ORIGINAL ARTICLE Effects of propofol on the leukocyte nitric oxide pathway: in vitro and ex vivo studies in surgical patients J. A. González-Correa & E. Cruz-Andreotti & M. M. Arrebola & J. A. López-Villodres & M. Jódar & J. P. De La Cruz Received: 6 September 2007 / Accepted: 8 November 2007 / Published online: 7 December 2007 # Springer-Verlag 2007 Abstract This study was designed to evaluate the mecha- nism 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 produc- tion and the activities of the enzymes nitric oxide synthase [inducible (iNOS) and constitutive (cNOS)] and cyclo- oxygenase [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. Keywords Propofol . Nitric oxide . Cyclooxygenase . Cytokines Introduction Propofol exerts a number of nonanesthetic effects, includ- ing inhibition of platelet functioning (De La Cruz et al. 1997, 1999a; Mendez et al. 2003). This effect has been demonstrated in vitro (De La Cruz et al. 1997, 1999a) and in surgical patients after either intravenous administration (Mendez et al. 2003) to induce anesthesia or intravenous infusion to maintain anesthesia. Propofol was also found to inhibit platelet thromboxane synthesis, thus decreasing concentrations of the main in vivo platelet activator (De La Cruz et al. 1999a; Hirakata et al. 1999). However, when the inhibition of thromboxane Naunyn-Schmiedeberg’ s Arch Pharmacol (2008) 376:331–339 DOI 10.1007/s00210-007-0220-4 J. A. González-Correa : J. A. López-Villodres : J. P. De La Cruz(*) Department of Pharmacology and Therapeutics, School of Medicine, University of Málaga, Campus de Teatinos s/n, 29071 Málaga, Spain e-mail: jpcruz@uma.es E. Cruz-Andreotti Anesthesiology Unit, Hospital Universitario Carlos Haya, Málaga, Spain M. M. Arrebola Clinical Laboratory, Hospital Universitario Carlos Haya, Málaga, Spain M. Jódar Ophthalmology Unit, Hospital Universitario Carlos Haya, Málaga, Spain