title: Natriuretic Peptides as Cardiovascular Safety Biomarkers in Rats: Comparison With Blood Pressure, Heart Rate, and Heart Weight.
abstract: Cardiovascular (CV) toxicity is an important cause of failure during drug development. Blood-based biomarkers can be used to detect CV toxicity during preclinical development and prioritize compounds at lower risk of causing such toxicities. Evidence of myocardial degeneration can be detected by measuring concentrations of biomarkers such as cardiac troponin I and creatine kinase in blood; however, detection of functional changes in the CV system, such as blood pressure, generally requires studies in animals with surgically implanted pressure transducers. This is a significant limitation because sustained changes in blood pressure are often accompanied by changes in heart rate and together can lead to cardiac hypertrophy and myocardial degeneration in animals, and major adverse cardiovascular events (MACE) in humans. Increased concentrations of NPs in blood correlate with higher risk of cardiac mortality, all-cause mortality, and MACE in humans. Their utility as biomarkers of CV function and toxicity in rodents was investigated by exploring the relationships between plasma concentrations of NTproANP and NTproBNP, blood pressure, heart rate, and heart weight in Sprague Dawley rats administered compounds that caused hypotension or hypertension, including nifedipine, fluprostenol, minoxidil, L-NAME, L-thyroxine, or sunitinib for 1-2 weeks. Changes in NTproANP and/or NTproBNP concentrations were inversely correlated with changes in blood pressure. NTproANP and NTproBNP concentrations were inconsistently correlated with relative heart weights. In addition, increased heart rate was associated with increased heart weights. These studies support the use of natriuretic peptides and heart rate to detect changes in blood pressure and cardiac hypertrophy in short-duration rat studies.
authors.affiliation: Lilly Research Laboratories, Division of Eli Lilly and Company, Indianapolis, Indiana 46285 englesk@lilly.com davewatson@lilly.com.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Engle
authors.affiliation: Lilly Research Laboratories, Division of Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: David E
authors.initials: DE
authors.lastname: Watson
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood*; D015415:Biomarkers; D001794:Blood Pressure / Q000187:drug effects*; D006332:Cardiomegaly / Q000139:chemically induced*; D006339:Heart Rate / Q000187:drug effects*; D007211:Indoles / Q000633:toxicity; D008297:Male; D008914:Minoxidil / Q000633:toxicity; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity; D020097:Natriuretic Peptide, Brain / Q000097:blood*; D009543:Nifedipine / Q000633:toxicity; D009929:Organ Size / Q000187:drug effects; D010446:Peptide Fragments / Q000097:blood*; D011461:Prostaglandins F, Synthetic / Q000633:toxicity; D011758:Pyrroles / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077210:Sunitinib; D013974:Thyroxine / Q000633:toxicity
chemical_list: D015415:Biomarkers; D007211:Indoles; D010446:Peptide Fragments; D011461:Prostaglandins F, Synthetic; D011758:Pyrroles; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; C006326:fluprostenol; D008914:Minoxidil; D009320:Atrial Natriuretic Factor; D009543:Nifedipine; D013974:Thyroxine; D019331:NG-Nitroarginine Methyl Ester; D000077210:Sunitinib
keywords: biomarkers; cardiac hypertrophy; cardiovascular, blood pressure; natriuretic peptides; rat