Pharmacological analysis of endotoxin-induced cardiovascular dysfunction

内毒素给药后，诱导了许多生物活性物质，引起各种心血管作用。其中肾上腺髓质素是最近发现的一种血管抑制肽。在本研究项目中，我首先研究了这种肽对内毒素诱导的器官功能障碍的靶器官之一肾脏的作用模式和机制。结果表明，这种肽elerative一氧化氮介导的肾血管舒张和利尿，提示肾上腺髓质素可能的保护作用，内毒素诱导的肾insulation.Next，我检查的全身血流动力学序列后内毒素管理。本实验采用PAF受体拮抗剂TCV-309、环氧合酶抑制剂布洛芬和血栓素A2/前列腺素H2受体拮抗剂S-1452，阐明了内源性PAF和环氧合酶代谢产物在实验性大鼠内毒素休克中的作用部位。我发现所有这些药物都能减弱内毒素引起的心输出量减少和红细胞压积增加。因此，这表明PAF和环氧合酶产物，特别是血栓素A2引起大鼠内毒素休克心输出量的减少。布洛芬和S-1452均仅在内毒素给药后不久减弱低血压，而TCV-309仅在内毒素给药后3小时减弱低血压。总血管阻力增加的内毒素是由这三种药物衰减，这表明这些药物改善内毒素诱导的血流动力学恶化，通过阻断心输出量减少和改善外周血流动力学。此外，还发现除血栓素A_2以外的前列腺素类物质参与了内毒素诱发的心动过速。

Following endotoxin administration, a number of biologically active substances are induced that elicit various cardiovascular actions. Among those, adrenomedullin is a vasodepressor peptide recently discovered. In the present research project, I first examine the mode and mechanisms of action of this peptide on the kidney, one of the target organ of endotoxin-induced organ dysfunction. The results suggest that this peptide elicits nitric oxide-mediated renal vasodilation and diuresis, suggesting the possible protective role of adrenomedullin in endotoxin-induced renal insult.Next, I examine the sequences of systemic hemodynamics following endotoxin administration. In the experiment, I used TCV-309 (a PAF receptor antagonist), ibuprofen (a cyclooxygenase inhibitor) and S-1452 (a thromboxane A2/prostaglandin H2 receptor antagonist) and elucidated the sites of action of endogenous PAF and cyclooxygenase metabolites in experimental rat endotoxic shock. I found that all of these drugs attenuated endotoxin-induced decrease in cardiac output and increase in hematocrit. Thus, it was suggested that PAF and cyclooxygenase products, particularly thromboxane A2 elicited the reduction in cardiac output in rat endotoxic shock. Both ibuprofen and S-1452 attenuated hypotension only shortly after endotoxin administration whereas TCV-309 attenuated it only 3 hr after endotoxin. Total vascular resistance was increased by endotoxin that was attenuated by these three drugs, suggesting these drugs improve endotoxin-induced hemodynamic deterioration by blocking reduction in cardiac output and improving peripheral hemodynamics. In addtion, it was found that prostanoid other than thromboxane A2 is involved in the endotxin-induced tachycardia.