A hormone family of cardiac peptides has recently been isolated and biochemically and pharmacologically characterized by the relaxation of vascular smooth muscle, diuretic and natriuretic activities. The cardiac hormones are stored in specific granules of the atrial myoendocrine cells. Since data is available only from mammals (rat, pig, man) we started a phylogenetic study by investigating representatives of the higher vertebrate classes (birds, reptiles, amphibians, bony fish) as well as an invertebrate species, the gastropod mollusc Helix pomatia. Homologous cardiac hormones of the cardiodilatin (CDD) family which exerted a dose-dependent relaxant effect on the rabbit aorta were extracted from the atria of all species studied and from the ventricles of amphibians and teleosts. The storage sites of cardiac hormones were localized by electronmicroscopy and immunocytochemistry using antisera against several sequences of pig CDD and applying the peroxidase-antiperoxidase technique. CDD-immunoreactivity (CDD-IR) was observed in myoendocrine cells in the atria of all vertebrate species studied, and in amphibians and teleosts also in the ventricles. In the snail, however, CDD-IR was present in nerve endings of the atrium and in perikarya of the subesophageal ganglion as well as in fibers of the intestinal nerve, while no CDD-IR was detected in heart muscle cells. In correlation, no "specific" granules were observed in myocardiocytes of the snail and vascular smooth muscle relaxant bioactivity was present in extracts of the subesophageal ganglion. The findings indicate that in the vertebrates studied the cardiodilatin-immunoreactive substances seem to constitute an endocrine system in the heart. In the snail, in contrast, they are present in a neuro-cardiac axis. This seems to represent a model unique in phylogeny.