title: Measurement of hyper- and hypotension during repeated dose toxicity studies in either freely moving or physically restrained cynomolgus monkeys.
abstract: BACKGROUND
  The measurement of cardiovascular endpoints in standard toxicology studies remains a challenge as the routinely used non-invasive methods require physical restraint, causing an increase of sympathetic neural activity, leading to excitement and potentially hypertension in the experimental animals. In this study, a miniature telemetry blood pressure transmitter was used to evaluate if the acute hyper- and hypotension could be detected in free moving cynomolgus monkeys as well as physically restrained animals using positive control drugs. Furthermore, as a comparator, routine high definition oscillometry (HDO) was performed in restrained animals.
  
  
  METHODS
  Hemodynamic parameters were monitored continuously from conscious, freely moving animals following oral administration of vehicle (water) or 1 and 10mg/kg of etilefrine, and 1 and 4mg/kg of dihydralazine as positive control articles. A second dose session was performed to confirm the reproducibility of results and a third dose session combined with physical restraint procedures for blood collection and HDO measurements.
  
  
  RESULTS
  There was a dose-dependent, statistically significant increase in the systolic blood pressure following oral doses of etilefrine at all 3 dose sessions. This effect was less apparent during session 3, probably due to the physical restraint applied for the blood sampling and HDO measurement. No differences in the blood pressure were measured using HDO. On all three dose sessions following oral doses of dihydralazine the expected statistically significant decrease in the diastolic pressure could be clearly measured even when the telemetric data recordings were combined with physical restraint.
  
  
  CONCLUSIONS
  Due to the advantages of the minimally invasive telemetry technique compared to HDO and the possibility of prolonged measurement periods, it is an invaluable tool for blood pressure measurement in freely moving animals in toxicology studies.
authors.affiliation: Covance Laboratories GmbH, Kesselfeld 29, 48163 Muenster, Germany. Electronic address: marc.niehoff@covance.com.
authors.forename: Marc O
authors.initials: MO
authors.lastname: Niehoff
authors.affiliation: Covance Laboratories GmbH, Kesselfeld 29, 48163 Muenster, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Niggemann
authors.affiliation: Covance Laboratories GmbH, Kesselfeld 29, 48163 Muenster, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Sternberg
authors.affiliation: Covance Laboratories Inc., 3301 Kinsman Boulevard, Madison, WI 53704-2595, United States.
authors.forename: Angela
authors.initials: A
authors.lastname: Jenkins
authors.affiliation: Covance Laboratories Ltd., Otley Road, Harrogate, North Yorkshire, HG3 1PY, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Holbrook
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D018660:Blood Pressure Monitoring, Ambulatory / Q000662:veterinary*; D015924:Blood Pressure Monitors / Q000662:veterinary; D004078:Dihydralazine / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005039:Etilefrine / Q000008:administration & dosage / Q000633:toxicity*; D008252:Macaca fascicularis / Q000502:physiology*; D023421:Models, Animal; D012149:Restraint, Physical / Q000662:veterinary*
chemical_list: D004078:Dihydralazine; D005039:Etilefrine
keywords: Cardiovascular; Cynomolgus monkey; HDO; Hemodynamic; Hypertension; Hypotension; JET; Method; Safety pharmacology; Telemetry