Interleukin 1 induces prolonged L-arginine-dependent cyclic guanosine monophosphate and nitrite production in rat vascular smooth muscle cells.

Abstract

The cytokine interleukin 1 (IL-1) inhibits contractile responses in rat aorta by causing endothelium-independent and prolonged activation of soluble guanylate cyclase. The present study tested whether IL-1 activates guanylate cyclase by inducing prolonged production of nitric oxide in cultured rat aortic vascular smooth muscle cells (VSMC). IL-I induced a marked timedependent increase in cyclic guanosine monophosphate (cGMP) in VSMC which was significant at 6 h, and increased progressively for up to 36 h. This effect of IL-1 was abolished when protein synthesis was inhibited with cycloheximide or actinomycin D, suggesting that the effect of IL-1 involves new protein synthesis. IL-1-induced cGMP accumulation was inhibited by the soluble guanylate cyclase inhibitors, methylene blue, LY83583, and hemoglobin and by the L-arginine analogue NGmonomethyl-L-arginine (L-NMMA). The inhibitory effect of L-NMMA was reversed by a 10-fold excess of L-arginine, but not by D-arginine. Nitrite, an oxidation product of nitric oxide, accumulated in the media of VSMC incubated with IL-1 for 24 h in the presence of L-arginine, whereas both IL-i-induced cGMP accumulation and nitrite production were attenuated in VSMC incubated in L-arginine-deficient medium. In L-arginine-depleted VSMC, IL-I-induced cGMP accumulation was restored to control levels by a 15-min incubation with L-arginine. These results demonstrate that IL-1 activates guanylate cyclase in rat VSMC by inducing production of nitric oxide via a pathway dependent on extracellular L-arginine. (J.

Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells

“…At the concentrations tested, both compounds are rather specific in their action. 48,49 However, as shown in Figure 5A, inhibition of either guanylyl cyclase or PKG did not affect the inhibitory effect of NTG. Identical results were obtained when the action of both compounds was tested on the inhibitory effect of SNAP and when a wider range of concentrations was used in the same experiment (LY-83583, 10 Ϫ11 to 10 Ϫ6 mol/L; KT5823, 0.05-2.0 mol/L) (data not shown).…”

“…This discrepancy with the working hypothesis was initially ascribed to a possible lack of specificity of both LY-83583 and KT5823, although they were used according to the modalities and dosages reported in the literature. 48,49 However, showing that stimulation with NO donors does not result in increased cGMP levels confirmed the possibility of an impairment of this system in activated human HSCs. To gain further insight, the expression of the heterodimeric form ␣ 1 ␤ 1 of sGC was analyzed in different cell lines of activated human HSCs.…”

Possible Involvement of K+ Channel Opening to the Interleukin-1.BETA.-Induced Inhibition of Vascular Smooth Muscle Contraction.

“…Prolonged exposure to interleukin-1β decreases vascular tone and causes systematic vasodilation [1,11]. Since interleukin-1β stimulates the expression of inducible form of NO synthase in the vascular smooth muscle cells which generates large quantities of NO over prolonged period, the vasodilatory effect of interleukin-1β has been suggested to be mediated by NO [2,3,6].Our recent study showed that phenylephrine-induced contraction was inhibited by in vitro pre-incubation of the rat aorta with interleukin-1β [1,6,15]. Analyzing the mechanisms of interleukin-1β-induced inhibition, we have shown that interleukin-1β-induced vasodilation was mediated not only by NO-dependent mechanism but also by NO-independent mechanism(s) [15].…”

Dexamethasone Inhibits Nitric Oxide Synthase mRNA Induction by Interleukin-la and Tumor Necrosis Factor-α in Vascular Smooth Muscle Cells

“…Our results show that IL-la (up to 100 U/ml) does not induce nitric oxide synthase mRNA, although inter leukin-18 (IL-1(3) has been demonstrated to induce nitric oxide activity in smooth muscle cells (4,22). It has been shown that IL-la and IL-l jl do not always share the same biological activities (23).…”