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

Objectives: Our aims were to investigate the systemic hemodynamic effects of 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 hyperdynamic circulatory reaction was elicited by a 2-hour infusion of Escherichia coli endotoxin (ETX) in a dose of 5.3 μg/kg. The animals in group 3 were treated with 12.5 mg/kg nonselective NOS inhibitor N-w-nitro-L-arginine methyl 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), cardiac output (CO) and myocardial contractility (MC) were measured, and total peripheral resistance (TPR) was calculated. The eNOS and iNOS activities were determined in myocardial biopsy samples taken after 8 h of endotoxemia. Results: ETX induced significant decreases in TPR and MAP, a transient myocardial depression, and increased the myocardial eNOS and iNOS activities. L-NAME decreased the activities of both isoenzymes, increased MC but induced a fall in CO. SMT inhibited iNOS by 60%, without influencing the eNOS activity, increased MAP and contractility in the early phase of endotoxemia, and induced only a slight decrease in CO. Conclusions: Nonselective NOS inhibition restores the arterial pressure and exerts a positive inotropic effect, but decreases CO. SMT selectively decreases the iNOS activation without disturbing the vasoregulatory function of the eNOS-derived nitric oxide in hyperdynamic endotoxemia in the dog.