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Combination of non-hypotensive doses of valsartan and enalapril improves survival of spontaneously hypertensive rats with endothelial dysfunction

Novartis Pharma AG, Metabolic, Cardiovascular and Endocrine Therapeutic Area, 4002 Basel, Switzerland, marc.de_ gasparo{at}pharma.novartis.com

Patrick Hess

Actelion Ltd/Innovation Centre, Gewerbestrasse 16, 4123 Allschwil Switzerland

Barbara Nuesslein-Hildesheim

Novartis Pharma AG, Metabolic, Cardiovascular and Endocrine Therapeutic Area, 4002 Basel, Switzerland

Patrick Bruneval

Service d'Anatomie Pathologique, Hôpital Broussais 96, Rue Didot, Paris, France

Jean-Paul Clozel

Actelion Ltd/Innovation Centre, Gewerbestrasse 16, 4123 Allschwil Switzerland

There is increasing evidence to suggest endothelial dysfunction as a critical factor in vascular diseases. Genetically predisposed spontaneously hypertensive rats (SHR) treated with inhibitors of nitric oxide (NO) synthase, develop a severe hypertensive nephrosclerosis without the necessity for surgical reduction in renal mass, nephrectomy, renal infarction or nephrotoxic drugs. In these animals, endothelial dysfunction is considered a valid model for assessment of the efficacy of cardiovascular therapy. SHR were treated with either the angiotensin-converting enzyme inhibitor enalapril or the angiotensin II (Ang II) AT₁-receptor antagonist (AIIA) valsartan at sub-hypotensive doses and the effects on survival rates, cardiac and renal changes were monitored. Rats treated with valsartan, alone or in combination with enalapril, showed markedly higher survival rates (67—85%, respectively) than untreated animals (37%) or those treated with enalapril alone (55%). Valsartan at a dose which attenuated blood pressure increase led to even greater survival rates (95%). Despite these improved survival rates, at non-hypotensive doses the drugs had no effect on histological appearance, nor was kidney function improved. Plasma creatinine levels were reduced by valsartan, alone or in combination with enalapril, but proteinuria persisted with all treatments over the 12 weeks of the study. Aldosterone levels were significantly reduced by all treatments. The results suggest a beneficial role for endothelium in hypertension. Reduced renal perfusion pressure probably underlies the beneficial renal effects of high-dose valsartan.

Key Words: angiotensin • angiotensin receptor antagonist • angiotensin converting enzyme • nitric oxide synthase • nitric oxide • L-NAME • hypertension • renoprotection

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Journal of Renin-Angiotensin-Aldosterone System, Vol. 1, No. 2, 151-158 (2000)
DOI: 10.3317/jraas.2000.019


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