Interleukin-1 beta-induced, nitric oxide-dependent and -independent inhibition of vascular smooth muscle contraction

Stimulation of vascular smooth muscle by bacterial lipopolysaccharide has been shown to produce interleukin-1 beta and to induce vasodilation in septic shock. To understand the mechanisms of interleukin-1 beta-induced relaxation, we examined the effects of interleukin-1 beta on contractility and cyclic GMP contents of vascular smooth muscle. After treatment of the rat aorta with interleukin-1 beta (20 ng/ml) for 6 h, the cyclic GMP content increased and the contraction induced by phenylephrine(1 mu M) was partially inhibited. An inhibitor of nitric oxide (NO) synthase, N-G-monomethyl-L-arginine (L-NMMA, 100 mu M), prevented the inhibitory effect of interleukin-1 beta. After treatment with interleukin-1 beta for 24 h, the phenylephrine-induced contraction was inhibited more strongly. Neither L-NMMA (100 mu M) nor aminoguanidine (100 mu M) reversed the inhibition, whereas methylene blue (10 mu M) partially reversed the inhibition. After treatment with interleukin-1 beta for 12 or 24 h, the cyclic GMP content increased but to a level lower than that obtained with a 6-h treatment. The effects of sodium nitroprusside (1 mu M) to inhibit the phenylephrine-induced contraction and to increase the cyclic GMP content were markedly suppressed by the 24-h interleukin-1 beta treatment. In contrast, the 24-h interleukin-1 beta treatment did not change the ability of 8-bromo-cGMP to relax the phenylephrine-stimulated aorta. Addition of L-NMMA (1 mM) during the 24 h treatment prevented NO production and preserved the sodium nitroprusside-induced cGMP generation by interleukin-1 beta. The 24 h interleukin-1 beta treatment increased the threshold concentration of KCI needed to induce contraction without changing the maximum contraction. In the presence of 25.4 mM KCl or the non-selective K+ channel inhibitor, tetraethylammonium, the inhibitory effect of the 24-h interleukin-1 beta treatment on phenylephrine-induced contraction was restored. These results suggest that interleukin-1 beta inhibits vascular smooth muscle contraction by a time-dependent, dual mechanism. After a 6-h treatment with interleukin-1 beta, the NO/cyclic GMP system is activated. After a 24-h interleukin-1 beta treatment, in contrast, the NO/cyclic GMP system may be desensitized and the contraction of vascular smooth muscle is inhibited by another mechanism, possibly membrane hyperpolarization. (C) 1997 Elsevier Science B.V.