NG-methyl-L-arginine, an inhibitor of nitric oxide formation, reverses IL-2-mediated hypotension in dogs.
The effects of NG-methyl-L-arginine (L-NMA), an inhibitor of nitric oxide formation, were studied in dogs treated with interleukin-2 (IL-2). The administration of IL-2 to dogs resulted in hypotension within 3 days of treatment. The development of hypotension correlated with accumulation in the serum of nitrate, which is a stable breakdown product of nitric oxide. Administration of L-NMA decreased serum nitrate levels and increased the mean arterial pressure. The antihypotensive effect was dose dependent with a maximum effect observed at a dose of 20 mg/kg. Administration of a continuous infusion of L-NMA (5 mg.kg-1.h-1) maintained the mean arterial pressure for 48 h with concurrent administration of IL-2. Evaluation of IL-2-induced lymphokine-activated killer cell proliferation and tumoricidal activity toward a canine glioblastoma target cell line was unaffected by L-NMA. These studies imply that L-NMA may effectively ameliorate the dose-limiting hypotension associated with administration of IL-2 without adversely affecting the antitumor effects.
Kilbourn
R G
RG
Department of Genitourinary Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Owen-Schaub
L B
LB
Cromeens
D M
DM
Gross
S S
SS
Flaherty
M J
MJ
Santee
S M
SM
Alak
A M
AM
Griffith
O W
OW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001806:Blood Urea Nitrogen; D002455:Cell Division / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D004285:Dogs; D004798:Enzymes / Q000097:blood; D005910:Glioma / Q000378:metabolism / Q000503:physiopathology; D007022:Hypotension / Q000139:chemically induced / Q000517:prevention & control*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects; D007958:Leukocyte Count / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D009000:Monocytes / Q000187:drug effects; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000097:blood; D013921:Thrombocytopenia / Q000139:chemically induced; D014407:Tumor Cells, Cultured; D019323:omega-N-Methylarginine
D000970:Antineoplastic Agents; D004798:Enzymes; D007376:Interleukin-2; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D003404:Creatinine