Negative and reversible feedback inhibition of the endothelial nitric oxide (NO) synthesis by interleukin-1β (IL-1β)-induced generation of nitric oxide
© Current Science Ltd 1997
Published: 1 March 1997
The synthesis of NO in endothelial cells plays a major role in the control of vascular homeostasis in part due to its ability to inhibit vascular tone and activation of platelets. Inflammatory mediators such as IL-1β impair the NO-mediated endothelium-dependent relaxations in isolated blood vessels. Since IL-1β is a potent inducer of the inducible NO synthase (iNOS), the role of the induced synthesis of NO and the inhibitory effect of IL-1β was examined.
Materials and methods
Vascular reactivity studies were performed with rabbit carotid arteries with endothelium using organ chambers and the release of biologically active NO was assessed under bioassay conditions.
The concentration-dependent relaxations to acetylcholine, substance P and to the calcium ionophore A23187 were inhibited in IL-1β (100 U/ml for 7 h)-treated compared to control carotid arteries while those to sodium nitroprusside were not affected. No inhibitory effect was obtained in carotid arteries which had been exposed to IL-1β (100 U/ml) for only 15 min or to IL-1β (100 U/ml for 7 h) in the presence of either cycloheximide (20 μg/ml, an inhibitor of the protein synthesis), N-α-tosyl-L-lysine chloromethyl ketone (100 μM, an inhibitor of iNOS expression) or S-methylisothiourea sulfate (l0 μM, a preferential inhibitor of iNOS activity). Perfusates from IL-1β (100 U/ml for 7 h)-treated carotid arteries relaxed detector blood vessels without endothelium to a smaller extent than those from control arteries. Similar relaxations to acetylcholine were obtained in control carotid arteries and in IL-1β (100 U/ml for 7 h followed by a 17 h incubation in medium without the cytokine, a condition which is not associated with an induced synthesis of No)-treated arteries.
Summary and conclusions
These findings indicate that the IL-1β-mediated inhibitory effect on the endothelium-dependent relaxations is due to an inhibition of the calcium-dependent NO synthase activity in endothelial cells by the induced synthesis of NO. Such an inhibitory mechanism may help to explain the blunted endothelium-dependent vasodilatory capacity of arteries subjected to an inflammatory response such as in sepsis and in atherosclerosis. Since the effect of IL-1β is reversible. it may represent a mechanism which prevents an excessive production of NO in the blood vessel wall at sites of injury.