Occurrence of vasoactive intestinal polypeptide (VIP)-like immunoreactivity in certain cholinergic neurons of the cat: evidence from combined immunohistochemistry and acetylcholinesterase staining.

Overactive bladder (OAB) is a syndrome characterized by urinary urgency, with or without urgency urinary incontinence, usually with frequency and nocturia. OAB symptoms are often associated with detrusor overactivity (DO). Like OAB symptoms, the prevalence of DO increases with age and can have a neurogenic and/or myogenic aetiology. Bladder outlet obstruction can be a contributing factor in DO, possibly through cholinergic denervation of the detrusor and supersensitivity of muscarinic receptors to acetylcholine, although the prevalence of OAB is similar in men and women across age groups. Acetylcholine is the primary contractile neurotransmitter in the human detrusor, and antimuscarinics exert their effects on OAB/DO by inhibiting the binding of acetylcholine at muscarinic receptors M(2) and M(3) on detrusor smooth muscle cells and other structures within the bladder wall. Worldwide, there are six antimuscarinic drugs currently marketed for the treatment of OAB: oxybutynin, tolterodine, propiverine, trospium, darifenacin, and solifenacin. Each has demonstrated efficacy for the treatment of OAB symptoms, but their pharmacokinetic and adverse event profiles differ somewhat due to structural differences (tertiary vs quaternary amines), muscarinic receptor subtype selectivities, and organ selectivities. Antimuscarinics are generally well tolerated, even in special populations (e.g. men with bladder outlet obstruction, elderly patients, children). The most frequently reported adverse events in clinical studies of antimuscarinics are dry mouth, constipation, headache, and blurred vision; few patients withdraw from clinical trials because of adverse events. Development of an antimuscarinic with functional selectivity for the bladder would reduce the occurrence of antimuscarinic adverse events. The therapeutic potential of several other agents, such as alpha(3)-adrenoceptor agonists, purinergic receptor antagonists, phosphodiesterase inhibitors, neurokinin-1 receptor antagonists, opioids, and Rho-kinase inhibitors, is also under investigation for the treatment of OAB.

Muscarinic receptor antagonists for overactive bladder

https://www.cell.com/trends/pharmacological-sciences/pdf/S0165-6147(09)00013-3.pdf

Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders

The salivary secretion from the cat submandibular salivary gland induced by parasympathetic nerve stimulation is considered to be due to release of acetylcholine (ACh) which binds to muscarinic receptors and activates secretory elements1. Recent evidence suggests that cholinergic neurones in the cat submandibular gland contain and release another neurotransmitter candidate, vasoactive intestinal polypeptide (VIP)2,3. Although VIP per se does not induce salivary secretion, it potentiates the secretion induced by ACh infusions2,3. The present study offers a possible explanation for this potentiation by showing that VIP in physiologically relevant concentrations enhances the binding of muscarinic cholinergic ligands in the cat submandibular gland.

Vasoactive intestinal polypeptide enhances muscarinic ligand binding in cat submandibular salivary gland.

This study examined the signal transduction correlates of mu opioid agonist efficacy in two systems: mu receptor-transfected mMOR-CHO cell and rat thalamic membranes. The potency and maximal stimulation of [35S]GTP gamma S binding by various agonists was measured in the presence of excess GDP and compared with receptor binding affinity under identical assay conditions. Results showed that the relative maximal stimulation produced by these agonists was greater in mMOR-CHO cell than in rat thalamic membranes; some drugs that were full agonists in mMOR-CHO cells were partial agonists in the thalamus, and some partial agonists in the transfected cells were full antagonists in the thalamus. Furthermore, there was receptor reserve for G-protein activation by some agonists in mMOR-CHO cell membranes, but no receptor reserve was detected in rat thalamic membranes. Saturation analysis of agonist-stimulated [35S]GTP gamma S binding revealed that full agonists produced both a higher Bmax and apparent affinity of [35S]GTP gamma S binding than partial agonists. Correlation of the Bmax and KD of agonist-stimulated [35S]GTP gamma S binding with agonist intrinsic efficacy revealed only a moderate correlation with either parameter alone, but a highly significant correlation (r > 0.9) with a combination of the two parameters (Bmax/KD). These results suggest that the intrinsic efficacy of agonists at G-protein-coupled receptors is determined primarily by the ability of the agonist-occupied receptor to promote high-affinity GTP binding to the G-protein and to catalytically activate a maximal number G-proteins.

Signal transduction correlates of mu opioid agonist intrinsic efficacy: receptor-stimulated [35S]GTP gamma S binding in mMOR-CHO cells and rat thalamus.

Edith Heilbronn

Papers

Muscarinic acetylcholine receptor