Adrenomedullin (ADM), a 52-amino acid peptide, elicits differential cardiovascular responses when it is administered systemically or directly to the brain. We evaluated in the present study the hypothesis that ADM may modulate baroreceptor reflex (BRR) response through an ADM receptor-mediated cAMP/ protein kinase A (PKA)-dependent mechanism in the nucleus tractus solitarii (NTS), the terminal site for primary baroreceptor afferents, using Sprague-Dawley rats. Our immunoblot and immunohistochemical results showed that the two component proteins of the ADM1 receptor complex, calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein (RAMP)-2, were uniformly distributed and highly co-localized in the NTS. Site-specific microinjection of ADM (0.02-0.2 pmol) unilaterally into the NTS significantly increased BRR response and sensitivity in a time- and dose-related manner, without affecting arterial pressure and heart rate. The BRR enhancing effect of ADM was also temporally correlated with an up-regulation of PKAβ, the active form of PKA and an increase in PKA activity. In addition, the ADM-evoked BRR enhancement or PKA activation was abolished by co-microinjection with a selective ADM1 receptor antagonist, ADM22-52, an adenylyl cyclase inhibitor, SQ22536, or a PKA inhibitor, Rp-8-bromo-cAMP. These results suggest that ADM enhances BRR via activation of a cAMP/PKA-dependent mechanism by acting site-specifically on ADM1 receptors in NTS.