- Meeting abstract
- Open Access
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
- Nitric Oxide
- Sodium Nitroprusside
- Calcium Ionophore A23187
- Chloromethyl Ketone
- Rabbit Carotid Artery
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.
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.
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.