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Clinical Science (2003) 104, (341–347) (Printed in Great Britain)

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Cardiovascular hypertrophy in diabetic spontaneously hypertensive rats: optimizing blockade of the renin–angiotensin system

Markus LASSILA*, Belinda J. DAVIS*, Terri J. ALLEN*, Louise M. BURRELL†, Mark E. COOPER* and Zemin CAO*

*Baker Heart Research Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, Victoria 8008, Australia, and †Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Waterdale Road, Heidelberg West, Victoria 3081, Australia

Key words: angiotensin-converting enzyme, angiotensin receptor, calcium channel antagonist, cardiovascular hypertrophy, diabetes, vasopeptidase inhibitor, hypertension.

Abbreviations: ACE, angiotensin-converting enzyme; HbA1c, glycated haemoglobin; NEP, neutral endopeptidase; RAS, renin–angiotensin system; SHR, spontaneously hypertensive rats; VPI, vasopeptidase inhibitor.

Correspondence: Dr Zemin Cao (e-mail zemin.cao@baker.edu.au).

The aim of the present study was to compare the antihypertrophic effects of blockade of the renin–angiotensin system (RAS), vasopeptidase inhibition and calcium channel antagonism on cardiac and vascular hypertrophy in diabetic spontaneously hypertensive rats (SHR). SHR with streptozotocin-induced diabetes were treated with one of the following therapies for 32 weeks: the angiotensin-converting enzyme (ACE) inhibitor captopril (100mg/kg); the angiotensin AT₁ receptor antagonist valsartan (30mg/kg); a combination of captopril with valsartan; the vasopeptidase inhibitor mixanpril (100mg/kg); or the calcium channel antagonist amlodipine (6mg/kg). Systolic blood pressure and cardiac and mesenteric artery hypertrophy were assessed. Mean systolic blood pressure in diabetic SHR (200±5mmHg) was reduced by captopril (162±5mmHg), valsartan (173±5mmHg), mixanpril (176±2mmHg) and amlodipine (159±4mmHg), and was further reduced by the combination of captopril with valsartan (131±5mmHg). Captopril, valsartan and mixanpril reduced heart and left ventricle weights by approx. 10%. The combination of captopril and valsartan further reduced heart weight (-24%) and left ventricular weight (-29%). Amlodipine did not affect cardiac hypertrophy. Only mixanpril and the combination of captopril and valsartan significantly reduced mesenteric weight. The mesenteric wall/lumen ratio was reduced by all drugs, and to a greater extent by the combination of captopril and valsartan. We conclude that optimizing the blockade of vasoconstrictive pathways such as the RAS, particularly with the combination of ACE inhibition and AT₁ receptor antagonism, is associated with antitrophic effects in the context of diabetes and hypertension. In contrast, calcium channel blockade, despite similar effects on blood pressure, confers less antitrophic effects in the diabetic heart and blood vessels.

Received 29 July 2002/29 November 2002; accepted 7 January 2003

The Biochemical Society and the Medical Research Society © 2003