We have studied the effect of the 37-amino acid cardioactive peptide, calcitonin gene-related peptide (CGRP) on cytosolic [Ca2+] in guinea-pig ventricular myocytes following depolarization. Cytosolic [Ca2+] was measured in single myocytes using fura-2. The application of 20 mM K+ led to a transient rise of cytosolic [Ca2+] followed by an exponential decline. The subsequent application of 2 nM CGRP resulted in a marked increase in cytosolic [Ca2+]. In contrast, no such response was obtained without prior depolarization. The results suggest a basis for the cardiotropic effects of CGRP through an influence on cytosolic [Ca2+].