ISOPROTERENOL REGULATES TUMOR-NECROSIS-FACTOR, INTERLEUKIN-10, INTERLEUKIN-6 AND NITRIC-OXIDE PRODUCTION AND PROTECTS AGAINST THE DEVELOPMENT OF VASCULAR HYPOREACTIVITY IN ENDOTOXEMIA

Pro-inflammatory cytokines, such as tumour necrosis factor (TNF) and f ree radicals, such as nitric oxide (NO), are mediators of endotoxaemia . Catecholamines are in clinical use to treat the haemodynamic consequ ences of severe septic shock. Beta-adrenergic agonists exert many of t heir effects by elevation of intracellular cyclic AMP (cAMP) concentra tion. Cyclic AMP can modulate endotoxin-induced cytokine and NO produc tion. Here we investigate the effect of isoproterenol pretreatment on the cytokine and NO production induced by bacterial lipopolysaccharide (LPS, 4-10 mg/kg). Pretreatment with isoproterenol (10 mg/kg) blunted the LPS-induced TNF response, increased the LPS-induced formation of interleukin-10 and interleukin-6 and reduced the LPS-induced productio n of NO in conscious mice. In anaesthetized rats, pretreatment with is oproterenol prevented the LPS-induced suppression of vascular contract ility to norepinephrine in the thoracic aorta ex vivo. The hyporeactiv ity is due to expression of the inducible isoform of NO synthase (iNOS ) and was restored by in vitro administration of N-G-methyl-L-arginine (L-NMA), an inhibitor of NO synthase, However, L-NMA did not alter va scular contractility in control vessels or in rings taken from the LPS -treated rats pretreated with isoproterenol. Our findings suggest that , in addition to its haemodynamic actions, isoproterenol may also exer t beneficial effects by modulating the endotoxin-induced inflammatory response.