The ventricle of the mussel Geukensia demissa is inhibited by 5-hydroxytryptamine and excited by the molluscan neuropeptide FMRFamide. Supra-threshold doses of amide result in marked positive chronotropy and inotropy within 5-15 s. 5-Hydroxytryptamine at 10(-8) M produces diastolic arrest within 10 s. A 1-min exposure to FMRFamide (5 x 10(-8) M) results in a small increase in the cytoplasmic levels of adenosine 3',5'-cyclic monophosphate; shorter or longer exposures have no effect. The cAMP content of ventricles incubated in 5 x 10(-8) M 5-hydroxytryptamine for 1 min decreases by 2.3 pmol/mg protein; longer or shorter incubations have no effect. Treatment with forskolin results in 3- or 4-fold increases in adenosine 3',5'-cyclic monophosphate, but forskolin has no effect on the mechanical activity of the ventricle. The levels of inositol monophosphate, inositol 1,4-diphosphate, and inositol 1,4,5-triphosphate in tissues exposed to 5-hydroxytryptamine are not different from levels in control tissues. FMRFamide decreases the levels of these phosphoinositides by 50% or more. Lower concentrations of phorbol 12,13-diacetate (10(-8) to 10(-7) M) and phorbol 12-myristate,13-acetate (10(-6) M) cause positive chronotropy in the isolated ventricle; higher concentrations induce systolic arrest. These results suggest that the effects of 5HT on the ventricle are not mediated by adenosine 3',5'-cyclic monophosphate or inositol 1,4,5-triphosphate. The effects of FMRFamide may involve a decrease in inositol 1,4,5-triphosphate. The effects of amide may involve a decrease in inositol 1,4,5-triphosphate. The response of the ventricles to phorbol esters suggest that protein kinase C may be involved in the regulation of cardiac contractility.