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...

Snake venom toxins first transit the lymphatic system before entering the bloodstream. Ointment containing a nitric oxide donor, which impedes the intrinsic lymphatic pump, prolonged lymph transit time in rats and humans and also increased rat survival time after injection of venom. This pharmacological approach should give snakebite victims more time to obtain medical care and antivenom treatment.

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BackgroundThis study examines the use of topical pharmacological agents as a snakebite first aid where slowing venom reaching the circulation prevents systemic toxicity. It is based on the fact that toxin molecules in most snake venoms are large molecules and generally first enter and traverse the lymphatic system before accessing the circulation. It follows on from a previous study where it was shown that topical application of a nitric oxide donor slowed lymph flow to a similar extent in humans and rats as well as increased the time to respiratory arrest for subcutaneous injection of an elapid venom (Pseudonaja textilis, Ptx; Eastern brown snake) into the hind feet of anaesthetized rats.Methodology/Principal FindingsThe effects of topical application of the L-type Ca2+ channel antagonist nifedipine and the local anesthetic lignocaine in inhibiting lymph flow and protecting against envenomation was examined in an anaesthetized rat model. The agents significantly increased dye-measured lymph transit times by 500% and 390% compared to controls and increased the time to respiratory arrest to foot injection of a lethal dose of Ptx venom by 60% and 40% respectively. The study also examined the effect of Ptx venom dose over the lethal range of 0.4 to 1.5 mg/kg finding a negative linear relationship between increase in venom dose and time to respiratory arrest.Conclusions/SignificanceThe findings suggest that a range of agents that inhibit lymphatic flow could potentially be used as an adjunct treatment to pressure bandaging with immobilization (PBI) in snakebite first aid. This is important given that PBI (a snakebite first aid recommended by the Australian National Health and Medical research Council) is often incorrectly applied. The use of a local anesthetic would have the added advantage of reducing pain.

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