A comparison was made between the properties of the norepinephrine- and caffeine-sensitive Ca2+ store in both intact and skinned smooth muscle of the rabbit mesenteric artery. After a first application of 10(-5) M norepinephrine, reapplication of norepinephrine did not induce a second contraction in Ca2+-free medium. However, following this sequence 25 mM caffeine still induced a large contraction. The rates of Ca2+ leakage and Ca2+ filling of the norepinephrine-sensitive store were much faster than those of the caffeine-sensitive one. The amplitude of the norepinephrine-induced contraction in Ca2+-free medium also depended on the amount of Ca2+ present in the caffeine-sensitive store. In the saponin-treated skinned muscle caffeine induced a Ca2+ release only after loading with Ca2+, whereas norepinephrine was unable to induce Ca2+ release in the skinned preparation even after loading with Ca2+. The release of Ca2+ from the caffeine-sensitive store could be activated by Ca2+ itself when the skinned muscle was loaded with Ca2+ above 10(-6) M. These results suggest that the norepinephrine-sensitive Ca2+ store is distinct from a large fraction of the caffeine-sensitive one, and that the norepinephrine-sensitive store is close to the cell membrane. In vascular smooth muscle, under physiological conditions, Ca2+ released from the norepinephrine-sensitive store by norepinephrine may induce Ca2+ release from the caffeine-sensitive Ca2+ store which may be comprised of the sarcoplasmic reticulum.