tentials evoked by intracellular current injection in single bundles of circular smooth muscle taken from guinea pig antrum have the characteristics of the secondary regenerative component of the slow wave occurring in the same muscle layer. Such regenerative depolarizations might result from a mechanism that responds to membrane polarization with a delayed increase in the rate of production of unitary potentials detected in this tissue. To test this possibility, a two-stage reaction leading to the formation of an intracellular messenger was proposed. The first forward reaction was voltage-dependent, in the manner described by the HodgkinHuxley transient Na conductance formalism, allowing simulation of anode break excitation, stimulus threshold strength-duration characteristics, and refractory behavior. A conventional dose-effect relationship was proposed to describe the dependence of the mean rate of discharge of unitary potentials on messenger concentration. Unitary potentials were modeled as unitary membrane conductance modulations with an empirically derived amplitude distribution and Poisson-distributed intervals. The model reproduces a range of spontaneous and evoked membrane potential changes characteristic of antral circular muscle bundles. mathematical model; stomach; slow wave; interstitial cells of Cajal; inositol 1,4,5-trisphosphate MOST REGIONS OF THE GASTROINTESTINAL tract generate rhythmic contractions in the absence of neuronal or hormonal stimulation. Each contraction is associated with a wave of depolarization called a slow wave (25,30). In the guinea pig gastric antrum, slow waves are initiated by pacemaker potentials generated in myenteric interstitial cells of Cajal (ICC MY ) (5). Waves of pacemaker depolarization spread passively to the longitudinal and circular muscle layers. In the circular muscle layer, the waves of depolarization initiate the secondary regenerative component of the slow wave (5). The secondary component is dependent on the presence of intramuscular ICC (ICC IM ), which is absent in the gastric antrum of mutant mice that lack this population of cells (4).Regenerative potentials that share the characteristics of the secondary component of the slow wave can be initiated in isolated individual bundles of circular muscle (6, 28). Preparations were impaled with two intracellular electrodes, with one electrode to pass depolarizing current pulses and the other to record membrane potential (E m ) changes. Depolarization evoked a regenerative response with a minimum latency of ϳ1 s (28). The repolarizing step, ending a period of membrane hyperpolarization, also evoked a regenerative response but with a longer minimum latency of ϳ2.5 s (28). Regenerative responses appear to depend on the release of Ca 2ϩ from intracellular stores followed by the activation of anion-selective ion channels (13). They are abolished by depleting internal Ca 2ϩ stores (28), by buffering the cytosolic free Ca 2ϩ concentration, [Ca 2ϩ ] i to low levels (6), and by 2-APB (9, 13, 14), an agent that preve...