Glaucoma, frequently associated with high IOP (intra-ocular pressure), is a leading cause of
blindness, characterized by a loss of retinal ganglion cells and the corresponding optic nerve fibres. In the present study, acutely and transiently elevated IOP, characteristic of acute
angle-closure glaucoma in humans, was observed in CLR (
calcitonin receptor-like receptor) transgenic mice between 1 and 3 months of age. Expression of CLR under the control of a smooth muscle
alpha-actin promoter in these mice augmented signalling of the smooth-muscle-relaxing
peptide adrenomedullin in the pupillary sphincter muscle and resulted in pupillary
palsy. Elevated IOP was prevented in CLR transgenic mice when mated with hemizygote
adrenomedullin-deficient mice with up to 50% lower plasma and organ
adrenomedullin concentrations. This indicates that endogenous
adrenomedullin of iris ciliary body origin causes pupillary
palsy and angle closure in CLR transgenic mice overexpressing
adrenomedullin receptors in the pupillary sphincter muscle. In human eyes, immunoreactive
adrenomedullin has also been detected in the ciliary body. Furthermore, the CLR and RAMP2 (receptor-activity-modifying protein 2), constituting
adrenomedullin receptor heterodimers, were identified in the human pupillary sphincter muscle. Thus, in humans, defective regulation of
adrenomedullin action in the pupillary sphincter muscle, provoked in the present study in CLR transgenic mice, may cause acute and chronic atony and, thereby, contribute to the development of
angle-closure glaucoma. The CLR transgenic mice used in the present study provide a model for acute
angle-closure glaucoma.