Adrenomedullin enhances baroreceptor reflex response via cAMP/PKA signaling in nucleus tractus solitarii of rats.
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 ADM(1) 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 (0.02-0.2pmol) 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 PKA(beta), 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 ADM(1) receptor antagonist, ADM(22-52), 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 ADM(1) receptors in NTS.
Ho
L K
LK
Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, Republic of China.
Chen
K
K
Ho
I-C
IC
Shen
Y-C
YC
Yen
D H T
DH
Li
F C H
FC
Lin
Y C
YC
Kuo
W-K
WK
Lou
Y J
YJ
Yen
J C
JC
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D053607:Adrenomedullin / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D017704:Baroreflex / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D001993:Bronchodilator Agents / Q000494:pharmacology*; D058286:Calcitonin Receptor-Like Protein; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D017552:Solitary Nucleus / Q000187:drug effects* / Q000378:metabolism; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors
C105593:8-bromoadenosine-3',5'-cyclic monophosphorothioate; D001993:Bronchodilator Agents; D058286:Calcitonin Receptor-Like Protein; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin; D013873:Thionucleotides; C104782:adrenomedullin (22-52); D053607:Adrenomedullin; C017759:9-(tetrahydro-2-furyl)-adenine; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000225:Adenine