Muscarinic receptor subtypes modulating smooth muscle contractility in theurinary bladder

Normal physiological voiding as well as generation of abnormal bladder cont ractions in diseased states is critically dependent on acetylcholine-induce d stimulation of contractile muscarinic receptors on the smooth muscle (det rusor) of the urinary bladder. Muscarinic receptor antagonists are efficaci ous in treating the symptoms of bladder hyperactivity, such as urge inconti nence, although the usefulness of available drugs is limited by undesirable side-effects. Detrusor smooth muscle is endowed principally with M-2 and M -3 muscarinic receptors with the former predominating in number. M-3 muscar inic receptors, coupled to stimulation of phosphoinositide turnover, mediat e the direct contractile effects of acetylcholine in the detrusor. Emerging evidence suggests that M-2 muscarinic receptors, via inhibition of adenyly l cyclase, cause smooth muscle contraction indirectly by inhibiting sympath etically (ss-adrenoceptor)-mediated relaxation. In certain diseased states, M-2 receptors may also contribute to direct smooth muscle contraction. Oth er contractile mechanisms involving M-2 muscarinic receptors, such as activ ation of a non-specific cationic channel and inactivation of potassium chan nels, may also be operative in the bladder and requires further investigati on. From a therapeutic standpoint, combined blockade of M-2 and M-3 muscari nic receptors would seem to be ideal since this approach would evoke comple te inhibition of cholinergically-evoked smooth muscle contractions. However , if either the M-2 or M-3 receptor assumes a greater pathophysiological ro le in disease states, then selective antagonism of only one of the two rece ptors may be the more rational approach. The ultimate therapeutic strategy is also influenced by the extent to which pre-junctional M-1 facilitatory a nd M-2 inhibitory muscarinic receptors regulate acetylcholine release and a lso which subtypes mediate the undesirable effects of muscarinic receptor b lockade such as dry mouth. Finally, the consequence of muscarinic receptor blockade in the central nervous system on the micturition reflex, an issue which is poorly studied and seldom taken into consideration, should not be ignored.