Differences between cytokine effects in the microcirculation of the rat

Abstract

We studied by in vivo microscopy in rat cremaster muscle the acute and delayed effects of short exposure to tumor necrosis factor (TNF), interleukin (IL)-1 beta, and IL-6 on basal tone and vascular reactivity of second- to fourth-order arterioles (A2-A4). A 20-min exposure to recombinant human (rh) TNF (0.1-10 ng/ml) induced a significant arteriolar vasodilation, but no significant changes in basal tone were found after exposure to the same doses of IL-1 beta. In contrast, the same exposure to IL-6 (0.1-10 ng/ml) induced a significant dose-dependent vasoconstriction (i.e., 8, 15, and 21% at 10 ng/ml in A2-A4 arterioles, respectively). This vasoconstriction was inhibited by the thromboxane A2 receptor antagonist SQ-29548. We did not find any significant effect of rhTNF or IL-6 on vascular reactivity to norepinephrine immediately after exposure to these two cytokines or 100 min after the end of the exposure. Contrastingly, a large dose-dependent decrease in reactivity to norepinephrine was found immediately after exposure to IL-1 beta and still persisted 100 min after the end of the exposure. Such a decrease was not found for the vasoconstriction in response to KCl. We conclude that, at the microvascular level, large differences exist between the three cytokines generally considered to mediate the harmful cardiovascular effects in sepsis. 1) TNF but not IL-1 beta is responsible for a vasodilatory effect, whereas the effect of IL-6 is a thromboxane A2-mediated vasoconstriction. 2) Short exposure to IL-1 beta but not to rhTNF or IL-6 diminishes the response of the arterioles to norepinephrine but not to KCl.