Effects of propofol on the leukocyte nitric oxide pathway: in vitro and ex vivo studies in surgical patients

• Published in: Naunyn-Schmiedeberg's archives of pharmacology Vol. 376; no. 5; pp. 331 - 339
• Main Authors: González-Correa, J. A., Cruz-Andreotti, E., Arrebola, M. M., López-Villodres, J. A., Jódar, M., De La Cruz, J. P.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-01-2008
• Subjects: Adult; Anesthetics, Intravenous - administration & dosage; Anesthetics, Intravenous - pharmacology; Biomedical and Life Sciences; Biomedicine; Cyclooxygenase 1 - drug effects; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - drug effects; Cyclooxygenase 2 - metabolism; Dose-Response Relationship, Drug; Female; Humans; In Vitro Techniques; Infusions, Intravenous; Interleukins - metabolism; Leukocytes - drug effects; Leukocytes - metabolism; Male; Middle Aged; Neurosciences; Nitric Oxide - biosynthesis; Nitric Oxide Synthase Type I - drug effects; Nitric Oxide Synthase Type I - metabolism; Nitric Oxide Synthase Type II - drug effects; Nitric Oxide Synthase Type II - metabolism; Original Article; Pharmacology/Toxicology; Propofol - administration & dosage; Propofol - pharmacology; Tumor Necrosis Factor-alpha - drug effects; Tumor Necrosis Factor-alpha - metabolism; Cyclooxygenase; Propofol; Cytokines; Nitric oxide
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-007-0220-4

This study was designed to evaluate the mechanism by which propofol modifies leukocyte production of nitric oxide (NO) in humans. In vitro experiments used whole blood from healthy volunteers (
n
 = 10 samples/experiment). Ex vivo experiments studied the effects of an intravenous dose of 2.5 mg propofol per kilogram body weight followed by intravenous infusion of 4 mg kg
−1
h
−1
in surgical patients in ASA class I or II (
n
 = 20). In whole blood, neutrophils and plasma, we measured NO production and the activities of the enzymes nitric oxide synthase [inducible (iNOS) and constitutive (cNOS)] and cyclooxygenase [constitutive (COX-1) and inducible (COX-2)]. Concentrations of interleukins (IL-1β, IL−6, and IL−10) and tumor necrosis factor-alpha (TNFα) were measured in plasma. In blood from healthy donors, propofol increased NO production and cNOS activity. The concentration of propofol that increased NO production by 50% (EC
50
) was 23.5 μM, and the EC
50
of propofol for cNOS was 18.6 μM. In blood from surgical patients, propofol increased NO production by 52% and cNOS activity by 57%. Propofol inhibited iNOS activity in vitro; the concentration that reduced activity by 50% (IC
50
) was 19.9 μM. In surgical patients propofol inhibited iNOS activity by 53%. COX-1 and COX-2 activities were inhibited in vitro (IC
50
32.6 and 187 μM, respectively) and in surgical patients (53 and 81% inhibition, respectively). Plasma concentrations of IL-1β, IL-6, and TNFα were significantly reduced in surgical patients (32, 23, and 21% inhibition, respectively). None of these parameters were modified in a group of patients (
n
 = 10) anesthetized with sevoflurane. We conclude that propofol stimulated constitutive NO production and inhibited inducible NO production, possibly by curtailing the stimulation of iNOS by inflammatory mediators in surgical patients.