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首页> 外文期刊>American Journal of Physiology >Role of cyclooxygenase in ventricular effects of adrenomedullin: is adrenomedullin a double-edged sword in sepsis?
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Role of cyclooxygenase in ventricular effects of adrenomedullin: is adrenomedullin a double-edged sword in sepsis?

机译：环氧合酶在肾上腺髓质素的心室作用中的作用：肾上腺髓质素是败血症的双刃剑吗？

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Adrenomedullin (ADM) is upregulated in cardiac tissue under various pathophysiological conditions. However, the direct inotropic effect of ADM on normal and compromised cardiomyocytes is not clear. In rat ventricular myocytes, ADM produced an initial (<30 min) increase in cell shortening and Ca(2+) transient and, on prolonged incubation (>1 h), a marked decrease in cell shortening and Ca(2+) transient. Both effects were sensitive to inhibition by the ADM antagonist ADM-(22-52). The increase and decrease in cell shortening and Ca(2+) transient were attenuated by pretreatment with indomethacin [a nonspecific cyclooxygenase (COX) inhibitor], nimesulide and SC-236 (specific COX-2 inhibitors), and tranylcypromine (a prostacyclin synthase inhibitor); SQ-29548 (a thromboxane receptor antagonist) was without effect. Cells isolated from LPS-treated rats that were in the late, hypodynamic phase of septic shock also showed a marked decrease in cell shortening and Ca(2+) transient. Because ADM is overexpressed in sepsis, we repeated the above protocol in cells isolated from LPS-treated rats. At 4 h after LPS injection, ADM levels markedly increased in plasma, ventricles, and freshly isolated ventricular myocytes. Decreases in cell shortening and Ca(2+) transient in LPS-treated cells were reversed by pretreatment with ADM-(22-52). Anti-ADM (rat) IgG also reversed the decrease in cell shortening and other parameters of cell kinetics. Indomethacin, SC-236, and tranylcypromine restored cell contractility and the decrease in Ca(2+) transient, whereas SQ-29548 had no effect, implying that prostacyclin played a role in both effects. However, with regard to cell-shortening kinetics, indomethacin and SQ-29548 decreased the amount of time taken by the cells to return to baseline, whereas SC-236 and tranylcypromine did not, implying that not only prostacyclin, but also thromboxane, is involved. The results indicate that ADM interacts with COX to yield prostanoids, which mediate its negative inotropic effect in LPS-treated rat ventricular myocytes.
机译：在各种病理生理条件下，心脏组织中的肾上腺髓质素（ADM）上调。但是，尚不清楚ADM对正常和受损心肌细胞的直接变力作用。在大鼠心室肌细胞中，ADM产生细胞缩短和Ca（2+）瞬变的初始（<30分钟）增加，并且在延长的孵育时间（> 1 h）中，细胞缩短和Ca（2+）瞬变的显着减少。两种作用均对ADM拮抗剂ADM-（22-52）的抑制敏感。吲哚美辛[一种非特异性环氧合酶（COX）抑制剂]，尼美舒利和SC-236（特异性COX-2抑制剂）和反式环丙胺（一种前列环素合酶抑制剂）预处理可减轻细胞缩短和Ca（2+）瞬变的增加和减少。 ）; SQ-29548（血栓烷受体拮抗剂）无效。从LPS治疗的大鼠分离的细胞处于败血性休克的低动力后期，也显示出细胞缩短和Ca（2+）瞬变的明显减少。由于ADM在脓毒症中过表达，因此我们在从LPS处理的大鼠中分离的细胞中重复了上述方案。注射LPS后4小时，血浆，心室和新鲜分离的心室肌细胞中ADM含量明显增加。通过ADM-（22-52）预处理可以逆转LPS处理的细胞中细胞缩短和Ca（2+）瞬变的减少。抗ADM（大鼠）IgG也逆转了细胞缩短和细胞动力学其他参数的下降。消炎痛，SC-236和tranylcypromine恢复细胞收缩力和Ca（2+）瞬变的减少，而SQ-29548没有影响，这表明前列环素在这两种作用中均起作用。但是，关于细胞缩短动力学，消炎痛和SQ-29548减少了细胞恢复至基线所需的时间，而SC-236和tranylcypromine没有减少，这意味着不仅涉及前列环素，还涉及血栓烷。结果表明，ADM与COX相互作用产生前列腺素，其在LPS处理的大鼠心室肌细胞中介导其负性肌力作用。

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