Effect of peripherally restricted PEGylated Neuromedin U on cardiovascular function (837.14)

Background: Administration of NMU agonists have been shown to regulate smooth muscle contraction, stress, analgesia, and metabolism. Central NMU receptor activation has been shown to increase heart rate in rodent models. To further examine the effect of peripheral NMU receptor activation on cardiovascular function, a long acting pegylated (40Kda) neuromedin U analog (PEGNMU) was designed and its effect on cardiovascular function examined in rats and cynomolgus monkeys. Methods: cynomolgus monkey NMU receptors were cloned and expressed in HEK293 cells. The activity of NMU peptides was characterized in receptor binding and FLIPR based functional assays. Cardiovascular function was assessed by telemetry in instrumented rats and cynomolgus monkeys. Results: Cynomolgus monkey NMU (cNMU) receptors were >95% homologous to human receptors. NMU peptides activated both human and cynomolgus monkey receptors with similar potency and selectivity. PEGNMU was found to be a potent full agonist at both cNMU receptors and exhibited a half life in cynomolgus monkeys of 33 hours. Administration to rats and cynomolgus monkeys resulted in increased diastolic and systolic blood pressure with no change or slight decrease in heart rate and cardiac contractility. Conclusion: The data presented illustrate a role for peripheral neuromedin U receptors in the regulation of cardiovascular function in vivo .