Protective effect of N^G-monomethyl-L-arginine against hypotension inducted by combined tumour necrosis factor-α and whole body hyperthermia in rats

Abstract

We studied: (a) the adverse effects of tumour necrosis factor-α (TNF) given during whole body hyperthermia (WBH) on mean arterial pressure (MAP) and gut mucosa in anaesthetized rats; (b) the potential protective effect of N^G-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 (10⁵ or 10⁶ U/kg) did not cause hypotension, but increased MAP (p < 005). L-NMA alone (5, 10 and 20 mg/kg) increased MAP moderately and dose-dependently (p < 0.05). WBH (41.5d`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 30min post-WBH (MAP = 94 ± 5 mm Hg). WBH + TNF (10⁵ or 10⁶ 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 2h) post-WBH period of 17 and 100% at TNF dose of 10⁵ and 10⁶ U/kg TNF, respectively. L-NMA given to rats receiving WBH + TNF (10⁶ 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 (10⁶ U/kg) survived more than 12 h even with L-NMA (totally 40mg/kg). WBH + TNF(10⁵ and 10⁶ U/kg) also produced marked histo-pathological injury to the gut mucosa at 2h 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 (10⁵ 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 (10⁶ U/kg). Additionally, L-NMA reduces some of the toxicity of WBH + TNF (10⁵ 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.