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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

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

¹Department of Biology, Williams College, Williamstown, Massachusetts; ²Department of Medicine, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Canada; and ³Department 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

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