The efficacy of selective endothelin (ET) receptor antagonists may be limited by a functional interaction between the ET(A) and ET(B) receptors. This interaction, also termed "cross talk", is characterized by the dependency of the inhibition of an ET-1 response due to antagonism of one ET receptor subtype upon concomitant antagonism of the other ET receptor subtype. Although a reduction in ET(A)-ET(B) receptor cross talk would presumably increase the efficacy of selective ET receptor antagonists, an approach that accomplishes this aim is largely absent due to a lack of mechanistic understanding. Toward this goal, we evaluated the characteristics and potential dependencies of cross talk in smooth muscle. Smooth muscle was adopted as an exemplar not only because cross talk is widely reported in this tissue type, thereby allowing numerous comparisons, but also significant controversy surrounds the use of selective versus nonselective ET receptor antagonists in ET-1-related pathophysiologies involving smooth muscle. Based on this evaluation, we suggest that ET(A)-ET(B) receptor cross talk is a dynamic process directed by either or both ET receptor subtypes and expressed to varying magnitudes depending on the ET-1 and selective ET receptor antagonist concentrations, tone due to intraluminal pressure/stretch, agonists acting at receptors other than the ET(A)/ET(B) receptors, and endothelial/epithelial function. It is speculated that ET(A)-ET(B) receptor cross talk occurs through signal transduction pathways along with changes at the receptor level. Pharmacologic intervention of the signaling pathways could increase the therapeutic efficacy of ET receptor antagonists.

译文

:选择性内皮素(ET)受体拮抗剂的功效可能受到ET(A)和ET(B)受体之间功能相互作用的限制。这种相互作用,也称为“串扰”,其特征在于由于一种ET受体亚型的拮抗作用而伴随着另一种ET受体亚型的拮抗作用对ET-1应答的抑制的依赖性。虽然减少ET(A)-ET(B)受体的干扰可能会增加选择性ET受体拮抗剂的功效,但由于缺乏机械性理解,因此很大程度上缺乏实现该目标的方法。为了实现这一目标,我们评估了平滑肌中串扰的特征和潜在的依赖性。平滑肌被用作范例,不仅因为在这种组织类型中广泛报道了串扰,从而允许进行大量比较,而且在涉及平滑肌的与ET-1相关的病理生理学中选择性与非选择性ET受体拮抗剂的使用之间也存在重大争议。基于此评估,我们建议ET(A)-ET(B)受体串扰是一个由任一或两种ET受体亚型控制的动态过程,并根据ET-1和选择性ET受体拮抗剂的浓度而以不同的幅度表达,腔内压力/舒张引起的紧张,激动剂对除ET(A)/ ET(B)受体以外的受体起作用,以及内皮/上皮功能。据推测,ET(A)-ET(B)受体的串扰是通过信号转导途径以及受体水平的变化而发生的。信号通路的药理干预可以提高ET受体拮抗剂的治疗效果。

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