Calcitonin gene-related peptide (CGRP) is a nonadrenergic/noncholinergic (NANC) peptide with vasodilatative/inotropic action that may benefit the failing heart. However, precise mechanisms for its in vivo inotropic action remain unclear. To assess this, dogs with normal or failing (sustained tachypacing) hearts were instrumented for pressure-dimension analysis. In control hearts, CGRP (20 pmol/kg per minute) enhanced cardiac contractility (eg, +33+/-4.2% in end-systolic elastance) and lowered afterload (-14.2+/-2% in systemic resistance, both P<0.001). The inotropic response was markedly blunted by heart failure (+6.5+/-2%; P<0.001 versus control), whereas arterial dilation remained unaltered (-19.3+/-5%). CGRP-positive inotropy was not attributable to reflex activation because similar changes were observed in the presence of a ganglionic blocker. However, it was fully prevented by the beta-receptor antagonist (timolol), identifying a dominant role of sympatho-stimulatory signaling. In control hearts, myocardial interstitial norepinephrine assessed by microdialysis almost doubled in response to CGRP infusion, whereas systemic plasma levels were unchanged. In addition, CGRP receptors were not observed in ventricular myocardium but were prominent in coronary arteries and the stellate ganglia. Ventricular myocytes isolated from normal and failing hearts displayed no inotropic response to CGRP, further supporting indirect sympatho-stimulation as the primary in vivo mechanism. In contrast, the peripheral vasodilatative capacity of CGRP was similar in femoral vascular rings from normal and failing hearts in dogs. Thus, CGRP-mediated positive inotropy is load-independent but indirect and attributable to myocardial sympathetic activation rather than receptor-coupled stimulation in canine hearts. This mechanism is suppressed in heart failure, so that afterload reduction accounts for CGRP-enhanced function in this setting.