No abstract

Smooth muscles from the urethra and bladder display characteristic patterns of spontaneous contractile activity in the filling phase of the micturition cycle. Tonic contractions are seen in the urethral smooth muscles, and phasic contractions occur in the detrusor. Overactivity in the detrusor is a common clinical problem. The ion channels in the smooth muscle membranes play an important role in determining the functional properties, and are obvious targets for treatment of the overactive bladder. Recent evidence suggests that interstitial cells may also play a role in determining the pattern of spontaneous activity, although their precise role is less well established in the urinary tract than in the gut. The ion channels involved in these cells are also of interest. This review discusses what is known of ion channels in these tissues, and their implications for function.

1 To investigate the cellular mechanisms underlying spontaneous excitation of smooth muscle of the guinea-pig urinary bladder, isometric tension was measured in muscle bundles while recording the membrane potential from a cell in the bundle with a microeletrode. Changes in the intracellular calcium concentration ([Ca 2 þ ] i ; calcium transients) were recorded in strips loaded with the fluorescent dye, fura-PE3. 2 In 40% of preparations, individual action potentials and contractions, which were abolished by nifedipine (1 mM), were generated. In the remaining preparations, bursting action potentials and contractions were generated. Contractions were again abolished by nifedipine (1 mM), while higher concentrations of nifedipine (10-30 mM) were required to prevent the electrical activity. 3 Carbachol (0.1 mM) increased the frequency of action potentials and corresponding contractions. Apamin (0.1 mM) potentiated bursting activity and enhanced phasic contraction. Charybdotoxin (CTX, 50 nM) induced prolonged action potentials that generated enlarged contractions. In contrast, levcromakalim (0.1 mM) reduced the frequency of action potentials, action potential bursts and the size of the contractions. 4 Forskolin (0.1 mM), 8-bromoguanosin 3 0 , 5 0 cyclic monophosphate (8Br-cGMP, 0.1 mM) and Y-26763 (10 mM) suppressed contractions without reducing the amplitude of either action potentials or Ca transients. 5 This paper confirms that action potentials and associated calcium transients are fundamental mechanisms in generating spontaneous contractions in smooth muscles of the guinea-pig bladder. However, in parallel with the excitation-contraction coupling, the sensitivity of the contractile proteins for Ca 2 þ may play an important role in regulating spontaneous excitation and can be modulated by cyclic nucleotides and Rho kinase.

1 The regulatory mechanisms of spontaneous excitation in detrusor smooth muscles of the guineapig urinary bladder were investigated using intracellular microelectrode and muscle tension recording techniques. 2 Detrusor smooth muscle cells exhibited nifedipine-sensitive spontaneous action potentials. Their frequency was highly sensitive to membrane polarization and was reduced by lowering the temperature. Lowering the temperature also reduced the frequency of spontaneous contractions and increased their amplitude. 3 Charybdotoxin (50 nm) and iberiotoxin (0.1 mm) increased the amplitude and duration of action potentials, and abolished after hyperpolarizations (AHPs). Both agents also increased the amplitude and duration of spontaneous contractions, and reduced their frequency. Apamin (0.1 mm) did not change the shape of action potentials but often converted individual action potentials into bursts. It also increased the amplitude and duration of spontaneous contractions, and reduced their frequency. 4-aminopyrideine (4-AP, 1 mm) increased the frequency of action potentials without affecting their shape, and increased the amplitude and frequency of spontaneous contractions. 4 Cyclopiazonic acid (CPA, 10 mm) and ryanodine (50 mm) increased the amplitude of action potentials, and suppressed AHPs. Both agents also increased the amplitude and duration of spontaneous contractions, and reduced their frequency. 1,2-(Bis (2-aminophenoxy) ethane-N,N,N 0 , N 0 -tetraacetic acid tetrakis (acetoxymethyl ester) (50 mm) dramatically increased the amplitude and duration of the action potential, and abolished AHPs. 5 Spontaneous action potentials in detrusor smooth muscles cells result from the opening of L-type Ca 2 þ channels, and their frequency is regulated by voltage-dependent mechanisms and by some metabolic process. Both the activation of large conductance Ca 2 þ -activated K þ (BK) channels and Ca 2 þ -mediated inactivation of the Ca 2 þ channels are involved in the repolarizing phase of action potentials. The Ca 2 þ influx through L-type Ca 2 þ channels triggers calcium-induced calcium release via ryanodine receptors and activates BK channels to generate AHPs. Both small conductance Ca 2 þ -activated K þ channels and voltage-sensitive K þ channels may contribute to the resting membrane potential and regulate the frequency of action potentials. The regulatory mechanisms of action potentials are closely related to the regulation of spontaneous contractions.

Eighteen Landrace pigs and 12 Göttingen mini-pigs were evaluated in a study of experimental bladder outflow obstruction. Twenty-two of the animals underwent partial bladder outflow obstruction for periods up to 12 months. The subsequent changes were assessed using cystometric, physiological and morphological means. There was a consistent increase in the voiding pressures and a concomitant reduction in the flow rates in all the obstructed animals. Seventy-seven per cent of the obstructed animals showed cystometric evidence of bladder instability. In vitro studies showed an increase in sensitivity to exogenously applied agonists and a reduction in sensitivity to intramural nerve stimulation. Morphological studies showed an inverse correlation between neuronal density and the duration of obstruction. These changes are typical of post-junctional supersensitivity secondary to partial denervation. These results suggest that agents capable of stabilising the bladder smooth muscle membrane may be useful in the treatment of detrusor instability secondary to bladder outflow obstruction.