On a molar basis, adrenomedullin (AM) and calcitonin gene- related peptide (CGRP) are the most potent vasodilatators known so far. These peptides act via the calcitonin receptor-like receptor (CLR) that gains its ligand specificity by association with receptor-activity modifying proteins (RAMP)-1 or -2. Here we investigated the impact of smooth muscle a-actin promotor driven CLR overexpression on the systemic circulation in mice. Basal mean arterial pressure (BP) and heart rate (HR) were indistinguishable in CLR transgenic (CLR-tg) mice and control littermates. Whereas AM injection revealed no difference between CLR-tg and wild type (wt) mice CGRP injection resulted in an extreme and long lasting increase in HR in CLR-tg mice. This effect on HR could not be explained by a larger drop in BP since this was similar in CLR-tg and wt mice. The effect of CGRP on HR could be completely blocked by administration of propranolol whereas the drop in BP was not significantly affected. This is in line with the postulation of CGRP mediated modulation of the HR via the sympathetic nervous system and the intense expression of the transgene CLR that we found in the cervical sympathetic ganglia. CLR signaling appears to play a role in the modulation of the HR in sympathetic post-ganglionic neurons.