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VASCULAR AND HYPERTENSION

The Hemodynamic and Metabolic Profiles of Zucker Diabetic Fatty Rats Treated with a Single Molecule Triple Vasopeptidase Inhibitor, CGS 35601

P. Daull^*, A. Blouin, M. Beaudoin, S. Gadbois, K. Belleville, J. Cayer, N. Berthiaume, P. Sirois, F. Nantel, A. Y. Jeng and B. Battistini^*,,1

^* Laval Hospital Research Center, Quebec Heart & Lung Institute, Department of Medicine, Laval University, Quebec, QC, Canada G1V 4G5; IPS Pharma Inc., Sherbrooke, QC, Canada J1H 5N4; Institute of Pharmacology of Sherbrooke, Sherbrooke, QC, Canada J1H 5N4; and 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, QC, Canada, G1V 4G5. E-mail: bruno.battistini{at}med.ulaval.ca

Abstract

CGS 35601 is a triple vasopeptidase inhibitor (VPI) of angiotensin converting enzyme (ACE), neutral endopeptidase (NEP), and endothelin (ET) converting enzyme-1 (ECE-1), with respective IC₅₀ values of 22, 2, and 55 nM. The aim of the present study was to establish the hemodynamic profile of Zucker diabetic fatty (Zdf)-Fatty rats, a high-fat diet gene-prone model developing spontaneous Type 2 diabetes (T2D) and the effects of CGS 35601. Male Zdf-Fatty (14 weeks, n = 17–23), Zdf-Lean (14 weeks, n = 8–10), and Wistar (14 weeks, n = 9–10) rats on distinct diets were implanted with a catheter in the left carotid and placed individually in a metabolic cage for 30 days. The hemodynamic profile and some metabolic biomarkers were assessed daily. After a 7-day stabilization period, the Zdf-Fatty rats were divided into two groups: Group 1, controls (n = 7–10) receiving vehicle-saline (250 µl/hr) and Group 2, (n = 10–13) receiving increasing doses of CGS 35601 (0.1, 1, and 5 mg/kg/day x 6 days each, intra-arterially) followed by a 5-day washout period. Mean arterial blood pressure (MABP) of young Zdf-Fatty rats was compared with age-matched Zdf-Lean and Wistar rats, which were found similar. MABP decreased by 5.9% (from baseline at 102 ± 5 to 96 ± 4 mmHg), 12.7% (to 89 ± 6 mmHg) and 21.6% (to 80 ± 4 mmHg), at 0.1, 1, and 5 mg/kg/day, respectively, in CGS 35601-treated Zdf-Fatty rats. Systolic and diastolic blood pressures were similarly reduced. The heart rate was not affected. Hyperglycemic status and insulin-resistance were not modulated by short-term treatment. CGS 35601 presented an excellent short-term safety profile. This novel molecule and class of VPI may be of interest for lowering vascular tone. Further long-term studies, once cardiovascular and renal complications have developed in this T2D rat model are warranted to define the efficacy of this class of VPI.

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, K. Belleville, M. Beaudoin, D. Arsenault, H. Leonard, P. Sirois, F. Nantel, A. Y. Jeng, and B. Battistini Triple VPI CGS 35601 Reduces High Blood Pressure in Low-Renin, High-Salt Dahl Salt-Sensitive Rats. Experimental Biology and Medicine, June 1, 2006; 231(6): 830 - 833. [Abstract] [Full Text] [PDF]