Effects of selective nitric oxide synthase inhibition in hyperdynamic endotoxemia in dogs

Objectives: Our aims were to investigate the systemic hemodynamic effects o f constitutive endothelial nitric oxide synthase (eNOS) and inducible NOS ( iNOS) inhibitors in hyperdynamic endotoxemia. Patients and Methods: Group 1 comprised sham-operated controls, while in group 2, 3 and 4, a hyperdynami c circulatory reaction was elicited by a 2-hour infusion of Escherichia col i endotoxin (ETX) in a dose of 5.3 mu g/kg. The animals in group 3 were tre ated with 12.5 mg/kg nonselective NOS inhibitor N-omega-nitro-L-arginine me thyl ester (L-NAME), and those in group 4 with 2 mg/kg of the specific iNOS inhibitor S-methyl-isothiourea (SMT). Mean arterial pressure (MAP), cardia c output (CO) and myocardial contractility (MC) were measured, and total pe ripheral resistance (TPR) was calculated. The eNOS and iNOS activities were determined in myocardial biopsy samples taken after 8 h of endotoxemia. Re sults: ETX induced significant decreases in TPR and MAP, a transient myocar dial depression, and increased the myocardial eNOS and iNOS activities. L-N AME decreased the activities of both isoenzymes, increased MC but induced a fall in CO. SMT inhibited iNOS by 60%, without influencing the eNOS activi ty, increased MAP and contractility in the early phase of endotoxemia, and induced only a slight decrease in CO. Conclusions: Nonselective NOS inhibit ion restores the arterial pressure and exerts a positive inotropic effect, but decreases CO. SMT selectively decreases the iNOS activation without dis turbing the vasoregulatory function of the eNOS-derived nitric oxide in hyp erdynamic endotoxemia in the dog.