In response to extracellular application of 50 mM ATP, all individual porcine aortic smooth muscle cells respond with rapid rises from basal [Ca21]i to peak [Ca21]i within 5 s. The time from stimulus to the peak of the [Ca21]i response increases with decreasing concentration of ATP. At ATP concentrations of 0.5 mM and below, the time to the [Ca21]i peak varies more significantly from cell to cell than at higher concentrations, and each cell shows complicated initiation and decay kinetics. For any individual cell, the lag phase before a response decreases with increasing concentration of ATP. An increase in lag time with decreasing ATP concentration is also observed in the absence of extracellular Ca21, but the lag phase is more pronounced, especially at concentrations of ATP below 0.5 mM. Whole-cell patch-clamp electrophysiology shows that in porcine aortic smooth muscle cells, ATP stimulates an inward current carried mainly by Cl2 ion efflux with a time course similar to the [Ca21]i changes and no detectable current from an ATP-gated cation channel. A simple signal cascade initiation kinetics model, starting with nucleotide receptor activation leading to IP3-mediated Ca21 release from IP3-sensitive internal stores, fits the data and suggests that the kinetics of the Ca21 response are dominated by upstream signal cascade components.