Effect of the bradykinin B2 receptor antagonist Hoe140 in experimental pneumococcal meningitis in the rat.
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.
Lorenzl
S
S
Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilions-University of Munich, Germany.
Ködel
U
U
Frei
K
K
Pfister
H W
HW
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
D000890:Anti-Infective Agents; D065168:Bradykinin Receptor Antagonists; D015850:Interleukin-6; D009573:Nitrites; D043782:Receptor, Bradykinin B2; C065679:icatibant; D001920:Bradykinin