In a previous study using intravenous administration of subtype-selective muscarinic receptor antagonists and electrical stimulation of parasympathetic nerve pathways, it was suggested that endothelial M
3 receptors mediate choroidal vasodilation in pigeons.
31 In another study, in which a similar experimental approach has been used, M
3 and M
5 receptors were proposed to be involved in parasympathetic-mediated choroidal vasodilation in chronically sympathectomized rats.
32 However, the specificity of the pharmacologic agents tested has shown to be limited.
33 36 For example, the pharmacological properties of the M
3 receptor are similar to those of the M
5 subtype,
34 raising the possibility that responses previously thought to be mediated by M
3 receptors may involve the activation of M
5 receptors. Moreover, even selective M
1 and M
2 antagonists display high affinity for M
3 and M
4 receptors, respectively.
25 33 Consequently, it is difficult to discern the role of each muscarinic receptor subtype by using pharmacologic agents of limited specificity when two or more subtypes are simultaneously involved in a specific functional response. The use of genetically engineered mice lacking specific muscarinic receptor subtypes allows a more definitive determination of the physiological roles of M
3 and M
5 receptors in ocular vessels. Recently, the function of muscarinic receptor subtypes has been examined in other arterial beds of gene-targeted mice. In these studies, the M
3 subtype was shown to mediate cholinergic vasodilation in femoral
37 and coronary
30 arteries and in the aorta,
30 37 38 whereas the M
5 subtype mediated responses to acetylcholine in cerebral arteries and arterioles.
29 Remarkably, similar to our present findings in ophthalmic arteries, no functional role of M
5 receptors has been demonstrated for any extracerebral murine vascular bed tested thus far.
29