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VASCULAR AND HYPERTENSION

Triple VPI CGS 35601 Reduces High Blood Pressure in Low-Renin, High-Salt Dahl Salt-Sensitive Rats

P. Daull^*, A. Blouin, K. Belleville, M. Beaudoin, D. Arsenault^*, H. Leonard, P. Sirois, F. Nantel, A. Y. Jeng and B. Battistini^*,,1

^* Laval Hospital Research Center, Quebec Heart & Lung Institute, Department of Medicine, Faculty of Medicine, Laval University, Québec, Canada G1V 4G5; IPS Pharma Inc, Sherbrooke, Canada J1H 5N4; Institute of Pharmacology of Sherbrooke, Department of Pharmacology, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Canada J1H 5N4; and Cardiovascular Diseases Research, Novartis Institutes for BioMedical Research, East Hanover, New Jersey 07936

To whom requests for reprints should be addressed at ¹ Laval Hospital, Laval Hospital Research Center, Quebec Heart & Lung Institute, Pavilion Mallet-Room 2679, 2725 Chemin Ste-Foy, Ste-Foy, Canada, G1V 4G5. E-mail bruno.battistini{at}med.ulaval.ca

Abstract

We previously reported that CGS 35601, a potent triple inhibitor of angiotensin-converting enzyme, neutral endopeptidase, and endothelin-converting enzyme 1, completely normalized mean arterial blood pressure (MABP) in 36-week-old spontaneously hypertensive rats, a normal renin model. The aim of the present study was to determine the effects of this triple vasopeptidase inhibitor (VPI) on the hemodynamic profile of instrumented, conscious, and unrestrained Dahl salt-sensitive (DSS) rats, a gene-prone, high-salt diet–induced low-renin hypertension model. Male DSS rats (mean weight [±SEM], 385 ± 10 g) were fed a normal diet (Group 1) or a high-salt diet (Groups 2 and 3; 8% NaCl in food) for 6 weeks and then instrumented with a carotid catheter and placed individually in metabolic cages for 30 days. The hemodynamic, hematological, and biochemical profiles were assessed daily. Dose-dependent treatment started after a 7-day stabilization period in Groups 1 and 2 (vehicle dosage, 250 µl/hr) and Group 3 (CGS 35601 dosages of 0.1, 1, and 5 mg/kg/day for 6 days per dose by means of constant intra-arterial infusion), followed by a 5-day washout period. Two additional groups included normotensive Wistar rats (Group 4) and DSS rats that received a double high-salt solid (8% NaCl) and liquid (1% NaCl) diet (Group 5).The MABP in rats receiving CGS 35601 decreased in a dose-dependent fashion toward the baseline level observed in DSS rats receiving a normal diet. The heart rate was unaffected. The hemodynamic profile returned to normal during the washout period. This novel triple VPI is a potent and effective antihypertensive agent with a safe short-term profile that may be of interest for treating hypertension and other cardiovascular diseases. Other hypertensive rat models are being tested.

Key Words: angiotensin-converting enzyme • endothelin-converting enzyme • neutral endopeptidase 24.11 • vasopeptidase inhibitor CGS 35601

This article has been cited by other articles:

				P. Daull, A. Blouin, M. Beaudoin, S. Gadbois, K. Belleville, J. Cayer, N. Berthiaume, P. Sirois, F. Nantel, A. Y. Jeng, et al. The Hemodynamic and Metabolic Profiles of Zucker Diabetic Fatty Rats Treated with a Single Molecule Triple Vasopeptidase Inhibitor, CGS 35601. Experimental Biology and Medicine, June 1, 2006; 231(6): 824 - 829. [Abstract] [Full Text] [PDF]