Sustained, low level
muscarinic activity was induced in rats by feeding the
muscarinic agonist and experimental
drug candidate
CI-969 at 50, 100 and 200 mg/kg
body weight/day for 4 wk. Except for urine staining, clinical signs typical of acute high-dose exposure to
muscarinic agonists were not observed. A dose-related suppression of
body weight gain approached 60% at the high dose, but no significant effects on haematology or clinical chemical parameters were observed after 4 wk of exposure.
Corneal opacities with histopathological features including neovascularization, acanthosis and stromal proliferation were observed in a dose-related fashion in both sexes at 100 and 200 mg/kg/day.
Hypertrophy of the Harderian and lacrimal glands also occurred, probably as an adaptive response to sustained
muscarinic activity. Lacrimal gland concentrations of the
muscarinic agonist were in the range of pmol/mg tissue and therefore significant direct exposure of cornea to the compound through the tears was discounted. The presence of corneal
muscarinic receptors was investigated to determine whether opacities could be related to direct, receptor-mediated events in the cornea; however, no specific binding of the
muscarinic receptor radioligand [3H]quinuclidylbenzilate was detected. Because
muscarinic agonist-induced opacities can be inhibited by
scopolamine, the apparent lack of
muscarinic receptors in the cornea indicates that the opacities are not a direct effect, but are instead secondary to
muscarinic events at another site. To our knowledge, this is the first report of
corneal opacities induced by a
muscarinic agonist.