title: Actions of rilmenidine on neurogenic hypertension in BPH/2J genetically hypertensive mice.
abstract: OBJECTIVE
  BPH/2J hypertensive mice have an exaggerated sympathetic contribution to blood pressure (BP). Premotor sympathetic neurons within the rostroventrolateral medulla (RVLM) are a major source of sympathetic vasomotor tone and major site of action of the centrally acting sympatholytic agent, rilmenidine. The relative cardiovascular effect of rilmenidine in BPH/2J versus normotensive BPN/3J mice was used as an indicator of the involvement of the RVLM in the sympathetic contribution to hypertension in BPH/2J mice.
  
  
  METHODS
  BPH/2J and BPN/3J mice were pre-implanted with telemetry devices to measure BP in conscious unrestrained mice. Rilmenidine was administered acutely (n=7-9/group), orally for 14 days, at a wide range of doses (n=5/group), and also infused intracerebroventricularly for 7 days (n=6/group).
  
  
  RESULTS
  Acute intraperitoneal rilmenidine induced greater depressor and bradycardic responses in BPH/2J than BPN/3J mice (Pstrain<0.01). Both responses were reduced by atropine pre-treatment, with the remaining hypotensive effect being small and comparable between strains (Pstrain=1.0). This suggests that vagally induced reductions in cardiac output were responsible for the hypotension. Chronic intracerebroventricularly infused rilmenidine reduced BP from baseline marginally in BPH/2J mice during the dark (active) period (-6.5 ± 2 mmHg; P=0.006). Chronic orally administered rilmenidine (1-12 mg/kg per day) also had minimal effect on 24-h BP in both strains (P>0.16).
  
  
  CONCLUSIONS
  The sympathetic vasomotor inhibitory effect of rilmenidine is minimal in both strains and similar in hypertensive BPH/2J and BPN/3J mice. Thus, hypertension in BPH/2J mice is not likely mediated by greater neuronal activity in the RVLM, and agents such as rilmenidine would be an ineffective treatment for this form of neurogenic hypertension.
authors.affiliation: aNeuropharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne bDepartment of Pharmacology, Monash University, Clayton, Victoria, Australia *P.J.D. and G.A.H. are joint senior authors for this publication.
authors.forename: Kristy L
authors.initials: KL
authors.lastname: Jackson
authors.forename: Kesia
authors.initials: K
authors.lastname: Palma-Rigo
authors.forename: Thu-Phuc
authors.initials: TP
authors.lastname: Nguyen-Huu
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Davern
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Head
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001285:Atropine / Q000008:administration & dosage; D017704:Baroreflex / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002940:Circadian Rhythm; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D057967:Infusions, Intraventricular; D055104:Infusions, Subcutaneous; D007274:Injections, Intraperitoneal; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000503:physiopathology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010080:Oxazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D012149:Restraint, Physical; D000077769:Rilmenidine; D013312:Stress, Physiological; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D013566:Sympathomimetics / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D000959:Antihypertensive Agents; D010080:Oxazoles; D013566:Sympathomimetics; D001285:Atropine; D000077769:Rilmenidine