Intermedin (adrenomedullin-2) enhances cardiac contractile function via a protein kinase C- and protein kinase A-dependent pathway in murine ventricular myocytes.
Intermedin (IMD), also called adrenomedullin-2, is a 47-amino acid peptide from the calcitonin gene-related peptide (CGRP)/adrenomedullin family of peptides. Recent studies suggest that IMD may participate in the regulation of cardiovascular function and fluid and electrolyte homeostasis. To evaluate the role of IMD on cardiomyocyte contractile function, electrically paced murine ventricular myocytes were acutely exposed to IMD, and the following indexes were determined: peak shortening (PS), time to PS, time-to-90% relengthening, and maximal velocity of shortening and relengthening. Intracellular Ca(2+) was assessed using fura 2-AM fluorescent microscopy. Our results revealed that IMD (10 pM to 10 nM) significantly increased PS and maximal velocity of shortening and relengthening in ventricular myocytes, the maximal effect of which (approximately 46%) was somewhat comparable to those elicited by CGRP (1 nM) and adrenomedullin (100 nM). Exposure of IMD significantly shortened time-to-90% relengthening without affecting time to PS, similar to CGRP and adrenomedullin. IMD also enhanced intracellular Ca(2+) release, with a maximal increase of approximately 50%, and facilitated the intracellular Ca(2+) decay rate. The IMD-induced effects were abolished by the protein kinase C inhibitor chelerythrine (1 microM), downregulation of protein kinase C using phorbol 12-myristate 13-acetate (1 microM), and the protein kinase A inhibitor H89 (1 microM). Our data suggest that IMD acutely augments cardiomyocyte contractile function through, at least in part, a protein kinase C- and protein kinase A-dependent mechanism.
Dong
Feng
F
Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071-3375, USA.
Taylor
Meghan M
MM
Samson
Willis K
WK
Ren
Jun
J
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D009479:Neuropeptides / Q000008:administration & dosage*; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016276:Ventricular Function
D009479:Neuropeptides; C514552:intermedin protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C