EFFECTS OF TUMOR-NECROSIS-FACTOR AND INTERLEUKIN-1 ON THE CONSTRICTION INDUCED BY ANGIOTENSIN-II IN RAT AORTA

To better understand the different steps in the changes occurring in v ascular reactivity during sepsis, we studied the effects of a short ex posure to tumor necrosis factor (TNF) and interleukin-1 (IL-1) on the contraction in response to angiotensin II (ANG II). The contraction el icited by ANG II was studied by using standard isometric tension techn iques in aortic rings exposed for Ih to 25 ng/ml TNF or to 5 or 20 ng/ ml IL-1. This contraction was not significantly changed by TNF but was 109 +/- 23 and 190 +/- 38% greater than in control rings after 5 and 20 ng/ml IL-1, respectively. Because the contraction induced by ANG II is modulated by the simultaneous release of prostaglandins, we tested the hypothesis that IL-1 interferes with this modulation. We found th at the IL-1-induced increase in contraction in response to ANG II was completely inhibited by 10(-5) M of the cyclooxygenase inhibitor indom ethacin and also by 10(-5) M of the prostaglandin H-2/thromboxane AB-r eceptor antagonist SQ-29548. Note, however, that in rings exposed to I L-1 the contraction in response to the thromboxane A(2)-receptor agoni st U-46619 was not significantly different from the contraction in une xposed rings. Furthermore, no loss was observed in either the vasodila tor response to 10(-9)-10(-4) M of the endothelium-dependent-receptor agonist acetylcholine or in the receptor-independent contraction induc ed by 60 mM K+. We conclude that short exposure to IL-1, but not to TN F, produces a specific increase in the vasoconstrictor response to ANG II via mechanisms mediated by prostaglandin H-2/ thromboxane A(2). Th is increase might result from an IL-1-induced shift in favor of constr ictor prostanoids in the balance of the dilator/constrictor prostanoid s, the release of which is associated with stimulation by ANG II.