Decreased distribution of oxotremorine to brain after pharmacological blockade of its peripheral acetylcholine-like effects

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Abstract
The distribution of [3H]oxotremorine, after intravenous injection, to brain and tissues of rats and mice has been studied. In rats, oxotremorine (0·3 mg/kg) rapidly reached the brain with a peak concentration of 1200 ng/g at 1 min. Blockade of the peripheral muscarinic effects of oxotremorine with amitriptyline methyl iodide or atropine methyl nitrate (25 mg/kg, s.c.) markedly decreased the brain content of oxotremorine (peak concentration 400 ng/g), probably as a result of its more rapid distribution to peripheral tissues and an increased volume of distribution. The ratio of drug distribution between plasma and brain is unaffected by pretreatment with anticholinoceptive drugs. Also, the total body concentrations of oxotremorine are similar in pretreated rats and controls. A small dose of oxotremorine (10 μg/kg) is distributed similarly in pretreated rats (amitriptyline methyl iodide, 25 mg/kg, s.c.) and in controls. In mice there was a linear relation between dose, up to 180 μg/kg, and brain concentration of oxotremorine. At higher doses, relatively; more drug reached the brain. Oxotremorine induced a marked fall in blood pressure in the unanaesthetized rat that was reduced by amitriptyline methyl iodide and reversed by atropine methyl nitrate. It seems likely that differences in blood flow between pretreated rats and controls are responsible for the differences in the distribution of the drug.