Cyclophilin-facilitated bradykinin inactivation in the perfused rat lung.
Cyclophilin-facilitated bradykinin inactivation in the perfused rat lung.
复制标题
亲环蛋白促进灌注大鼠肺中的缓激肽失活。
DOI：
10.1016/0006-2952(95)02115-9
复制
发表时间：
1995
影响因子：
5.8
通讯作者：
Dawson,CA
中科院分区：
文献类型：
--
作者：
Merker,MP;Dawson,CA
X-脯氨酸（X-Pro）键的顺式和反式异构体可以影响肽代谢动力学的某些方面。我们先前使用肽基-脯氨酰顺式-反式异构酶，亲环素，以显示血管紧张素转化酶（ACE）优先水解含有C-末端脯氨酸的合成三肽的反式异构体（Dawson等人，Am J Physiol 257：H853-H865，1989; Merker等人，J Appl Physiol 75：1519-1524，1993）。缓激肽（Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg）在所有三个X-Pro键处均以顺式和反式异构体存在，尽管其在肺中被肺内皮肽酶广泛灭活，但通常一小部分肽通过肺存活。为了确定是否存在顺式X-Pro键可能会限制肺中缓激肽代谢的程度，我们研究了缓激肽的失活的隔离灌注大鼠肺使用兔颈静脉灌注肺静脉流出物作为缓激肽的生物测定。推注中的大部分（> 90%）缓激肽在通过肺循环的单次转运中被灭活，但在静脉流出物中出现了可检测的部分。将亲环素添加到推注中的缓激肽中，将从肺中出现的缓激肽降低到几乎检测不到的水平。当注射液中含有异构酶抑制剂环孢菌素A与缓激肽和亲环素时，亲环素的这种作用被逆转。这些观察结果表明，缓激肽的馏分，通常生存通过肺含有异构体，至少有一个X-Pro键，是难酶失活，其异构化时间常数是显着长于肺毛细血管通过时间。
Cis and trans isomers of X-proline (X-Pro) bonds can influence some aspects of the kinetics of peptide metabolism. We previously used the peptidyl-prolyl cis-trans isomerase, cyclophilin, to show that angiotensin converting enzyme (ACE) preferentially hydrolyzes the trans isomer of a synthetic tripeptide that contains a C-terminal proline (Dawson et al., Am J Physiol257: H853–H865, 1989; Merker et al., J Appl Physiol75: 1519–1524, 1993). Bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) exists as both cis and trans isomers at all three X-Pro bonds, and although its inactivation in the lung by pulmonary endothelial peptidases is extensive, commonly a small fraction of the peptide survives passage through the lung. To determine whether the presence of cis X-Pro bonds might limit the extent of bradykinin metabolism in the lung, we studied inactivation of bradykinin by the isolated perfused rat lung using the rabbit jugular vein superfused with the pulmonary venous effluent as a bioassay for bradykinin. A large fraction (> 90%) of the bradykinin in a bolus injection was inactivated in a single transit through the pulmonary circulation, but a detectable fraction emerged in the venous effluent. The addition of cyclophilin to the bradykinin in the bolus reduced the bradykinin emerging from the lungs to virtually undetectable levels. When the isomerase inhibitor cyclosporin A was included with bradykinin and cyclophilin in the injectate, this effect of cyclophilin was reversed. These observations suggest that the fraction of bradykinin that normally survives passage through the lungs contains isomers that have at least one X-Pro bond that is refractory to enzymatic inactivation and whose isomerization time constant is significantly longer than the pulmonary capillary transit time.