A role for calcium channels in the regulation of surfactant secretion is suggested by the observation that endothelin-1-stimulated surfactant secretion is inhibited by calcium channel blockers. 1,4-Dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridi ne carboxylic acid methyl ester (Bay K 8644), a dihydropyridine derivative, stimulates voltage-dependent and non-voltage-dependent calcium channels in a number of cell types. This study demonstrates that Bay K 8644 increased phosphatidylcholine (PC) secretion in isolated lung epithelial type II cells in a time- and concentration-dependent manner with an EC50 of 100 +/- 8 nM (mean +/- SEM, N = 6). The secretagogue effect of Bay K 8644 was independently decreased in the absence of external calcium, or in the presence of nifedipine, a calcium channel antagonist, or inhibitors of protein kinase C (PKC). Bay K 8644 increased intracellular calcium from 130 +/- 8 to 230 +/- 14 nM (N = 6, P < 0.05), an effect that was blocked by nifedipine. Bay K 8644 also increased the membrane-associated PKC activity in a concentration-dependent manner. In the membranes from Bay K 8644-stimulated cells, the increase in calcium-dependent PKC was greater than that in the calcium-independent PKC, suggesting preferential translocation of calcium-dependent PKC to the membranes. We suggest that both elevated calcium and activation of PKC are required for calcium agonist Bay K 8644-induced surfactant secretion in type II cells.