Interleukin-1beta-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-1beta and to induce vasodilation in septic shock. To understand the mechanisms of interleukin-1beta-induced relaxation, we examined the effects of interleukin-1beta on contractility and cyclic GMP contents of vascular smooth muscle. After treatment of the rat aorta with interleukin-1beta (20 ng/ml) for 6 h, the cyclic GMP content increased and the contraction induced by phenylephrine (1 microM) was partially inhibited. An inhibitor of nitric oxide (NO) synthase, N(G)-monomethyl-L-arginine (L-NMMA, 100 microM), prevented the inhibitory effect of interleukin-1beta. After treatment with interleukin-1beta for 24 h, the phenylephrine-induced contraction was inhibited more strongly. Neither L-NMMA (100 microM) nor aminoguanidine (100 microM) reversed the inhibition, whereas methylene blue (10 microM) partially reversed the inhibition. After treatment with interleukin-1beta 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 microM) to inhibit the phenylephrine-induced contraction and to increase the cyclic GMP content were markedly suppressed by the 24-h interleukin-1beta treatment. In contrast, the 24-h interleukin-1beta 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-1beta. The 24 h interleukin-1beta treatment increased the threshold concentration of KCl 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-1beta treatment on phenylephrine-induced contraction was restored. These results suggest that interleukin-1beta inhibits vascular smooth muscle contraction by a time-dependent, dual mechanism. After a 6-h treatment with interleukin-1beta, the NO/cyclic GMP system is activated. After a 24-h interleukin-1beta 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.
Takizawa
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Department of Veterinary Pharmacology, Graduated School of Agriculture and Life Sciences, The University of Tokyo, Bunkyo-ku, Japan.
Ozaki
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Karaki
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D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007375:Interleukin-1; D014665:Vasodilator Agents; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D011189:Potassium Chloride; D006152:Cyclic GMP