The First Preclinical Pharmacotoxicological Safety Assessment of CGS 35601, a Triple Vasopeptidase Inhibitor, in Chronically Instrumented, Conscious, and Unrestrained Spontaneously Hypertensive Rats

Autor:	K. Belleville, R. Lepage, M. Beaudoin, Bruno Battistini, J. Cayer, F. Nantel, O. Benrezzak, A. Blouin, Pierre Sirois, Arco Y. Jeng, Philippe Daull
Rok vydání:	2006
Předmět:	Male medicine.medical_specialty Indoles Endothelin converting enzyme 1 Health Toxicology and Mutagenesis medicine.medical_treatment Drug Evaluation Preclinical Hemodynamics Angiotensin-Converting Enzyme Inhibitors Blood Pressure Endothelin-Converting Enzymes Toxicology Nephrotoxicity Heart Rate Rats Inbred SHR Internal medicine Heart rate medicine Animals Aspartic Acid Endopeptidases education Saline Pharmacology education.field_of_study Chemical Health and Safety Dose-Response Relationship Drug Molecular Structure biology business.industry Public Health Environmental and Occupational Health Metalloendopeptidases Angiotensin-converting enzyme General Medicine Rats Disease Models Animal Endocrinology Anesthesia Hypertension Toxicity biology.protein Neprilysin business Blood sampling
Zdroj:	Drug and Chemical Toxicology. 29:183-202
ISSN:	1525-6014 0148-0545
Popis:	CGS 35601 is a triple vasopeptidase inhibitor (VPI) of angiotensin-converting enzyme, neutral endopeptidase, and endothelin-converting enzyme-1 with respective IC50 values of 22, 2, and 55 nM. We characterized the safety profile and toxicity of escalating doses of CGS 35601 over a 20-day period in chronically instrumented, unrestrained, conscious, male, spontaneously hypertensive rats (SHR). Once instrumented with an arterial catheter, the SHR were placed in metabolic cages allowing daily assessment of hemodynamics and blood sampling for biochemical and hematological measurements. After a 7-day stabilization period, the SHR were divided into 2 groups: Gr. 1, (n = 13 to 18) receiving CGS 35601 at 0.01, 0.1, 1 and 5 mg kg(-1) day(-1) (continuous i.a. infusion) for 5 consecutive days/dose, followed by a 5-day washout; and Gr. 2, (n = 10) receiving vehicle (saline). The highest dose of CGS 35601 dose-dependently reduced MABP from 156 +/- 4 up to 94 +/- 5 mm Hg, whereas heart rate, metabolic, electrolytic, and hematological profiles, growth, diuresis, and renal activity were unaffected, and no hepatic or liver toxicities were observed. These results suggest that this novel triple VPI presents no safety concerns at this stage and may become of interest for the treatment of hypertension and other cardiovascular disorders. Long-term chronic experiments are needed to assess possible angioedema and increases in vascular permeability.
Databáze:	OpenAIRE
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