The purpose of the study was to investigate the effects of H(1)-antihistamines of the 1(st) generation (antazoline, bromadryl, brompheniramine, dithiaden, cyclizine, chlorcyclizine, chlorpheniramine, clemastine) and the 2(nd) generation (acrivastine, ketotifen, and loratadine) on the respiratory burst of phagocytes. Reactive oxygen species generation in neutrophils isolated from rat blood was measured using luminol-enhanced chemiluminescence. Changes in nitrite formation and iNOS protein expression by RAW 264.7 macrophages were analysed using Griess reaction and Western blotting. The antioxidative properties of drugs in cell-free systems were detected spectrophotometrically, luminometrically, fluorimetrically, and amperometrically. The majority of the H(1)-antihistamines tested (bromadryl, brompheniramine, chlorcyclizine, chlorpheniramine, clemastine, dithiaden, and ketotifen) exhibited a significant inhibitory effect on the chemiluminescence activity of phagocytes. H(1)-antihistamines did not show significant scavenging properties against superoxide anion and hydroxyl radical, thus this could not contribute to the inhibition of chemiluminescence. H(1)-antihistamines had a different ability to modulate nitric oxide production by LPS-stimulated macrophages. Bromadryl, clemastine, and dithiaden were the most effective since they inhibited iNOS expression, which was followed by a significant reduction in nitrite levels. H(1)-antihistamines had no scavenging activity against nitric oxide. It can be concluded that the effects observed in the H(1)-antihistamines tested are not mediated exclusively via H(1)-receptor pathway or by direct antioxidative properties. Based on our results, antihistamines not interfering with the microbicidal mechanisms of leukocytes (antazoline, acrivastine and cyclizine) could be used preferentially in infections. Other antihistamines should be used, under pathological conditions accompanied by the overproduction of reactive oxygen species.

Institute of Biophysics Academy of Sciences of the Czech Republic Královopolská 135 612 65 Brno Czech Republic

Zobrazit více v PubMed

Bakker RA, Schoonus SB, Smit MJ, Timmerman H, Leurs R. Histamine H(1)-receptor activation of nuclear factor-kappa B: roles for G beta gamma- and G alpha(q/11)-subunits in constitutive and agonist-mediated signaling. Mol Pharmacol. 2001;60:1133–1142. PubMed

Church MK. H(1)-antihistamines and inflammation. Clin Exp Allergy. 2001;31:1341–1343. PubMed

Číž M, Čížová H, Denev P, Kratchanova M, Slavov A, Lojek A. Different methods for control and comparison of the antioxidant properties of vegetables. Food Control. 2010;21:518–523.

Číž M, Komrsková D, Prachařová L, Okénková K, Čížová H, Moravcová A, Jančinová V, Petríková M, Lojek A, Nosál R. Serotonin modulates the oxidative burst of human phagocytes via various mechanisms. Platelets. 2007;18:583–590. PubMed

De Vos C. H1-receptor antagonists: effects on leukocytes, myth or reality? Clin Exp Allergy. 1999;29:60–63. PubMed

Drábiková K, Nosál R, Jančinová V, Číž M, Lojek A. Reactive oxygen metabolites production is inhibited by histamine and H1-antagonist dithiaden in human PMN-leukocyte. Free Radical Res. 2002;36:975–980. PubMed

Králová J, Račková L, Pekarová M, Kubala L, Nosál R, Jančinová V, Číž M, Lojek A. The effects of H1-antihistamines on the nitric oxide production by RAW 264.7 cells with respect to their lipophilicity. Int Immunopharmacol. 2009;9:990–995. PubMed

Leurs R, Smit MJ, Timmerman H. Molecular pharmacological aspects of histamine receptors. Pharmacol Ther. 1995;66:413–463. PubMed

Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. 1993;329:2002–2012. PubMed

Nosál R, Jančinová V, Číž M, Drábiková K, Lojek A, Fábryová V. Inhibition of chemiluminescence by carvedilol in the cell-free system, whole human blood and blood cells. Scand J Clin Lab Invest. 2005;65:55–64. PubMed

Pavelková M, Kubala L. Luminol-, isoluminol- and lucigenin-enhanced chemiluminescence of rat blood phagocytes stimulated with different activators. Luminescence. 2004;19:37–42. PubMed

Pekarová M, Králová J, Kubala L, Číž M, Lojek A, Gregor Č, Hrbáč J. Continuous electrochemical monitoring of nitric oxide production in murine macrophage cell line RAW 264.7. Anal Bioanal Chem. 2009;394:1497–1504. PubMed

Tiligada E, Zampeli E, Sander K, Stark H. Histamine H3 and H4 receptors as novel drug targets. Expert Opin Investig Drugs. 2009;18:1519–1531. PubMed

Yang EJ, Yim EY, Song G, Kim GO, Hyun CG. Inhibition of nitric oxide production in lipopolysaccharide-activated RAW 264.7 macrophages by Jeju plant extracts. Interdiscip Toxicol. 2009;2:245–249. PubMed PMC

Serotonin and its metabolites reduce oxidative stress in murine RAW264.7 macrophages and prevent inflammation