Protective effect of NG-monomethyl-L-arginine against hypotension inducted by combined tumour necrosis factor-alpha and whole body hyperthermia in rats.
We studied: (a) the adverse effects of tumour necrosis factor-alpha (TNF) given during whole body hyperthermia (WBH) on mean arterial pressure (MAP) and gut mucosa in anaesthetized rats; (b) the potential protective effect of NG-monomethyl-L-arginine (L-NMA), an inhibitor of nitric oxide synthase; and (c) the influence of L-NMA on the antitumour effect of the trimodality therapy, WBH + TNF + Carboplatin (CBDCA). In normothermic rats, TNF alone (10(5) or 10(6) U/kg) did not cause hypotension, but increased MAP (p < 0.05). L-NMA alone (5, 10 and 20 mg/kg) increased MAP moderately and dose-dependently (p < 0.05). WBH (41.5 degrees C for 2 h) increased MAP markedly (from 103 +/- 4 to 161 +/- 4 mm Hg). This increase in MAP was sustained throughout the hyperthermia, but was followed by a transient relative hypotension (MAP = 80 +/- mm Hg) on cessation of WBH and an eventual return to near baseline at 30 min post-WBH (MAP = 94 +/- 5 mm Hg). WBH + TNF (10(5) or 10(6) U/kg) initially increased MAP similarly to WBH alone. During the second hour of WBH, however, MAP decreased towards pre-treatment levels, and cessation of WBH was followed by sustained hypotension. This late hypotensive state was associated with a mortality during the early (first 2 h) post-WBH period of 17 and 100% at TNF dose of 10(5) and 10(6) U/kg TNF, respectively. L-NMA given to rats receiving WBH + TNF (10(6) U/kg) maintained MAP at levels similar to WBH alone during WBH treatment. L-NMA prevented the post-WBH hypotension, and extended the survival beyond the early (first 2 h) post-WBH period. No rat, however, receiving high dose TNF (10(6) U/kg) survived more than 12 h even with L-NMA (totally 40 mg/kg). WBH + TNF (10(5) and 10(6) U/kg) also produced marked histopathological injury to the gut mucosa at 2 h post-treatment. L-NMA substantially protected the gut from this injury. In rats bearing a transplantable fibrosarcoma, L-NMA did not decrease the antitumour effect consisting of WBH + TNF (10(5) U/kg) + CBDCA, while it decreased (p < 0.05) the general toxicity (weight loss, diarrhea and foot oedema) of this combination. We conclude that L-NMA may prevent or ameliorate the early toxicity but not the late lethal effects of WBH + high dose TNF (10(6) U/kg). Additionally, L-NMA reduces some of the toxicity of WBH + TNF (10(5) U/kg) + CBDCA without decreasing the antitumour effect of this trimodality therapy. Inhibitors of nitric oxide synthase such as L-NMA may provide a novel approach to overcoming the toxicity of TNF in combination with WBH.
Makino
M
M
Department of Internal Medicine, University of Texas Medical School, Houston, USA.
Lodato
R F
RF
Stephens
L C
LC
Strebel
F R
FR
Jenkins
G
G
Ohno
S
S
Sakaguchi
Y
Y
Kostergaard
J
J
Tomasovic
S P
SP
Bull
J M
JM
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016190:Carboplatin / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005334:Fever; D006339:Heart Rate / Q000187:drug effects; D006651:Histocytochemistry; D007022:Hypotension / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000628:therapy; D009569:Nitric Oxide / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D011916:Rats, Inbred F344; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019323:omega-N-Methylarginine / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D016190:Carboplatin; D019001:Nitric Oxide Synthase