Adrenomedullin in the rostral ventrolateral medulla inhibits baroreflex control of heart rate: a role for protein kinase A.
1 The rostral ventrolateral medulla (RVLM) is an essential vasomotor center in the brainstem which participates in maintaining resting levels of arterial pressure and for regulating baroreflex activity. We have demonstrated that microinjections of adrenomedullin (ADM), a vasoactive neuropeptide, into the RVLM cause increased resting mean arterial pressure (MAP) and heart rate (HR). However, the effect of ADM on baroreflex function remains unclear. 2 The purposes of the present study were to investigate the effect of ADM in the RVLM on the regulation of baroreflex activity and to identify the underlying mechanisms. Baroreflex curves were generated with intravenous injections of multiple doses of phenylephrine and nitroprusside. The upper and lower plateaus, reflex range, MAP at the midpoint of HR range (MAP(50)), and gain were evaluated before and after various microinjections were made into the RVLM of urethane-anesthetized rats. 3 Microinjections of ADM decreased the upper plateau, reflex range, and gain, and increased MAP(50), indicating that ADM in the RVLM impairs baroreflex function. 4 ADM(22-52), a putative ADM receptor antagonist, significantly increased the baroreflex gain and upper plateau, demonstrating that endogenous ADM tonically inhibits the baroreflex. Coinjections of ADM(22-52) with ADM blocked the ADM-induced baroreflex responses. 5 ADM's effect was abolished with H-89, a protein kinase A (PKA) inhibitor. 6 Our results show that ADM in the RVLM exerts an inhibitory effect on baroreflex activity via an ADM receptor-mediated mechanism, and that activation of PKA is involved in this event.
Xu
Yong
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Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada T6G 2H7. teresa.krukoff@ualberta.ca
Krukoff
Teresa L
TL
D053607:Adrenomedullin / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D017704:Baroreflex / Q000187:drug effects*; D001794:Blood Pressure; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006339:Heart Rate; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects* / Q000201:enzymology; D008845:Microinjections; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058265:Receptors, Adrenomedullin; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
D007546:Isoquinolines; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D058265:Receptors, Adrenomedullin; D043562:Receptors, G-Protein-Coupled; D013449:Sulfonamides; C104782:adrenomedullin (22-52); C081830:adrenomedullin receptor, rat; D053607:Adrenomedullin; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide