Gardiner S M, Kemp P A, March J E, Woolley J, Bennett T
School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre.
Br J Pharmacol. 1998 Dec;125(7):1543-50. doi: 10.1038/sj.bjp.0702250.
Male, Long Evans rats (350-450 g) were anaesthetized and had pulsed Doppler probes and intravascular catheters implanted to allow monitoring of regional (renal, mesenteric and hindquarters) haemodynamics in the conscious state. Our main objectives were to:- assess the effects of administering human recombinant tumour necrosis factor (TNF)-alpha and human recombinant interleukin-1 (IL-1)beta, alone and together; determine the influence of pretreatment with a mixture of antibodies to TNF-alpha and IL-1beta on responses to co-administration of the cytokines; ascertain if pretreatment with a mixture of the antibodies to TNF-alpha and IL-1beta had any influence on the responses to lipopolysaccharide (LPS). TNF-alpha (10, 100 and 250 microg kg(-1), in separate groups, n=3, 9 and 8, respectively) caused tachycardia (maximum delta, +101+/-9 beats min(-1)) and modest hypotension (maximum delta, -10+/-2 mmHg), accompanied by variable changes in renal and mesenteric vascular conductance, but clear increases in hindquarters vascular conductance; only the latter were dose-related (maximum delta, +6+/-6, +27+/-9, and +61+/-12% at 10, 100 and 250 microg kg(-1), respectively). IL-1beta (1, 10, and 100 microg kg(-1) in separate groups, n = 8, 8 and 9, respectively) evoked changes similar to those of TNF-alpha (maximum delta heart rate, +69+/-15 beats min(-1); maximum delta mean blood pressure, -14+/-2 mmHg; maximum delta hindquarters vascular conductance, +49+/-17%), but with no clear dose-dependency. TNF-alpha (250 microg kg(-1)) and IL-1beta (10 microg kg(-1)) together caused tachycardia (maximum delta, +76+/-15 beats min(-1)) and hypotension (maximum A, -24+/-2 mmHg) accompanied by increases in renal, mesenteric and hindquarters vascular conductances (+52+/-6%, +23+/-8%, and +52+/-11%, respectively). Thereafter, blood pressure recovered, in association with marked reductions in mesenteric and hindquarters vascular conductances (maximum delta, -50+/-3% and -58+/-3%, respectively). Although bolus injection of LPS (3.5 mg kg(-1)) caused an initial hypotension (maximum delta, -27+/-11 mmHg) similar to that seen with co-administration of the cytokines, it did not cause mesenteric or hindquarters vasodilatation, and there was only a slow onset renal vasodilatation. The recovery in blood pressure following LPS was less than after the cytokines, and in the former condition there was no mesenteric vasoconstriction. By 24 h after co-administration of TNF-alpha and IL-1beta or after bolus injection of LPS, the secondary reduction in blood pressure was similar (-16+/-2 and -13+/-3 mmHg, respectively), but in the former group the tachycardia (+117+/-14 beats min(-1)) and increase in hindquarters vascular conductance (+99+/-21%) were greater than after bolus injection of LPS (+54+/-16 beats min ' and +439%, respectively). Pretreatment with antibodies to TNF-alpha and IL-1beta (300 mg kg(-1)) blocked the initial hypotensive and mesenteric and hindquarters vasodilator responses to co-administration of the cytokines subsequently. However, tachycardia and renal vasodilatation were still apparent. Premixing antibodies and cytokines before administration prevented most of the effects of the latter, but tachycardia was still present at 24 h. Pretreatment with antibodies to TNF-alpha and IL-1beta before infusion of LPS (150 microg kg(-1) h(-1) for 24 h) did not affect the initial fall in blood pressure, but suppressed the hindquarters vasodilatation and caused a slight improvement in the recovery of blood pressure. However, pretreatment with the antibodies had no effect on the subsequent cardiovascular sequelae of LPS infusion. the results indicate that although co-administration of TNF-alpha and IL-1beta can evoke cardiovascular responses which, in some respects, mimic those of LPS, and although antibodies to the cytokines can suppress most of the cardiovascular effects of the cytokines, the antibodies have little influence on the haemodynamic responses to LPS, possibly because, during infusion of LPS, the sites of production and local action of endogenous cytokines, are not accessible to exogenous antibodies.
雄性Long Evans大鼠（体重350 - 450克）麻醉后植入脉冲多普勒探头和血管内导管，以便在清醒状态下监测局部（肾、肠系膜和后肢）血流动力学。我们的主要目标是：评估单独及联合给予重组人肿瘤坏死因子（TNF）-α和重组人白细胞介素-1（IL-1）β的效果；确定用抗TNF-α和IL-1β抗体混合物预处理对细胞因子联合给药反应的影响；确定用抗TNF-α和IL-1β抗体混合物预处理对脂多糖（LPS）反应是否有任何影响。TNF-α（分别在不同组中给予10、100和250微克/千克，n分别为3、9和8）引起心动过速（最大变化量，+101±9次/分钟）和轻度低血压（最大变化量，-10±2毫米汞柱），伴有肾和肠系膜血管传导性的变化不定，但后肢血管传导性明显增加；只有后者与剂量相关（在10、100和250微克/千克时，最大变化量分别为+6±6%、+27±9%和+61±12%）。IL-1β（分别在不同组中给予1、10和100微克/千克，n分别为8、8和9）引起的变化与TNF-α相似（最大心率变化量，+69±15次/分钟；最大平均血压变化量，-14±2毫米汞柱；最大后肢血管传导性变化量，+49±17%），但无明显剂量依赖性。TNF-α（250微克/千克）和IL-1β（10微克/千克）联合给药引起心动过速（最大变化量，+76±15次/分钟）和低血压（最大变化量A，-24±2毫米汞柱），伴有肾、肠系膜和后肢血管传导性增加（分别为+52±6%、+23±8%和+52±11%）。此后，血压恢复，同时肠系膜和后肢血管传导性显著降低（最大变化量分别为-50±3%和-58±3%）。虽然静脉注射LPS（3.5毫克/千克）引起的初始低血压（最大变化量，-27±11毫米汞柱）与细胞因子联合给药时相似，但未引起肠系膜或后肢血管舒张，只有肾血管舒张缓慢出现。LPS给药后血压的恢复低于细胞因子给药后，且在前一种情况下没有肠系膜血管收缩。在联合给予TNF-α和IL-1β或静脉注射LPS后24小时，继发性血压降低相似（分别为-16±2和-13±3毫米汞柱），但在前一组中，心动过速（+117±14次/分钟）和后肢血管传导性增加（+99±21%）大于静脉注射LPS后（分别为+54±16次/分钟和+439%）。用抗TNF-α和IL-1β抗体（300毫克/千克）预处理随后可阻断细胞因子联合给药引起的初始降压以及肠系膜和后肢血管舒张反应。然而，心动过速和肾血管舒张仍然明显。给药前将抗体与细胞因子预混合可防止后者的大部分作用，但24小时时仍有心动过速。在输注LPS（150微克/千克·小时，持续24小时）前用抗TNF-α和IL-1β抗体预处理不影响初始血压下降，但抑制后肢血管舒张并使血压恢复略有改善。然而，抗体预处理对LPS输注后的后续心血管后遗症没有影响。结果表明，虽然联合给予TNF-α和IL-1β可引发心血管反应，在某些方面类似于LPS引发的反应，虽然细胞因子抗体可抑制细胞因子的大部分心血管作用，但抗体对LPS的血流动力学反应影响很小，可能是因为在输注LPS期间，内源性细胞因子的产生部位和局部作用部位对外源抗体不可及。
