Adrenaline Toxicity in Mice: Sensitization of α1 Adrenoreceptors by Nitroglycerin

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Abstract
In mice, injected s.c. with nitroglycerin (GTN) for 12 days, adrenaline [epinephrine, E] 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 E, measured 3 days after the last injection of GTN, was 9.1 mg/kg b.wt. (body weight, 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 E (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 E (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 E (P = 0.003 and P = 0.001, respectively). By contrast, the .alpha.2 adrenoceptor antagonist, yohimbine, (1 or 10 mg/kg b.wt.) was much less effective (P = 0.988 respectively). The lethal action of E evidently caused by stimulation of .alpha.1 adrenoceptors. 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.