The hemodynamic and metabolic profiles of Zucker diabetic fatty rats treated with a single molecule triple vasopeptidase inhibitor, CGS 35601.
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 IC(50) 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 microl/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.
Daull
P
P
Laval Hospital Research Center, Quebec Heart & Lung Institute, Department of Medicine, Laval University, Pavilion Mallet-Room 2679, 2725 Chemin Ste-Foy, Ste-Foy, QC, Canada, G1V 4G5.
Blouin
A
A
Beaudoin
M
M
Gadbois
S
S
Belleville
K
K
Cayer
J
J
Berthiaume
N
N
Sirois
P
P
Nantel
F
F
Jeng
A Y
AY
Battistini
B
B
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000008:administration & dosage / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000378:metabolism*; D004338:Drug Combinations; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D007211:Indoles / Q000008:administration & dosage / Q000819:agonists; D008297:Male; D008666:Metalloendopeptidases / Q000008:administration & dosage / Q000494:pharmacology; D015260:Neprilysin / Q000008:administration & dosage / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker
C511403:CGS 35601; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007211:Indoles; D007703:Peptidyl-Dipeptidase A; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes