Objective: Schlager hypertensive (BPH/2J) mice have been suggested to have high blood pressure (BP) due to an overactive sympathetic nervous system (SNS), but the contribution of the renin–angiotensin system (RAS) is unclear. In the present study, we examined the cardiovascular effects of chronically blocking the RAS in BPH/2J mice.
Methods: Schlager normotensive (BPN/3J, n = 6) and BPH/2J mice (n = 8) received the angiotensin AT1A-receptor antagonist losartan (150 mg/kg per day) in drinking water for 2 weeks. Pre-implanted telemetry devices were used to record mean arterial pressure (MAP), heart rate (HR) and locomotor activity.
Results: MAP was reduced by losartan treatment in BPN/3J (−23 mmHg, P < 0.01) and in BPH/2J mice (−25 mmHg, P < 0.001), whereas HR was increased. Losartan had little effect on initial pressor responses to feeding or to stress, but did attenuate the sustained pressor response to cage-switch stress. During the active period, the hypotension to sympathetic blockade with pentolinium was greater in BPH/2J than BPN/3J (suggesting neurogenic hypertension), but was not affected by losartan. During the inactive period, a greater depressor response to pentolinium was observed in losartan-treated animals.
Conclusion: The hypotensive actions of losartan suggest that although the RAS provides an important contribution to BP, it contributes little, if at all, to the hypertension-induced or the greater stress-induced pressor responses in Schlager mice. The effects of pentolinium suggest that the SNS is mainly responsible for hypertension in BPH/2J mice. However, the RAS inhibits sympathetic vasomotor tone during inactivity and prolongs sympathetic activation during periods of adverse stress, indicating an important sympatho-modulatory role.
aNeuropharmacology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
bINSERM U 970, Centre de Recherche Cardiovasculaire
cUniversité Paris Descartes, Paris, France
dDepartment of Pharmacology, Monash University, Clayton, Victoria, Australia
Correspondence to Geoffrey A. Head, Neuropharmacology Laboratory, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC 8008, AustraliaTel: +61 3 8532 1330; fax: +61 3 8532 1100; e-mail: firstname.lastname@example.org
Abbreviations: ACE, angiotensin-converting enzyme; Ang, angiotensin; BP, blood pressure; BPH/2J, Schlager hypertensive mouse; BPN/3J, Schlager normotensive mouse; HR, heart rate; MAP, mean arterial pressure; RAS, reninangiotensin system; SHRs, spontaneously hypertensive rats; SNS, sympathetic nervous system
Received 24 January, 2011
Revised 26 July, 2011
Accepted 8 August, 2011