1 We investigated muscarinic receptors in the detrusor and mucosa of the human bladder body. Radioligand-binding studies with [ 5 The presence of a high density of mainly M 2 muscarinic receptors in the mucosa appears to be a novel finding and raises the question of their physiological significance and the source of their endogenous ligand. 6 There was a negative correlation of receptor number (B max ) with age in detrusor muscle from male patients (P ¼ 0.02). Quantitative competitive RT-PCR demonstrated a selective age-related decrease in mRNA for muscarinic M 3 but not M 2 receptors, in both male (Po0.0001) and female (P ¼ 0.019) detrusor. These findings correspond with reports of decreased detrusor contractility with ageing.

The inhibitory effect of gallamine (1.1 μM‐1.1 mM) on negative inotropic responses to acetylcholine (ACh) or carbachol (CCh) was investigated in isolated electrically stimulated atria of the guinea‐pig. Gallamine caused parallel rightward shifts of the dose‐response curves to the agonists, with no depression of the maximal response. Gallamine (0.11‐1.1 mM) produced a greater degree of antagonism towards CCh than towards ACh. With either agonist, the degree of antagonism produced by gallamine in high concentrations was less than that expected for a competitive antagonist. Similar findings were made when either negative inotropic or chronotropic responses were recorded in spontaneously beating guinea‐pig atria. The inhibitory effect of gallamine against the negative inotropic response to cholinomimetics in electrically stimulated atria was not altered either in the presence of propranolol (17 μM) or in atria obtained from guinea‐pigs pretreated with diisopropylphosphorofluoridate (DFP) (12.5 μmol/kg, in divided doses over 3 days). When ACh was used as the agonist, combination of gallamine with atropine (0.05‐0.4 μM) produced dose‐ratios which were less than expected for combination of two competitive antagonists. The same phenomenon was observed in atria obtained from guinea‐pigs pretreated with DFP. It is suggested that the antagonism produced by gallamine is a type of non‐competitive inhibition, which has been termed ‘metaffinoid antagonism’. An antagonist of this type allosterically alters the affinity of the agonist for its binding site, rather than changing the effectiveness of the agonist‐receptor interaction.

1. We review literature demonstrating (a) the presence and (b) the actions of substances that mediate or modify neuroeffector transmission to the smooth muscle of the prostrate stroma of a number of species including man. 2. In all species studied prostatic stroma, but not secretory acini, receives rich noradrenergic innervation. Stimulation of these nerves causes contractions of prostate smooth muscle that are inhibited by guanethidine and by alpha1-adrenoceptor antagonists that probably act at the alpha1L-adrenoceptor. Such actions underlie the clinical use of alpha1-adrenoceptor antagonists in benign prostatic hyperplasia (BPH). 3. Acetylcholinesterase-positive nerves innervate prostatic stroma as well as epithelium. Atropine reduces nerve-mediated contractions of stromal muscle in the rat, guinea-pig and rabbit. M1, M2 and M3 muscarinic receptors have been implicated in eliciting or facilitating contraction in the prostate from guinea-pig, dog and rat, respectively. 4. Adenine nucleotides and nucleosides, nitric oxide (NO), opioids, neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) may act as co-transmitters or modulators in autonomic effector nerves supplying prostate stroma. Adenosine inhibits neurotransmission to the rat prostate, and NO is inhibitory in prostate from human, rat, rabbit, pig and dog. The activity of peptides present in the relatively sparse sensory innervation of the prostate exhibits species variation, but, when effective, calcitonin gene-related peptide is inhibitory while tachykinins are stimulant. The roles of NPY and VIP in modulating stromal contractility remain unclear. 5. Taken together the current literature indicates that, in addition to noradrenaline, other neurotransmitters and neuromodulators may regulate the tone of prostatic smooth muscle. Whether drugs that mimic or modify their actions might be useful in providing symptomatic relief of the urinary symptoms associated with BPH remains to be established.

SUMMARY1. An allosteric interaction occurs when the binding of a ligand to its site on a receptor is able to modify the binding of another ligand to a topographically distinct site on the same receptor and vice versa. The muscarinic cholinoceptors represent the best-studied examples of allosteric phenomena among the G-protein-coupled receptor superfamily.2. The simplest model describing allosteric interactions at muscarinic cholinoceptors is the ternary complex model, which allows for a three-way interaction between the receptor, a classical (orthosteric) ligand and an allosteric modulator. The interaction may be quantified using the dissociation constant of each ligand for its respective binding site on the free receptor and the 'co-operativity factor' ␣. This latter term is the ratio of affinities of a ligand for the occupied versus the unoccupied receptor and is a measure of the magnitude of the cooperativity between two concomitantly bound ligands.3. Identification of allosteric phenomena requires the utilization of both radioligand binding and functional approaches. Manifestations of allosterism include: (i) a limited ability to influence radioligand binding as the concentration of the latter is increased; (ii) alterations in the dissociation rate of orthosteric ligands; (iii) curvilinear Schild regressions; and (iv) nonadditivity of agonist/orthosteric antagonist/allosteric modulator combination concentration ratios.4. Allosteric modulators of muscarinic cholinoceptors represent a diverse range of compounds. Some of the most studied agents include gallamine, alcuronium and the bis-ammonium compounds, C7/3-phth and W84. Alcuronium has proven a most useful pharmacological tool, as it has been shown to display both positive and negative co-operativity, depending on the receptor subtype and orthosteric ligand involved in the interaction.5. Evidence has accumulated pointing to the existence of a common allosteric binding site on the muscarinic cholinoceptors, located close to the orthosteric site, but at a more extracellular level. However, the possibility of more than one accessory binding site on various receptor subtypes cannot be excluded.6. Allosteric modulators offer a number of potential therapeutic advantages, including a ceiling level to their effects and the possibility of 'absolute selectivity' of action, based on the degree of co-operativity rather than the affinity of the modulator for any one receptor subtype.

Part I of this article reviewed the pathophysiology of emesis, and its pharmacological treatment. Drug-induced vomiting was also discussed. In the second part of the review, other common causes of vomiting are considered.The basis of the use of antiemetics in morning sickness and migraine is still obscure; for the latter, serotonin 5-HT receptor agonists, 5-HT receptor antagonists and dopamine D receptor antagonists are effective. For motion sickness, control can be achieved with various antagonists of muscarinic or histamine H-receptors. Centrally active adrenoceptor agonists in combination with a muscarinic antagonist or H-receptor antagonist may offer better control of motion sickness and its associated symptoms than either antagonist alone; based on clinical studies, post-operative vomiting after opiate administration appears to be controlled by blocking dopamine D, histamine H-or muscarinic receptors.Radiation therapy appears to be similar to cytotoxic therapy in that the mediators produced or released by radiation activate both peripheral and central sites involved in the vomiting reflex. Blockade of dopamine D and 5-HT receptors may be effective.