Adrenaline toxicity in mice: sensitization of alpha 1 adrenoreceptors by nitroglycerin

In mice, injected subcutaneously with nitroglycerin (GTN) for 12 days, adrenaline exhibited an increased toxicity. The LD50 value for adrenaline in control animals was 11.1 mg/kg b.wt. In GTN-treated animals the LD50 value for adrenaline, measured 3 days after the last injection of GTN, was 9.1 mg/kg b.wt. (P = 0.05). In the animals sensitized with GTN, the adrenergic alpha-receptor blocker phentolamine (1 or 10 mg/kg b.wt.) protected from the lethal action of adrenaline (P = 0.06 and P = 0.001, respectively). A low dose (1 mg/kg b.wt.) of the adrenergic beta receptor blocker propranolol, was without effect while a higher dose (10 mg/kg b.wt.) potentiated the toxicity of adrenaline (P = 0.007). The alpha 1 adrenoreceptor antagonist, prazosin, (1 or 10 mg/kg b.wt.) was found to be highly effective in protecting the GTN-sensitized mice towards adrenaline (P = 0.003 and P = 0.001, respectively). By contrast, the alpha 2 adrenoreceptor antagonist, yohimbine, (1 or 10 mg/kg b.wt.) was much less effective (P = 0.988 and P = 0.111, respectively). It is concluded that the lethal action of adrenaline was caused by stimulation of alpha 1 adrenoreceptors, and that long term treatment with GTN caused a sensitization of these receptors in mice. The possible relevance of this finding for the reported withdrawal symptoms and sudden death phenomenon in nitroglycerin-exposed industrial workers is discussed.