Previous studies have reported that maximally effective concentrations of the "mixed" alpha and beta adrenoceptor agonists, epinephrine and norepinephrine, cause greater amounts of mucin secretion than the "pure" beta adrenoceptor agonist, isoproterenol, and that this response requires extracellular calcium. The purpose of the present study was to examine directly the nature of the effect of the putative pure alpha adrenoceptor agonist, phenylephrine, on isoproterenol-induced mucin secretion and the role of extracellular calcium in this interaction. We used a graphical method which provides a procedure for determining whether interaction between two drugs is additive, antagonistic or synergistic to analyze this interaction. Submandibular glands were removed from male rats, divided into sections and placed in modified Hank's balanced salt solution. Mucin secretion was measured as acid precipitable disintegrations per minute after labeling the submandibular gland with [14C]glucosamine. Phenylephrine caused a small but significant secretion of mucin which was blocked partially by phentolamine and completely by propranolol. Phenylephrine caused a significant shift of the isoproterenol concentration-response curve to the left of the theoretical curve expected if two drugs act additively. Mucin secretion induced by isoproterenol alone was independent of extracellular calcium concentration; however, the combination of isoproterenol and phenylephrine caused a concentration-dependency on extracellular calcium.