Platelet activation and modulation of the induction of nitric oxide synthase in the conscious rat

Injection of lipopolysaccharide (LPS) (Salmonella W. Typhosa i.v. bolus) in to conscious rats, induced a rapid drop of circulating platelets analogous to that induced by ADP. The animals showed a small fall in mean arterial bl ood pressure (MABP) an increase in heart rate and a significant increase in plasma nitrite and nitrate level. This result is consistent with the stimu lation of an inducible NO synthase (i-NOS). The administration of the stabl e prostacyclin analogue, iloprost plus ADP or LPS, significantly protected against the decrease in free platelet number induced by ADP or LPS. The pla sma nitrite and nitrate level stimulated by LPS was significantly reduced b y iloprost and also by prostacyclin. These results are consistent with an i nhibition of i-NOS by agents that increase the intracellular level of cAMP. The administration of the NO donor S-Nitroso-N-acetyl-D,L-penicillamine (S NAP) plus ADP or LPS, significantly prevented thrombocytopenia induced by A DP and by LPS. SNAP did not decrease the plasma nitrite and nitrate level s timulated by LPS; furthermore it induced a significant increase of heart ra te, without affecting MABP, suggesting a direct accelerating effect of NO o n the sino-atrial node. The administration of S-nitroso-glutathione (GSNO), a stable nitrosothiol, plus ADP or LPS, significantly prevented thrombocyt openia induced by ADP but not by LPS. GSNO significantly reduced the plasma nitrite and nitrate level stimulated by LPS. These data demonstrate that t he L-Arginine: NO pathway in vivo may be modulated by prostanoids and that compounds which increase cAMP, such as iloprost, are able to protect agains t LPS-induced early thrombocytopenia.