Prolonged exposure of venous-perfused bovine adrenal glands to high K in the presence of external Ca produces a transient increase in catecholamine output that reaches a maximum after about 1 min and then declines with a half-time of about 1-2 min. 2. The time course of the transient secretory response to high K does not depend appreciably on the total catecholamine output which indicates that depletion of releasable catecholamine is unlikely to be responsible for the transient nature of the response. 3. Application of 3-6 mM-Ba stimulates secretion from a gland after many minutes exposure to high K, when catecholamine output has declined close to resting levels. This provides further evidence that depletion does not play a major role in the transient response and shows that maintained depolarization does not inhibit the secretory mechanism. 4. Exposure to high K solutions in which Ca has been replaced isomotically by Mg does not evoke any catecholamine output. Subsequent application of Ca always elicits some secretion although the size of this response to added Ca declines rapidly during exposure to Ca-free, high K solutions. The failure of the secretory response in these experiments is more rapid, and earlier in onset than the declining phase of the normal secretory response evoked in the presence of calcium. 5. Pre-treatment with Ca-free solutions of intermediate K content reduces the response to subsequent simultaneous application of high K and Ca. There is a roughly sigmoidal relation between the reduction in response and the logarithm of the K concentration used for pre-treatment. 6. Thin slices of bovine adrenal medulla show qualitatively similar responses on exposure to high K. Examination of the flourescent signal from slices dyed with the potential-sensitive dye DiS-C(3)-(5) suggests that maintained exposure to high K produces a stable depolarization. 7. The most likely explanation for these results is that K-depolarization first activates and subsequently inactivates a potential-sensitive Ca permeability channel. This inactivation is time and possibly potential dependent. 8. The effect of high K on calcium movements in medullary slices was examined. Exposure to 72 mM-K increases (45)Ca uptake, the increase being greatest during the first 10 min. The efflux of Ca is also increased on exposure to high K in the presence of Ca. The net Ca uptake in 72 mM-K is smaller than the tracer uptake of Ca. These findings indicate that K depolarization stimulates a Ca-Ca exchange process. They are also consistent with, but do not offer strong positive support for, the idea that K-depolarization first activates and subsequently inactivates Ca entry. 9. It is suggested that Ca inactivation might play a role in the modulation of neurosecretion and neurotransmitter release by changes in membrane potential.