The influence of antibodies to TNF-alpha and IL-1 beta on haemodynamic responses to the cytokines, and to lipopolysaccharide, in conscious rats

1 Male, Long Evans rats (350-450 g) were anaesthetized and had pulsed Doppl er probes and intravascular catheters implanted to allow monitoring of regi onal (renal, mesenteric and hindquarters) haemodynamics in the conscious st ate. Our main objectives were to: assess the effects of administering human recombinant tumour necrosis factor (TNF)-alpha and human recombinant inter leukin-1 (IL-1)beta, alone and together; determine the influence of pretrea tment with a mixture of antibodies to TNF-alpha and IL-1 beta on responses to co-administration of the cytokines; ascertain if pretreatment with a mix ture of the antibodies to TNF-alpha and IL-1 beta had any influence on the responses to lipopolysaccharide (LPS). 2 TNF-alpha (10, 100 and 250 mu g kg(-1), in separate groups, n=3, 9 and 8, respectively) caused tachycardia (maximum Delta, +101+/-9 beats min(-1)) a nd modest hypotension (maximum Delta, - 10+/-2 mmHg), accompanied by variab le changes in renal and mesenteric vascular conductance, but clear increase s in hindquarters vascular conductance; only the latter were dose-related ( maximum Delta, + 6+/-6, +27+/-9, and + 61 +/- 12% at 10, 100 and 250 mu g k g(-1), respectively). 3 IL-1 beta (1, 10, and 100 mu g kg(-1) in separate groups, n=8, 8 and 9, r espectively) evoked changes similar to those of TNF-alpha (maximum a heart rate, + 69 +/- 15 beats min(-1); maximum Delta mean blood pressure, - 14 +/ - 2 mmHg; maximum Delta hindquarters vascular conductance, + 49 +/- 17%), b ut with no clear dose-dependency. 4 TNF-alpha (250 mu g kg(-1)) and IL-1 beta (10 mu g kg(-1)) together cause d tachycardia (maximum Delta, +76 +/- 15 beats min(-1)) and hypotension (ma ximum Delta, -24+/-2 mmHg) accompanied by increases in renal, mesenteric an d hindquarters vascular conductances (+52+/-6%, +23+/-8%, and +52+/-11%, re spectively). Thereafter, blood pressure recovered, in association with mark ed reductions in mesenteric and hindquarters vascular conductances (maximum Delta, -50+/-3% and -58+/-3% respectively). Although bolus injection of LP S (3.5 mg kg(-1)) caused an initial hypotension (maximum Delta, -27+/-11 mm Hg) similar to that seen with co-administration of the cytokines, it did no t cause mesenteric or hindquarters vasodilatation, and there was only a slo w 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 coadministration of TNF-alpha a nd IL-1 beta or after bolus injection of LPS, the secondary reduction in bl ood pressure was similar (-16+/-2 and -13+/-3 mmHg, respectively), but in t he former group the tachycardia (+117+/-14 beats min(-1)) and increase in h indquarters vascular conductance (+99+/-21%) were greater than after bolus injection of LPS (+54+/-16 beats min(-1) and +43+/-9%, respectively). 5 Pretreatment with antibodies to TNF-alpha and IL-1 beta (300 mg kg(-1)) b locked the initial hypotensive and mesenteric and hindquarters vasodilator responses to co-administration of the cytokines subsequently. However, tach ycardia and renal vasodilatation were still apparent. Premixing antibodies and cytokines before administration prevented most of the effects of the la tter, but tachycardia was still present at 24 h. 6 Pretreatment with antibodies to TNF-a and IL-IB before infusion of LPS (1 50 mu g kg(-1) h(-1) for 24 h) did not affect the initial fall in blood pre ssure, but suppressed the hindquarters vasodilatation and caused a slight i mprovement in the recovery of blood pressure. However, pretreatment with th e antibodies had no effect on the subsequent cardiovascular sequelae of LPS infusion. 7 The results indicate that although co-administration of TNF-alpha and IL- 1 beta can evoke cardiovascular responses which, in some respects, mimic th ose of LPS, and although antibodies to the cytokines can suppress most of t he cardiovascular effects of the cytokines, the antibodies have little infl uence on the haemodynamic responses to LPS, possibly because, during infusi on of LPS, the sites of production and local action of endogenous cytokines , are not accessible to exogenous antibodies.