCl-induced changes in beta1-adrenoceptors and adenylyl cyclase activity. These results suggest that HOCl may produce a defect in the beta-adrenoceptor linked signal transduction mechanism by affecting both beta1-adrenoceptors and adenylyl cyclase enzyme in the myocardium.
现已清楚知道，涉及β-肾上腺素能受体和腺苷酸环化酶的信号转导途径在缺血性心脏病中会发生改变。由于白细胞在缺血心脏中积聚并产生次氯酸（HOCl），我们通过用0.1 mM HOCl灌注大鼠心脏10分钟并分离心肌膜，研究了HOCl对β-肾上腺素能受体和腺苷酸环化酶活性的影响。观察到β1-肾上腺素能受体的密度和亲和力均显著降低，而在用HOCl灌注的心脏中，β2-肾上腺素能受体的亲和力或密度未见明显变化。用HOCl处理心脏后，使用β-肾上腺素能受体激动剂异丙肾上腺素的竞争曲线显示高亲和力结合位点的比例降低。在用HOCl灌注的心脏中，无论有无福斯高林、NaF、Gpp(NH)p或异丙肾上腺素，腺苷酸环化酶活性均降低；然而，这些试剂对腺苷酸环化酶的刺激作用未改变或增强。灌注培养基中存在蛋氨酸可防止HOCl诱导的β1-肾上腺素能受体和腺苷酸环化酶活性变化。这些结果表明，HOCl可能通过影响心肌中的β1-肾上腺素能受体和腺苷酸环化酶，在β-肾上腺素能受体相关的信号转导机制中产生缺陷。
