title: Effect of the bradykinin B2 receptor antagonist Hoe140 in experimental pneumococcal meningitis in the rat.
abstract: To elucidate the role of bradykinin in the complex pathophysiology of bacterial meningitis we investigated the effect of the bradykinin B2 receptor antagonist Hoe140, icatibant (D-Arg[Hyp3-Thi5-D-Tic7-Oic8]-bradykinin), on pathophysiological alterations in experimental pneumococcal meningitis. Untreated rats injected intracisternally (i.c.) with heat-killed pneumococci developed an increase of regional cerebral blood flow (185.4 +/- 27.4%, baseline 100%, mean +/- S.D.), brain water content (79.16 +/- 0.23%), intracranial pressure (21.4 +/- 6.0 mm Hg), and white blood cell count in the cerebrospinal fluid (CSF) (4621 +/- 1894 cells/microliter) within 6 h after i.c. challenge. Treatment with Hoe140 (0.1 mg/kg i.v. at baseline and 0.05 mg/kg s.c. at 2 h after i.c. challenge) attenuated the increase of brain water content (78.53 +/- 0.28%; P < 0.05), intracranial pressure (7.5 +/- 2.2 mm Hg; P < 0.05), and regional cerebral blood flow (128.6 +/- 23.1%; P < 0.05), and reduced CSF pleocytosis (2690 +/- 1898 cells/microliter. N.S.). When treatment was started 4 h after i.c. challenge Hoe140 reduced intracranial pressure (P < 0.05), but was no more capable to significantly influence the other pathophysiological parameters. Treatment with lower (0.01 mg/kg i.v. at baseline, followed by 0.005 mg/kg s.c. at 2 h) and higher (2 mg/kg i.v., followed by 1 mg/kg s.c. at 2 h) concentrations of Hoe140 was ineffective. Likewise, i.c. injection of Hoe140, at different dosages (4 nmol, 40 nmol, 400 nmol) did not significantly alter the pathophysiological parameters in pneumococci-induced meningitis, but caused changes in mean arterial blood pressure at dosages greater than 4 nmol. We conclude that bradykinin is involved as an inflammatory mediator of microvascular changes, brain edema, and increased intracranial pressure during the early phase of experimental pneumococcal meningitis.
authors.affiliation: Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilions-University of Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Lorenzl
authors.forename: U
authors.initials: U
authors.lastname: Ködel
authors.forename: K
authors.initials: K
authors.lastname: Frei
authors.forename: H W
authors.initials: HW
authors.lastname: Pfister
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001834:Body Water; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D065168:Bradykinin Receptor Antagonists; D001921:Brain / Q000098:blood supply / Q000187:drug effects; D004195:Disease Models, Animal; D015850:Interleukin-6 / Q000134:cerebrospinal fluid; D007427:Intracranial Pressure / Q000187:drug effects; D007958:Leukocyte Count; D008297:Male; D008586:Meningitis, Pneumococcal / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000503:physiopathology; D009573:Nitrites / Q000134:cerebrospinal fluid; D051381:Rats; D017208:Rats, Wistar; D043782:Receptor, Bradykinin B2
chemical_list: D000890:Anti-Infective Agents; D065168:Bradykinin Receptor Antagonists; D015850:Interleukin-6; D009573:Nitrites; D043782:Receptor, Bradykinin B2; C065679:icatibant; D001920:Bradykinin