Activation of purified cardiac ryanodine receptors by dihydropyridine agonists.
Activation of purified cardiac ryanodine receptors by dihydropyridine agonists.
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二氢吡啶激动剂激活纯化的心脏兰尼碱受体。
DOI：
10.1152/ajpheart.2001.280.3.h1201
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
Wasserstrom,JA
中科院分区：
文献类型：
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作者：
Sagawa,T;Nishio,M;Sagawa,K;Kelly,JE;Lokuta,AJ;Tsai,J;Kan,E;Wasserstrom,JA
先前的观察提出了二氢吡啶（DHP）激动剂直接影响肌浆网（SR）心脏Ca2+释放通道的可能性[即ryanodine受体（RyR）]。在纯化犬心脏RyR的单通道记录中，DHP激动剂(−)-BAY K 8644和(+)-SDZ202-791添加到通道的细胞质面时，增加了RyR的打开概率。重要的是，DHP拮抗剂硝苯地平和(−)-SDZ202-791单独或与激动剂激活通道后都没有竞争性阻断作用。因此，SDZ202-791具有立体特异性作用，即激动剂激活通道，而拮抗剂对通道活性几乎没有影响。进一步的实验表明，DHP激动剂通过抑制Ca2+诱导的通道失活来改变RyR的激活。我们得出结论，DHP激动剂还可以直接影响位于通道细胞质表面的独特变构位点的RyR单通道活性。在人纯化的心脏RyR中也得到了类似的结果。这些数据的一个含义是，DHP激动剂激活RyR可能导致SR中Ca2+的损失，并有助于其他研究者报道的这些药物的负性肌力作用。我们的研究结果支持这一观点，即DHP激动剂的负性肌力作用部分源于RyRs活性的直接改变。
Prior observations have raised the possibility that dihydropyridine (DHP) agonists directly affect the sarcoplasmic reticulum (SR) cardiac Ca2+release channel [i.e., ryanodine receptor (RyR)]. In single-channel recordings of purified canine cardiac RyR, both DHP agonists (−)-BAY K 8644 and (+)-SDZ202-791 increased the open probability of the RyR when added to the cytoplasmic face of the channel. Importantly, the DHP antagonists nifedipine and (−)-SDZ202-791 had no competitive blocking effects either alone or after channel activation with agonist. Thus there is a stereospecific effect of SDZ202-791, such that the agonist activates the channel, whereas the antagonist has little effect on channel activity. Further experiments showed that DHP agonists changed RyR activation by suppressing Ca2+-induced inactivation of the channel. We concluded that DHP agonists can also influence RyR single-channel activity directly at a unique allosteric site located on the cytoplasmic face of the channel. Similar results were obtained in human purified cardiac RyR. An implication of these data is that RyR activation by DHP agonists is likely to cause a loss of Ca2+from the SR and to contribute to the negative inotropic effects of these agents reported by other investigators. Our results support this notion that the negative inotropic effects of DHP agonists result in part from direct alteration in the activity of RyRs.