Mechanisms and biomarkers of cardiovascular injury induced by phosphodiesterase inhibitor III SK&F 95654 in the spontaneously hypertensive rat.
The cardiovascular injury of the type III selective PDE inhibitor SK&F 95654 was investigated in SHR. Twenty-four hours after a single sc injection of 100 or 200 mg/kg of the drug, rats exhibited cardiomyocyte necrosis and apoptosis, interstitial inflammation, hemorrhage and edema, as well as mesenteric arterial hemorrhage and necrosis, periarteritis, EC and VSMC apoptosis, EC activation, and MC activation and degranulation. Elevated serum levels of cTnT and decreased cTnT immunoperoxidase staining on cardiomyocytes were detected in the drug-treated rats. Serum levels of alpha2-macroglobulin and IL-6 were significantly elevated following drug treatment. NMR spectral patterns of urine samples are significantly different between the drug-treated and control rats. These results indicate that measurement of serum cTnT, acute phase proteins, and cytokines as well as metabonomic urine profiles may serve as potential biomarkers for drug-induced cardiovascular injury in rats. Increased expression of CD63 on MC (tissue biomarker of MC), of nitrotyrosine on MC and EC (an indirect indicator of NO in vivo), and of iNOS on MC and EC (source of NO) suggest that NO produced by activated and degranulated MC as well as activated EC play an important role in SK&F 95654-induced mesenteric vascular injury.
Zhang
Jun
J
Division of Applied Pharmacology Research (HFD-910), Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland 20993, USA. jun.zhang@fda.hhs.gov
Herman
Eugene H
EH
Robertson
Donald G
DG
Reily
Michael D
MD
Knapton
Alan
A
Ratajczak
Helen V
HV
Rifai
Nader
N
Honchel
Ronald
R
Blanchard
Kerry T
KT
Stoll
Raymond E
RE
Sistare
Frank D
FD
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000032:analysis*; D002318:Cardiovascular Diseases / Q000097:blood / Q000139:chemically induced* / Q000652:urine; D002319:Cardiovascular System / Q000187:drug effects* / Q000473:pathology; D003401:Creatine / Q000652:urine; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006626:Hippurates / Q000652:urine; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000473:pathology; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000633:toxicity*; D011724:Pyridazines / Q000494:pharmacology / Q000633:toxicity*; D011725:Pyridines / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D011918:Rats, Inbred SHR; D013654:Taurine / Q000652:urine; D014336:Troponin / Q000032:analysis / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D000511:alpha-Macroglobulins / Q000032:analysis
D015415:Biomarkers; D006626:Hippurates; D015850:Interleukin-6; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D011725:Pyridines; D014336:Troponin; D014409:Tumor Necrosis Factor-alpha; D000511:alpha-Macroglobulins; C060368:SK&F 95654; D013654:Taurine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003401:Creatine; C030514:hippuric acid