Forskolin and caffeine induce Ca2+ release from intracellular stores in rabbit aorta

We combined techniques of 45Ca efflux and computer-assisted kinetic analysis to investigate the effects of forskolin and caffeine on intracellular Ca2+ metabolism in intact rabbit aortic segments. When either 1 microM forskolin or 10 mM caffeine was present during the 45Ca load and efflux, the amount of 45Ca released from the tissue was reduced during the interval between 50 and 250 min of efflux. In contrast caffeine but not forskolin induced an acute increase in 45Ca efflux when added to the perfusion medium after 1 h of efflux in physiological salt solution. Preincubation with caffeine abolished phenylephrine-stimulated 45Ca release, but preincubation with forskolin had no effect. Kinetic analysis of these data indicated that caffeine reduced the Ca2+ content of the same intracellular compartment depleted by phenylephrine, whereas forskolin depleted a different intracellular Ca2+ store. Forskolin-induced depletion of an intracellular Ca2+ store was surprising in light of current evidence suggesting adenosine 3',5'-cyclic monophosphate stimulation of sarcoplasmic reticular Ca2+ uptake, but hypotheses that included only this mechanism are inconsistent with our findings.