In the vascular system, endothelium-derived relaxing factor (EDRF) is the name of the local hormone released from endothelial cells in response to vasodilators such as acetylcholine, bradykinin and histamine. It diffuses into underlying smooth muscle where it causes relaxation by activating guanylate cyclase, so producing a rise in cyclic GMP levels. It has been known for many years that in the central nervous system (CNS) the excitatory neurotransmitter glutamate can elicit large increases in cGMP levels, particularly in the cerebellum where the turnover rate of cGMP is low. Recent evidence indicates that cell-cell interactions are involved in this response. We report here that by acting on NMDA (N-methyl-D-aspartate) receptors on cerebellar cells, glutamate induces the release of a diffusible messenger with strikingly similar properties to EDRF. This messenger is released in a Ca2+-dependent manner and its activity accounts for the cGMP responses that take place following NMDA receptor activation. In the CNS, EDRF may link activation of postsynaptic NMDA receptors to functional modifications in neighbouring presynaptic terminals and glial cells.

The function of the bladder urothelium in modulating contractile responses of the underlying detrusor smooth muscle to muscarinic stimulation has been examined in the pig bladder. Saturation curves for [ 3 H]-QNB binding demonstrated a greater muscarinic receptor density in the urothelium than in the detrusor smooth muscle. The presence of an intact urothelium on isolated bladder strips inhibited contractions induced by carbachol but not KCl. Contractions of a urothelium-denuded muscle strip were inhibited in the presence of a second bladder strip with an intact urothelium, but not if the second strip was denuded. The urothelium-induced inhibition of contractions was not prevented in the presence of L-NOARG, methylene blue, indomethacin, propranolol, suramin, TEA or apamin. The data suggest the presence of a diusable, urothelium-derived inhibitory factor, which could not be identi®ed but appears to be neither nitric oxide, a cyclo-oxygenase product, a catecholamine, adenosine, GABA nor an EDHF sensitive to apamin.

1 b-adrenoceptors mediate relaxation of bladder detrusor smooth muscle. This study investigates the contribution of b 3 -adrenoceptors to relaxation of the pig urinary bladder. 2 Cell membranes were prepared from detrusor muscle of the pig bladder dome and competition experiments with [ 3 H]-dihydroalprenolol (DHA), a non-selective b-adrenoceptor antagonist was used as a speci®c radioligand to determine the presence of b-adrenoceptor subtypes. In functional experiments, isolated detrusor muscle strips were used to determine the potency of agonists and the a nity of antagonists. 4 In functional studies, isoprenaline and salbutamol (b 2 -adrenoceptor agonist) relaxed KCl precontracted muscle strips with high potency (pEC 50 7.7 and 7.2, respectively), whilst CGP12177 and BRL37344 (b 3 -adrenoceptor agonists) had low potency and were partial agonists. CGP20712A and atenolol (b 1 -adrenoceptor antagonists) antagonised responses with a low a nity. ICI118551 antagonized responses to isoprenaline and salbutamol with a high a nity (pK B =7.8 and 8.7, respectively), but the Schild slopes were low suggesting that responses were mediated by more than one b-adrenoceptor. The Schild plot for SR59230A was biphasic, apparent pK B values for 3 ± 10 nM SR59230A being 8.6 and those for 30 nM ± 1 mM being 7.7. 5 These data suggest that b 3 -adrenoceptors are the predominant b-adrenoceptor subtype present in the pig bladder and that b-adrenoceptor mediated responses of this tissue are mediated via both the b 2 -and b 3 -adrenoceptor subtypes.

In this article, the recent developments in basic science related to the pathogenesis and pharmacological basis for future drug targets for effective management of overactive bladder are discussed.

1 Noradrenaline and isoprenaline were infused subcutaneously in rats by use of Alzet osmotic minipumps. The