1 The effectiveness of antimuscarinic agents in the treatment of the overactive bladder (OAB) syndrome is thought to arise through blockade of bladder muscarinic receptors located on detrusor smooth muscle cells, as well as on nondetrusor structures. 2 Muscarinic M 3 receptors are primarily responsible for detrusor contraction. Limited evidence exists to suggest that M 2 receptors may have a role in mediating indirect contractions and/or inhibition of detrusor relaxation. In addition, there is evidence that muscarinic receptors located in the urothelium/suburothelium and on afferent nerves may contribute to the pathophysiology of OAB. Blockade of these receptors may also contribute to the clinical efficacy of antimuscarinic agents. 3 Although the role of muscarinic receptors in the bladder, other than M 3 receptors, remains unclear, their role in other body systems is becoming increasingly well established, with emerging evidence supporting a wide range of diverse functions. Blockade of these functions by muscarinic receptor antagonists can lead to similarly diverse adverse effects associated with antimuscarinic treatment, with the range of effects observed varying according to the different receptor subtypes affected. 4 This review explores the evolving understanding of muscarinic receptor functions throughout the body, with particular focus on the bladder, gastrointestinal tract, eye, heart, brain and salivary glands, and the implications for drugs used to treat OAB. The key factors that might determine the ideal antimuscarinic drug for treatment of OAB are also discussed. Further research is needed to show whether the M 3 selective receptor antagonists have any advantage over less selective drugs, in leading to fewer adverse events.
Investigation of retinal neurochemistry in a well-defined chick model of form-deprivation myopia indicated that dopamine and its metabolite 3,4-dihydroxyphenylacetic acid are reduced in myopic as compared to control eyes. The reduction in retinal dopamine is evident only during light adaptation and is accompanied by a decreased rate ofdopamine biosynthesis. To test whether the alteration in dopamine metabolism is related to eye growth, agents known to interact with dopamine receptors were administered locally to deprived eyes. Remarkably, the expected growth in the axial dimension was reduced, while that in the equatorial dimension was not. Therefore retinal dopamine may participate in the pathway linking visual experience and the postnatal regulation of the eye's growth in the axial dimension. The mechanism for control of chick eye growth in the equatorial dimension remains unknown.Eye growth during normal childhood development coordinates with progressive changes in the optical power of the cornea and lens to maintain image focus on the plane of the retina (1). Observations after unilateral visual deprivation have indicated that retinal image quality influences postnatal growth. Deprivation of form vision in juvenile monkeys (2-4), chicks (5-9), or humans (10-12) disrupts normal regulation and leads to excessive eye size; distant images now focus in front of the retina, causing a myopic refractive error. This link of visual quality to eye size implicates the nervous system in growth control. Moreover, recent observations hint that such control is largely local. (i) Form-deprivation myopia in both monkeys and chicks takes place even after optic nerve transection interrupts the direct pathway from retina to brain (3, 13). (ii) Application of a partial occluder in chicks to restrict vision either in the nasal or temporal visual field induces excessive eye growth only along the corresponding ocular dimension. For example, occlusion of the nasal visual field causes excessive growth of the temporal part of the globe (14-16). We now report in avian myopia that neonatal deprivation of form vision alters retinal dopamine metabolism at the same time as the eye enlarges. Under the identical condition, ocular administration of dopaminerelated agents hinders the expected elongation of the eye in the axial but not in the equatorial dimension. These findings buttress the hypothesis of local growth control and suggest the participation of retinal dopamine in the regulatory sequence. They also speak for separate mechanisms underlying the regulation of axial and equatorial growth of the eye.
We describe a protocol to rapidly and reliably visualize blood vessels in experimental animals. Blood vessels are directly labeled by cardiac perfusion using a specially formulated aqueous solution containing 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI), a lipophilic carbocyanine dye, which incorporates into endothelial cell membranes upon contact. By lateral diffusion, DiI also stains membrane structures, including angiogenic sprouts and pseudopodial processes that are not in direct contact. Tissues can be immediately examined by conventional and confocal fluorescence microscopy. High-quality serial optical sections using confocal microscopy are obtainable from thick tissue sections, especially at low magnification, for three-dimensional reconstruction. It takes less than 1 h to stain the vasculature in a whole animal. Compared with alternative techniques to visualize blood vessels, including space-occupying materials such as India ink or fluorescent dye-conjugated dextran, the corrosion casting technique, endothelial cell-specific markers and lectins, the present method simplifies the visualization of blood vessels and data analysis.
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