Organization and function of ICC in the urinary tract

Abstract

ICC are found in both the upper and lower urinary tract. They are not found in the ureter itself but are confined to the lamina propria of the renal pelvis and pelvi-calyceal junction. They do not appear to have a primary pacemaker role (this is ascribed to atypical smooth muscle cells in the same location) but rather conduct and amplify the pacemaker signals generated by the atypical smooth muscle cells. In the bladder, ICC are widely distributed in the sub-urothelial region, in the lamina propria and at the margins of the detrusor smooth muscle bundles. Again they appear not to have a pacemaking role and such evidence as there is would suggest that they have a role in the modulation of signal transduction. The strongest evidence that ICC in the urinary tract act as pacemakers comes from studies of those in the urethra. Isolated ICC show regular spontaneous depolarizations in current clamp which resemble very closely the slow waves recorded from intact tissue. In voltage clamp they show abundant calcium-activated chloride current and spontaneous transient inward currents which can be blocked by chloride channel blockers. However, their role in the modulation of urethral tone has yet to be fully elucidated.

Figure 1. Flow through a cannulated rat urethra that is connected to a constant pressure reservoir of Krebs solution

Under resting conditions flow was about 20% of maximum. Stimulation of the inhibitory nerves caused the urethra to relax and flow to exceed 80% of maximum. When 30 μm wortmanin was added, flow increased almost to the level seen when the inhibitory nerves were stimulated.

Figure 2. Whole mount of rabbit urethra labelled with anti-Kit antibody

ICC are evident as irregular elongated cells of about 80–100 μm in length between and surrounding the smooth muscle bundles (the latter are evident because of their weak autofluoresence).

Figure 3. Contrasting electrical properties of interstitial and smooth muscle cells

Interstitial cells showed regular ‘slow-wave’ depolarizations in current clamp (A) while smooth muscle cells were quiescent, although they could produce an action potential in response to depolarizing current (B). Under voltage clamp, interstitial cells exhibited both L-type calcium currents and calcium-activated chloride currents (C) while the smooth muscle cells showed only L-type calcium currents (D). E and F show summaries of the currents measured in 26 interstitial and 21 smooth muscle cells (redrawn from Sergeant et al. 2000).

Figure 4. The effect of anthracene-9-carboxcylic acid on flow through the isolated urethra

A-9-C (1 μm), like wortmanin, caused an increase in flow almost equal to the effect of stimulation of the inhibitory nerves.