Calcitonin gene-related peptide (CGRP) is present in sensory nerve fibers in the heart and around peripheral arteries. On interaction with specific CGRP binding sites and activation of adenylate cyclase, CGRP causes vasodilation and has positive inotropic and chronotropic effects on the heart. In the present study, human CGRP I and II exerted positive inotropic effects on isolated human right auricles and relaxed small arteries from human skeletal muscle precontracted with norepinephrine (ECS0 for CGRP 10.59 nM and for CGRP II 0.37 nM). CGRP I and II (3.2 nmol) administered i.v. to 6 normal subjects exerted positive inotropic actions on the human heart concomitant with positive chronotropic effects, hypotension, and vasodilation. CGRP may, therefore, be of importance for cardiovascular control in man.