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.

Hypertensive Response to Acute Stress Is Attenuated in Interleukin-6 Knockout Mice

“…24 Also, IL-6 causes thromboxane A2-mediated vasoconstriction in rat cremaster muscle arterioles. 25 Although some reports indicate that acute IL-6 infusion does not cause vasoconstriction or Figure 2. A, PRA during baseline conditions and 10 minutes during stress for WT (baseline nϭ9; stress nϭ8) and IL-6 KO (baseline nϭ8; stress nϭ9) mice.…”

Reactive Hyperemia and Interleukin 6, Interleukin 8, and Tumor Necrosis Factor-α in the Diagnosis of Early-Onset Neonatal Sepsis

“…Besides vasoconstriction, the accumulation and adherence of leukocytes to the vascular wall seen in sepsis may add to the impaired microcirculation. [27][28][29] Possible mediators of these early microvascular changes include cytokines, which have been reported to increase vascular tone, 18 and endothelial expression of adhesion molecules in early stages of sepsis. 30 In later stages of the disease, the microvascular tone and reactivity, as well as their correlation to cytokine levels, may well differ from the findings in our study.…”

“…7,8,14 -17 In sepsis, cytokines are involved in activating vascular and endothelial defense mechanisms that may cause changes in perfusion and vascular resistance in the microcirculation. 18,19 Accordingly, it is possible that cytokine activation is reflected in vascular reactivity. This study was conducted to evaluate the diagnostic use of a vascular reactivity test as compared with that of circulating cytokine levels in infants with suspected sepsis.…”

Role of TNF-α in Local Surgical Trauma-Induced Microvascular Dysfunction

“…Several in vivo studies have demonstrated that TNF-α in itself has a vasodilatory effect on second, third, and fourth order arterioles [17]and that TNF-α affects microvascular reactivity to catecholamines [18]. Moreover, TNF-α can regulate several endogenous mediators as being one of the early proinflammatory cytokines, especially in critical conditions.…”

“…Moreover, TNF-α can regulate several endogenous mediators as being one of the early proinflammatory cytokines, especially in critical conditions. These mediators include potent vasoconstrictive compounds, such as endothelin [19]and interleukin-6 [18]. However, in the present study pretreatment with anti-TNF-α antibody influenced neither the degree of initial surgical trauma-induced vasoconstriction nor the recovery process during the following 24 h. This finding is in line with those of Worrall et al [20], demonstrating that administration of low-dose recombinant TNF-α to healthy rats did not cause local blood flow alterations.…”