Electrical pacemakerÏrhythmic activity has been observed and extensively studied in the brain and other body organs, yet with the exception of the heart, the underlying mechanisms responsible for this rhythmicity remain largely unresolved. Electrical pacemaking in smooth muscle syncytia has been interpreted by at least two different classes of models: one based on voltage-dependent mechanisms (see Tomita, 1981;Publicover & Sanders, 1989;Publicover, 1995) and the other on chemically based intracellular mechanisms (see Tomita, 1981; Daniel et al. 1994). More recent findings provide support for the latter type of mechanism, one which involves Ca¥ release from intracellular Ca¥ stores (Van Helden, 1993;Liu et al. 1995;Hashitani et al. 1996;Van Helden et al. 1996;Komori et al. 1993).Evidence for a Ca¥ store-based electrical pacemaker was first derived from studies of lymphatic smooth muscle (Van Helden, 1993), a tissue that exhibits strong vasomotion, and from rhythmically active single isolated smooth muscle cells (Komori et al. 1993). Studies on a syncytial smooth muscle (lymphatic vessels) provided evidence that the action potentials that led to the rhythmic constrictions were initiated by underlying pacemaker activity. This activity was found to arise through a summation of more elementary events referred to as spontaneous transient depolarizations (STDs). STDs also occurred in denervated tissues and had a pharmacology indicating that they arose through Ca¥ release from stores, which generated a transient inward current across the cell membrane. Consistent with this, Journal of Physiology (2000) 1. Intracellular recordings made in single bundle strips of a visceral smooth muscle revealed rhythmic spontaneous membrane depolarizations termed slow waves (SWs). These exhibited 'pacemaker' and 'regenerative' components composed of summations of more elementary events termed spontaneous transient depolarizations (STDs). 2. STDs and SWs persisted in the presence of tetrodotoxin, nifedipine and ryanodine, and upon brief exposure to Ca¥-free Cd¥-containing solutions; they were enhanced by ACh and blocked by BAPTA AM, cyclopiazonic acid and caffeine. SWs were also inhibited in heparinloaded strips. 3. SWs were observed over a wide range of membrane potentials (e.g. −80 to −45 mV) with increased frequencies at more depolarized potentials. 4. Regular spontaneous SW activity in this preparation began after 1-3 h superfusion of the tissue with physiological saline following the dissection procedure. Membrane depolarization applied before the onset of this activity induced bursts of STD-like events (termed the 'initial' response) which, when larger than threshold levels initiated regenerative responses. The combined initial-regenerative waveform was termed the SW-like action potential. 5. Voltage-induced responses exhibited large variable latencies (typical range 0·3-4 s), refractory periods of •11 s and a pharmacology that was indistinguishable from those of STDs and spontaneous SWs. 6. The data indicate that SWs arise through...

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Intracellular microelectrode recordings were used to determine whether nitric oxide (NO), affects the pacemaker events that initiate vasomotion in lymphatic vessels of the guinea pig mesentery. This pacemaker activity is recorded as spontaneous transient depolarizations (STDs) and is likely to arise through synchronized Ca2+ release from intracellular stores. We show here that acetylcholine-induced endothelium-derived NO and exogenous NO released by sodium nitroprusside (SNP; 100 microM) and DEA-NONOate (500 microM) reduced the frequency and amplitude of STDs. This inhibition of STD frequency and amplitude was independent of the NO-induced hyperpolarization of the smooth muscle. The SNP-induced inhibition of STD frequency and amplitude was abolished during superfusion with the soluble guanylyl cyclase inhibitor ODQ (10 microM) and was diminished in the presence of cGMP and cAMP-dependent protein kinase inhibitors. The data are consistent with the hypothesis that NO inhibits vasomotion primarily by production of cGMP and activation of both cGMP- and cAMP-dependent protein kinases, which reduce the size and frequency of STDs, probably by acting on the underlying synchronized Ca2+ release from intracellular stores.