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).
Conclusion: 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.
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.
Correspondence to Geoffrey A. Head, Neuropharmacology Laboratory, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne 8008, AustraliaTel: +61 3 8532 1330; fax: +61 3 8532 1100; e-mail: firstname.lastname@example.org
Abbreviations: BP, blood pressure; BPH/2J, blood pressure high mice; BPN/3J, blood pressure normal mice; CNS, central nervous system; DAP, diastolic arterial pressure; HR, heart rate; ICV, intracerebroventricular; MAP, mean arterial pressure; PVN, paraventricular nucleus; ROR, rate of rise; RVLM, rostroventrolateral medulla; SAP, systolic arterial pressure; SHR, spontaneously hypertensive rats; SNS, sympathetic nervous system
Received 24 May, 2012
Accepted 30 September, 2013
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