Interaction between interstitial cells and smooth muscles in the lower urinary tract and penis

Abstract

Smooth muscles in the lower urinary tract and corporal tissue exhibit spontaneous contractile activity which depends on L-type Ca(2+) channels. The mechanism underlying this activity is spontaneous electrical activity which shows varied form and property between these tissues. Recent studies revealed that interstitial cells (ICs) are widely distributed in the genitourinary system, and suggested their involvement in spontaneous muscle activity. ICs in the system are not a simple analogy of interstitial cells of Cajal (ICC) in the gut, which act as electrical pacemaker, but represent variability amongst tissues which may account for individual characteristics of each organ. In the bladder and corporal tissue, where smooth muscle cells are capable of generating spontaneous electrical activity, ICs may modulate smooth muscle activity. ICs in corporal tissue release prostaglandins via cyclooxygenase-2 (COX-2) activity and reinforce not only spontaneous but also nerve-mediated alpha-adrenergic contractions. In the bladder, their fundamental role in the integration of signals between populations of cells has been proposed, and thus changes in ICs may contribute to an overactive bladder, a pathological condition which results from increased excitability in detrusor smooth muscles. In the urethra, ICs may act as electrical pacemakers as do ICC. However, overall contractility of urethral smooth muscles does not necessarily rely on pacemaking of ICs, and thus some population of smooth muscles may also have their own excitability.

Figure 1. Function and distribution of COX-2-immunoreactive interstitial cells in corpus cavernosum

In a CCSM preparation that generated spontaneous contractions, NS-398 (1 μm) abolished the contractions (A). When changes in tension were measured simultaneously with changes in [Ca²⁺]_i in another preparation, transmural stimulation evoked phasic contractions (Ba) and corresponding increases in [Ca²⁺]_i (Bb). NS-398 (1 μm) strongly suppressed nerve-evoked contractions (Ca), and also reduced the amplitude of the initial phase of Ca²⁺ transients by about 50% (Cb). HE staining of the smooth muscle cells and ICs in corpus cavernosum (Da). Smooth muscle cells had a large, clear nucleus (arrowheads), while ICs were characterized by their smaller, darker nucleus (arrows). ICs typically had spindle- or star-shaped cell bodies and had some branches (arrows) which connected with neighbouring cells (Db). COX-2-immunoreactive cells, which had spindle- or star-shaped cells with some branches, were widely distributed throughout the corpus cavernosum (Ea). COX-2-immunoreactive cells were also stained for Kit antibody (Eb and Ec). COX-2-immunoreactive ICs in the corpus cavernosum (Fa) were also stained for vimentin (Fb and Fc).

Figure 2. Role of interstitial cells in regulating cavernosal smooth muscle (CSM) tone

In corpus cavernosum, both spontaneous activity of CSM and neurally released noradrenaline (NAd; pink arrow) contract CSM. Spontaneously produced prostaglandins (PGs) via COX-2 activity in interstitial cells (ICs) not only reinforce spontaneous excitation of CSM (lower red arrow) but also facilitate nerve-mediated α-adrenergic contractions (upper red arrow). Conversely, spontaneously released nitric oxide (NO) from endothelium (EC) suppresses excitation (green arrow). Thus, the balance between spontaneously released PGs and NO is important in regulating CCSM tone to determine the contractile state of the penis.

Figure 3. Ca²⁺ transients recorded from smooth muscles and interstitial cells in the guinea-pig bladder

Kit-positive ICs having spindle-shaped cell bodies, some 80 μm in length and less than 10 μm in width, are shown located adjacent to a pair of muscle bundles (Aa). The same images were superimposed on the plane images of the smooth muscle bundles (Ab). In a preparation loaded with fluo-4, IC located near the muscle boundary had a higher fluorescence intensity than that of smooth muscle (Ba). A plane image with Nomarski optics visualized the cell body of IC (Bb). When Ca²⁺ transients were recorded from the IC (area 1) and from two smooth muscle areas (areas 2 and 3), synchronous Ca²⁺ waves were detected at areas 2 and 3 (Bc). However, IC generated slow Ca²⁺ transients independently from those of smooth muscles (Bc). In another fluo-4-loaded preparation which had been exposed to nifedipine (10 μm) for 30 min, IC continued to generate slow Ca²⁺ transients (Ca). A series of frames with intervals of 2 s demonstrates a Ca²⁺ transient originating from the IC (Cb).

Figure 4. Ca²⁺ transients recorded from smooth muscles and interstitial cells in the rabbit urethra

In a preparation loaded with fluo-4, urethral IC located near the muscle boundary generated slow Ca²⁺ transients (A). A series of frames with intervals of 2 s demonstrates a Ca²⁺ transient originating from the IC (A). Note that Ca²⁺ transients were initiated at the point indicated by an arrow, and then propagated upward and downward. In a different preparation, Ca²⁺ transients recorded from urethral smooth muscles were largely attenuated by nicardipine (1 μm) (Ba and C). In another preparation, Ca²⁺ transients recorded from urethral IC were virtually insensitive to nicardipine (1 μm) (Ca and b). The scale bar in Bb also refers to Ba. The scale bar in Cb also refers to Ca.