THE CARDIODEPRESSANT AND VASODEPRESSANT EFFECTS OF TUMOR-NECROSIS-FACTOR IN RAT ISOLATED ATRIAL AND AORTIC TISSUES

1 The ability of recombinant human tumour necrosis factor-alpha (rec huTNF) to elicit cardiodepressor and vasodepressor effects in rat isolated tissues was investigated. 2 rec huTNF (3 x 10(-11)-3 x 10(-8) M) administered directly to the organ bath, caused a concentration-dependent relaxation of the isoprenaline-induced inotropic response in electrically stimulated rat left atria. This occurred within 20 min of administration. In contrast, rec huTNF was without effect on the chronotropic response to isoprenaline in isolated spontaneously beating atria. 3 rec huTNF (1-mu-g kg-1) was also given systemically to rats and the atria studied in vitro. Only 60 min of rec huTNF pretreatment was sufficient to cause a marked attenuation of the isoprenaline-induced inotropic response. This effect was not further augmented when rats were pretreated with rec huTNF for 24 h. 4 In isolated aortic rings taken from rats 60 min after rec huTNF (1-mu-g kg-1, i.v.) administration, there was no effect seen on the constriction induced by phenylephrine in either endothelium-intact or denuded tissues. In addition, any responses to L-arginine or N(G)-nitro-L-arginine methyl ester (L-NAME) administration were unaffected by rec huTNF pretreatment. 5 In aortic rings taken from rats 24 h after rec huTNF administration, the phenylephrine-induced constriction was significantly attenuated in tissues with an intact endothelium. Furthermore, the relaxation to subsequent L-arginine administration was greater in these tissues than in those from saline-treated rats. In addition, in both endothelium-intact and denuded tissues, the vasoconstrictor response to L-NAME (10(-3) M) was significantly augmented. 6 These data suggest that rec huTNF possesses both cardiodepressant properties with a rapid onset of action and vasodepressant properties with a slow onset of action. The latter could be mediated through the induction of a non-constitutive form of the NO-synthase enzyme present within the vascular wall.