Rebound excitation and alternating slow wave patterns depend upon eicosanoid production in canine proximal colon.

In many regions of the gastrointestinal (GI) tract phasic contractile activity is timed by electrical slow waves (see Szurszewski, 1987). Slow waves are spontaneous, rhythmic depolarizations that result in opening of L-type Ca2+ channels and influx of Ca2+ (Ozaki et al. 1991). In some muscles the opening of Ca2+ channels results in Ca2+ action potentials superimposed upon the plateau phase of slow waves and in others, enhanced Ca2+ current increases the amplitude and duration of slow waves (Szurszewski, 1987). In either case the rise in intracellular Ca2+ initiates and regulates the force of contraction. In canine colonic muscles the amplitude and duration of slow waves often varies from event to event, resulting in an alternating electrical pattern in which long-duration slow waves are interspersed with several short-duration events (see Huizinga et al. 1984; Sanders & Smith, 1986a). The mechanisms responsible for alternating patterns are unknown. During the slow wave cycle, intracellular Ca2+ fluctuates as a result of depolarization and Ca2+ influx (Ozaki et al. 1991). In a tissue undergoing an alternating electrical pattern, cytoplasmic Ca2+ fluctuations would tend to mirror the changes in slow wave duration. Therefore, it is possible that periodic high and low Ca2+ levels could provide feedback to the mechanisms responsible for slow waves. Alternating patterns of slow waves could be regulated by pacemaker cells (i.e. interstitial cells of Cajal; see Sanders, 1996) or smooth muscle cells. Alternating patterns of slow waves could also occur by periodic neural signalling. Such activity has been proposed as a means of producing oscillatory activity over periods longer than the slow wave cycle in colonic muscles (Lyster et al. 1995). Others have reported that inhibition of excitatory neural inputs can inhibit the alternating pattern in some colonic muscles (Sanders & Smith, 1986a, b). An alternating pattern of slow waves could also result from periodic activation of enteric inhibitory neurons. In colonic muscles stimulation of inhibitory nerves elicits inhibition during the stimulus followed by transient excitation after the stimulus. This post-stimulus excitation has been termed ‘rebound’ excitation, and periodic inhibition and rebound excitation could generate an electrical pattern similar to that observed in colonic muscles. A number of mechanisms have been put forward to explain rebound excitation in GI muscles (see discussion in Ward et al. 1992). It appears that the mechanism of rebound depends to some extent upon stimulus parameters: repetitive stimuli at relatively high frequencies (i.e. 5–20 Hz) can activate release of non-cholinergic excitatory peptides, such as substance P and neurokinin A (Shuttleworth et al. 1993); stimulation at lower frequencies produces rebound that does not depend upon neurokinin release (Ward et al. 1992). Several studies have suggested that eicosanoids might be involved in rebound excitation because these responses can be blocked by non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin (Burnstock et al. 1975; Bennett & Stockley, 1977; Den Hertog & Van den Akker, 1979; Ward et al. 1992). This mechanism, however, needs to be reconsidered in light of the ability of indomethacin to inhibit L-type Ca2+ current (e.g. Sawdy et al. 1998), which could also affect rebound responses. In the present study we have investigated the role of eicosanoid synthesis in rebound excitation in canine colonic circular muscles. We also tested whether rebound was a specific response to nitrergic stimulation or a more general response elicited by other inhibitory stimuli. Finally, we investigated alternating slow wave patterns to determine whether this pattern is due to periodic transmitter release and related to NSAID-sensitive rebound responses. Our data suggest there are similarities between rebound responses and the alternating slow wave pattern in that they both depend upon eicosanoid production, but the alternating pattern in canine colon does not appear to require neural inputs.