Beneficial effects of L-canavanine, a selective inhibitor of inducible nitric oxide synthase, on lactate metabolism and muscle high energy phosphatesduring endotoxic shock in rats

Overproduction of NO by an inducible NO synthase (iNOS) plays a role in the pathophysiology of septic shock. in such situations, NOS inhibition might be of therapeutic value, although detrimental side effects possibly related to inhibition of constitutive NOS have been reported. The use of L-canavan ine, a selective inhibitor of iNOS, might be more suitable. The aim of the study was to compare in a rodent endotoxic shock the effects of saline (2 m L/h), N-G-methyl-L-arginine(L-NMMA) (10 mg/kg/h) and L-canavanine (100 mg/k g/h) on muscle intracellular pH (pH(i)) and intracellular bioenergetic patt erns (ATP, phosphocreatine/inorganic phosphate ratio) using in vivo P-31 ma gnetic resonance spectroscopy ((P-31 MRS). Three groups of anesthetized, me chanically ventilated and paralyzed rats received an intravenous infusion o f 15 mg/kg of endotoxin. A fourth time-matched control group (n = 8) receiv ed 2 mL/h of saline. Mean arterial pressure, femoral blood flow, arterial b lood gases, lactate, nitrate level, and P-31 nuclear magnetic resonance (P- 31 MRS) measurements were acquired at onset (T = 0), 90 min (T = 90), and 1 80 min (T180) after the endotoxin challenge. Femoral oxygen delivery was ca lculated as the product of femoral blood flow (mL/min) and arterial oxygen content. Endotoxin induced a marked decrease in arterial pressure and femor al oxygen delivery and an increase in lactate level. Intracellular pH and p hosphocreatine/inorganic phosphate ratio decreased. ATP level did not chang e. Both L-NMMA and L-canavanine reversed the endotoxin-induced decrease in arterial pressure. L-NMMA attenuated the decrease in femoral oxygen deliver y and the increase in lactate level while these were corrected by L-canavan ine. Considering P-31 MRS derived bioenergetic indices, the endotoxin-induc ed decrease in pH(i) and Pcr/P-i was attenuated by L-NMMA and corrected by L-canavanine. In conclusion, in a rodent model of endotoxinic shock, the co ntinuous infusion of L-canavanine, a selective iNOS inhibitor, improved the systemic hemodynamic parameters and the intracellular bio-energetic patter ns estimated by in vivo P-31 MRS. To the contrary, the continuous infusion of both constitutive and inducible NOS inhibitor L-NMMA was not followed by the same achievement.