Spontaneous activity of lower urinary tract smooth muscles: correlation between ion channels and tissue function

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.

Figure 1. Examples of spontaneous mechanical activity in strips dissected from the bladders of rabbit, pig and man

From Sibley (1984).

Figure 2. Electrical coupling between cells in a muscle bundle of pig detrusor

A, axial direction. Intracellular current injected through the microelectrode hyperpolarized the cell (a). Simultaneous recording of the electrotonic potential change in a cell 200 μm (b) and 400 μm away (c) in the axial direction. Action potentials recorded simultaneously in two cells separated by 400 μm occur at the same time (d and e). B, transverse direction. Intracellular current injected through the microelectrode hyperpolarized the cell (a). Simultaneous recording of the electrotonic potential change in a cell 50 μm away (b). Action potentials recorded simultaneously in two cells separated by 100 μm occur with a delay (c and d). The resting potential was –40 mV. Adapted from Hashitani & Brading (2003a).

Figure 3. Spontaneous mechanical activity recorded from strips of human detrusor

Left: from a normal bladder. Right: from the bladder of a patient with overactive bladder syndrome, showing tetanic contractions. Figure courtesy of I. Mills.

Figure 4. Membrane potential of pig urethral myocytes under current clamp conditions

Whole cell recordings with a pipette solution containing 140 mm KCl, 2 mm Mg²⁺, 2 mm ATP and 50 μm EGTA. Bath solution contained 140 mm NaCl, 2 mm Ca²⁺, 5 mm KCl and 1.2 mm Mg²⁺. Upper trace, under normal depolarizations. Lower trace more compressed, showing that the maxi-K channel blocker iberiotoxin blocks the large spontaneous hyperpolarizations. Figure courtesy of N. Teramoto.

Figure 5. Contractile activity in a strip of smooth muscle dissected from a pig urethra

The tissue develops spontaneous tone after an initial tensioning to 1 g. It responds to stimulation of its intrinsic nerves (EFS) with a biphasic relaxation which is blocked by TTX. Applications of noradrenaline (NAd) and acetylcholine (ACh) contract the tissue further, but the nitric oxide donor sodium nitroprusside (SNP) and the K_ATP channel opener cromakalim both relax the tissue, as does removal of extracellular calcium. Adapted from Greenland et al. (1996).

Figure 6. Correlation between electrical and mechanical activity and intracellular calcium simultaneously recorded from two strips of guinea-pig detrusor

In A spontaneous action potentials were generated individually, and in B the action potentials occurred in bursts. Aa and Ba, membrane potential. Ab and Bb, calcium transient. Ac and Bc, tension. Ad, on a faster time scale the three signals are superimposed. The action potential and calcium transient were followed by the contraction. From Hashitani et al. (2004a).

Figure 7. Microelectrode recordings from guinea-pig detrusor: effects of depolarizing and hyperpolarizing current injection on action potential frequency

Horizontal bars indicate extracellular polarization applied through partition electrodes. Figure courtesy of J. Mostwin.

Figure 8. Effects of apamin on action potentials recorded from strips of guinea-pig detrusor

A, action potentials before (a) and after apamin (b). B, superimposed action potentials from the two conditions. Ca, spontaneous contractile activity from a strip and the effects of apamin. Cb, expanded view of a single contraction before and after apamin. From Hashitani & Brading (2003b).

Figure 9. Effects of Ca²⁺-activated K⁺ channel blocker charybdotoxin on action potentials in guinea-pig detrusor

The lower trace is an overlay of an action potential before and after charybdotoxin. From Hashitani & Brading (2003b).