title: Hemodynamic correlates of drug-induced vascular injury in the rat using high-frequency ultrasound imaging.
abstract: Several classes of drugs have been shown to cause drug-induced vascular injury (DIVI) in preclinical toxicity studies. Measurement of blood flow and vessel diameter in numerous vessels and across various tissues by ultrasound imaging has the potential to be a noninvasive translatable biomarker of DIVI. Our objective was to demonstrate the utility of high-frequency ultrasound imaging for measuring changes in vascular function by evaluating blood flow and vessel diameter in the superior mesenteric arteries (SMA) of rats treated with compounds that are known to cause DIVI and are known vasodilators in rat: fenoldopam, CI-1044, and SK&F 95654. Blood flow, vessel diameter, and other parameters were measured in the SMA at 4, 8, and 24 hr after dosing. Mild to moderate perivascular accumulations of mononuclear cells, neutrophils in tunica adventitia, and superficial tunica media as well as multifocal hemorrhage and necrosis in the tunica media were found in animals 24 hr after treatment with fenoldopam and SK&F 95654. Each compound caused marked increases in blood flow and shear stress as early as 4 hr after dosing. These results suggest that ultrasound imaging may constitute a functional correlate for the microscopic finding of DIVI in the rat.
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut, USA.
authors.forename: Terri A
authors.initials: TA
authors.lastname: Swanson
authors.affiliation: FUJIFILM VisualSonics, Inc., Toronto, Ontario, Canada.
authors.forename: Teri
authors.initials: T
authors.lastname: Conte
authors.affiliation: FUJIFILM VisualSonics, Inc., Toronto, Ontario, Canada.
authors.forename: Ben
authors.initials: B
authors.lastname: Deeley
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Portugal
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Kreeger
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Obert
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut, USA.
authors.forename: E Clive
authors.initials: EC
authors.lastname: Joseph
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut, USA.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Wisialowski
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut, USA.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Sokolowski
authors.affiliation: Pfizer Worldwide Research and Development, Andover, Massachusetts, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Rief
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Nugent
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lawton
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut, USA bradley.e.enerson@pfizer.com.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Enerson
mesh_terms: D000818:Animals; D001381:Azepines / Q000009:adverse effects; D064420:Drug-Related Side Effects and Adverse Reactions; D018818:Fenoldopam / Q000009:adverse effects; D006439:Hemodynamics; D008297:Male; D008638:Mesenteric Arteries / Q000000981:diagnostic imaging / Q000187:drug effects; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives; D011724:Pyridazines / Q000009:adverse effects; D011725:Pyridines / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014463:Ultrasonography / Q000379:methods*; D057772:Vascular System Injuries / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000473:pathology*
chemical_list: D001381:Azepines; D011724:Pyridazines; D011725:Pyridines; C060368:SK&F 95654; D009536:Niacinamide; D018818:Fenoldopam; C418118:CI 1044
keywords: CI-1044; SK&F 95654; biomarker; drug-induced vascular injury; fenoldopam.; high-frequency ultrasound imaging