Wilson D D, de Garavilla L, Kuhn W, Togo J, Burch R M, Steranka L R
Nova Pharmaceutical Corporation, Baltimore, Maryland 21224.
Circ Shock. 1989 Feb;27(2):93-101.
The kallikrein-kinin system is activated during endotoxic shock, suggesting that bradykinin plays a role in the pathology of this disease. To test this hypothesis, a bradykinin antagonist, D-Arg-Hyp3-D-Phe7-bradykinin (NPC 567), was studied in conscious, chronically catheterized rats undergoing lipopolysaccharide (LPS)-induced endotoxic shock. LPS treatment resulted in an increase in circulating bradykinin from less than 23 pg/ml to 144 +/- 18 pg/ml at 1 hr. Intravenous administration of LPS resulted in a 38% drop in mean arterial pressure at 1 hr which was partially reversed by NPC 567. NPC 567 did not affect the moderate tachycardia observed following LPS. NPC 567 infusion at 8 nmol/kg/min dramatically reduced mortality from 100% to 50% at 24 hr (P less than 0.01). In response to LPS, blood thromboxane B2 (TXB2) rose from less than 200 pg/ml to 2,298 +/- 64 pg/ml, while 6-keto-prostaglandin-F1 alpha (6kPGF1 alpha) rose from 289 +/- 23 pg/ml to 7,927 +/- 822 pg/ml. NPC 567 reduced the rise in 6kPGF1 alpha by 42% (P less than 0.05), without affecting TXB2. In summary, NPC 567 reduced mortality in rats treated with LPS, reduced the rise in 6kPGF1 alpha and partially reversed the hypotensive effects. These results suggest that bradykinin plays a significant role in the pathology of endotoxic shock.
激肽释放酶 - 激肽系统在内毒素休克期间被激活，这表明缓激肽在该疾病的病理过程中发挥作用。为了验证这一假设，在清醒的、长期插管的大鼠中研究了一种缓激肽拮抗剂D - Arg - Hyp3 - D - Phe7 - 缓激肽（NPC 567），这些大鼠正在经历脂多糖（LPS）诱导的内毒素休克。LPS处理导致循环缓激肽在1小时内从低于23 pg/ml增加到144±18 pg/ml。静脉注射LPS导致平均动脉压在1小时内下降38%，而NPC 567可部分逆转这一情况。NPC 567不影响LPS后出现的中度心动过速。以8 nmol/kg/min的速度输注NPC 567可使24小时死亡率从100%显著降低至50%（P < 0.01）。对LPS的反应中，血中血栓素B2（TXB2）从低于200 pg/ml升至2298±64 pg/ml，而6 - 酮 - 前列腺素 - F1α（6kPGF1α）从289±23 pg/ml升至7927±822 pg/ml。NPC 567使6kPGF1α的升高降低了42%（P < 0.05），而不影响TXB2。总之，NPC 567降低了LPS处理大鼠的死亡率，降低了6kPGF1α的升高，并部分逆转了低血压效应。这些结果表明缓激肽在内毒素休克的病理过程中起重要作用。
