Oxyntomodulin increases intrinsic heart rate in mice independent of the glucagon-like peptide-1 receptor

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2007-02, Vol.292 (2), p.R962-R970
• Main Authors: Sowden, Gillian L, Drucker, Daniel J, Weinshenker, David, Swoap, Steven J
• Format: Article
• Language: English
• Subjects: Animals; Autonomic Nervous System - drug effects; Blood Pressure - drug effects; Blood Pressure - physiology; Body Temperature - drug effects; Diabetes Mellitus, Experimental - physiopathology; Diabetes Mellitus, Type 1 - physiopathology; Dopamine beta-Hydroxylase - genetics; Dose-Response Relationship, Drug; Eating - drug effects; Electrocardiography; Epinephrine - deficiency; Epinephrine - physiology; Female; Glucagon - pharmacology; Glucagon-Like Peptide-1 Receptor; Heart - drug effects; Heart rate; Heart Rate - drug effects; Hormones; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity - physiology; Norepinephrine - deficiency; Norepinephrine - physiology; Oxyntomodulin - pharmacology; Peptides; Peptides - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Glucagon - drug effects; Receptors, Glucagon - genetics; Receptors, Glucagon - physiology; Rodents; Telemetry; Temperature; Venoms - pharmacology
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00405.2006

1 Department of Biology, Williams College, Williamstown, Massachusetts; 2 Department of Medicine, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Canada; and 3 Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia Submitted 9 June 2006 ; accepted in final form 9 October 2006 Oxyntomodulin (OXM), a postprandially released intestinal hormone, inhibits food intake via the glucagon-like peptide-1 receptor (GLP-1R). Although OXM may have clinical value in treating obesity, the cardiovascular effects of OXM are not well understood. Using telemetry to measure heart rate (HR), body temperature (T b ), and activity in conscious and freely moving mice, we tested 1 ) whether OXM affects HR and 2 ) whether this effect is mediated by the GLP-1R. We found that peripherally administered OXM significantly increased HR in wild-type mice, raising HR by >200 beats/min to a maximum of 728 ± 11 beats/min. To determine the extent to which the sympathetic nervous system mediates the tachycardia of OXM, we delivered this hormone to mice deficient in dopamine- -hydroxylase [ Dbh (–/–) mice], littermate controls [ Dbh (+/–) mice], and autonomically blocked C57Bl mice. OXM increased HR equally in all groups (192 ± 13, 197 ± 21, and 216 ± 11 beats/min, respectively), indicating that OXM elevated intrinsic HR. Intrinsic HR was also vigorously elevated by OXM in Glp-1R (–/–) mice (200 ± 28 beats/min). In addition, peripherally administered OXM inhibited food intake and activity levels in wild-type mice and lowered T b in autonomically blocked mice. None of these effects were observed in Glp-1R (–/–) mice. These data suggest multiple modes of action of OXM: 1 ) it directly elevates murine intrinsic HR through a GLP-1R-independent mechanism, perhaps via the glucagon receptor or an unidentified OXM receptor, and 2 ) it lowers food intake, activity, and T b in a GLP-1R-dependent fashion. glucagon receptor; core body temperature; exendin-4; insulin; food intake; mean arterial pressure; rats; activity Address for reprint requests and other correspondence: S. J. Swoap, Dept. of Biology, Williams College, Williamstown, MA 01267 (e-mail: sswoap{at}williams.edu )