Chodimella V, Skidgel R A, Krowiak E J, Murlas C G
Department of Medicine, Rush University, Chicago, Illinois.
Am Rev Respir Dis. 1991 Oct;144(4):869-74. doi: 10.1164/ajrccm/144.4.869.
We investigated the effect of inhibition of carboxypeptidase, neutral endopeptidase, or angiotensin converting enzyme on airway reactivity to intravenous bradykinin in guinea pigs. Bradykinin reactivity in intact, unanesthetized, spontaneously breathing animals was determined by measuring specific airway resistance in response to increasing doses of intravenous bradykinin or acetylcholine. We found that phosphoramidon and/or captopril (specific antagonists of neutral endopeptidase and angiotensin converting enzyme, respectively) increased airway reactivity to bradykinin, but the combination had no effect on muscarinic reactivity. Although 2-mercaptomethyl-3-guanidinoethylthiopropanoic acid (MGTA, a carboxypeptidase inhibitor) alone did not alter bradykinin reactivity, MGTA in the presence of both phosphoramidon and captopril significantly potentiated bradykinin-induced airway reactivity. In comparison, this did not affect reactivity to acetylcholine. Having found that carboxypeptidase inhibition could augment kinin-induced airway reactivity, we subsequently assayed for and identified carboxypeptidase M activity in guinea pig lung. We found considerable carboxypeptidase M activity in guinea pig lung subcellular fractions, the 100,000 x g membrane pellet having the highest specific activity. Our data indicate that airway reactivity to intravenous bradykinin is modulated by the activity of endogenous neutral endopeptidase, angiotensin converting enzyme, and carboxypeptidase, all of which are present in lung cell membranes. This study also suggests that the influence of carboxypeptidase per se may be substantially enhanced if endogenous pulmonary neutral endopeptidase and angiotensin converting enzyme activities are reduced.
我们研究了抑制羧肽酶、中性内肽酶或血管紧张素转换酶对豚鼠气道对静脉注射缓激肽反应性的影响。在完整、未麻醉、自主呼吸的动物中，通过测量对递增剂量静脉注射缓激肽或乙酰胆碱的反应来测定气道比阻力，从而确定缓激肽反应性。我们发现磷酰胺素和/或卡托普利（分别为中性内肽酶和血管紧张素转换酶的特异性拮抗剂）增加了气道对缓激肽的反应性，但联合使用对毒蕈碱反应性没有影响。虽然单独使用2-巯基甲基-3-胍基乙基硫代丙酸（MGTA，一种羧肽酶抑制剂）不会改变缓激肽反应性，但在磷酰胺素和卡托普利同时存在的情况下，MGTA显著增强了缓激肽诱导的气道反应性。相比之下，这并不影响对乙酰胆碱的反应性。在发现抑制羧肽酶可增强激肽诱导的气道反应性后，我们随后测定并鉴定了豚鼠肺中的羧肽酶M活性。我们在豚鼠肺亚细胞组分中发现了相当高的羧肽酶M活性，其中100,000×g膜沉淀的比活性最高。我们的数据表明，气道对静脉注射缓激肽的反应性受内源性中性内肽酶、血管紧张素转换酶和羧肽酶活性的调节，所有这些酶都存在于肺细胞膜中。这项研究还表明，如果内源性肺中性内肽酶和血管紧张素转换酶活性降低，羧肽酶本身的影响可能会大大增强。
