Lipopolysaccharides (LPS) can be used to induce experimental endotoxic shock, which is characterized by a significant decrease in mean arterial pressure (MAP) and a decreased vasoconstrictor response that have been attributed to excessive nitric oxide production. Inhibitors of 3-hydroxi-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), in addition to lowering serum cholesterol levels, exert many pleiotropic effects, including anti-inflammatory action. In the present study, we investigated the effect of simvastatin, an HMG-CoA reductase inhibitor, on the production of nitric oxide and the cardiovascular response to LPS. Male Wistar rats were pretreated with different doses of simvastatin (10, 20, 40, and 80 mg/kg, i.p.) or saline 20 min before i.v. injection of LPS (1.5 mg/kg) or saline (control). MAP was continuously recorded and nitrate plasma concentration was determined during the 6-h experimental session at 1-h intervals. The pressor response to phenylephrine (1 μg/kg) was evaluated before and 6 h after LPS administration. In the LPS-treated group, there was a time-dependent increase in nitrate plasma concentration (P < 0.001), and this response was decreased in simvastatin pretreated rats (P < 0.001). We also observed that LPS decreased the pressor response to phenylephrine (P < 0.001), an effect that was reverted by simvastatin pretreatment (P < 0.05). However, simvastatin did not modify the decrease of MAP induced by LPS. We concluded that simvastatin decreases nitrate plasma concentration in response to LPS and recovers vascular responsiveness during an experimental endotoxic shock. These data suggest the potential use of HMG-CoA reductase inhibitors as a coadjuvant in the treatment of septic shock.

Septic shock is characterized by arteriolar vasodilation and hypotension. We have tested the hypothesis that nitric oxide arising from inducible nitric oxide synthase in the central nervous system is responsible for the deficiency in vasopressin release and consequent hypotension during experimental septic shock. Septic shock was induced in male Wistar rats by intravenous injection of 1.5 mg/kg lipopolysaccharide. After lipopolysaccharide administration, we found a significant decrease in mean arterial pressure with a concomitant increase in heart rate, a significant decrease in diuresis, and a transitory decrease in body temperature. An increase in plasma vasopressin concentrations occurred in these animals and was present for 2 hrs after lipopolysaccharide administration, returning close to basal concentrations thereafter and remaining unchanged for the next 24 hrs. When lipopolysaccharide was combined with central administration of aminoguanidine, an inducible nitric oxide synthase inhibitor, we observed a sustained increase in plasma vasopressin concentration and in the maintenance of blood pressure at 4 and 6 hrs after lipopolysaccharide treatment compared with rats treated with lipopolysaccharide alone. These data indicate that central nitric oxide arising from the inducible nitric oxide synthase pathway plays an important inhibitory role in vasopressin release during experimental septic shock and may be responsible for the hypotension occurring in this vasodilatory shock.