Endothelial Hypertrophy in Acute Phase of Arteritis Induced by Fenoldopam, a Vasodilator, in Rats.

Ikegami, Hiroki; Kajikawa, Satoru; Miura, Hisaki; Ito, Kyoko; Okamiya, Hideaki; Nakayama, Hiroyuki; Doi, Kunio

doi:10.1293/tox.15.119

Cited by 3 publications

(4 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Endothelial hypertrophy has been observed in the capillaries of the parotid glands of rats treated with isoproterenol and in the pancreatic arteries of rats infused with fenoldopam ( Hand and Ho 1985 ; Ikegami 2002 ). The endothelium of fenoldopam-treated pancreatic arteries was immunohistochemically observed to have increased vWF and Factor VIII content compared to saline controls; this was interpreted to be the result of increased protein synthesis.…”

Section: Nomenclature Diagnostic Criteria and Differential Diagnosementioning

confidence: 99%

See 1 more Smart Citation

Non-proliferative and Proliferative Lesions of the Cardiovascular System of the Rat and Mouse

Berridge

Mowat²,

Nagai

et al. 2016

J Toxicol Pathol

View full text Add to dashboard Cite

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Japan (JSTP), Europe (ESTP), Great Britain (BSTP) and North America (STP) to develop an internationally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory animals. The primary purpose of this publication is to provide a standardized nomenclature for characterizing lesions observed in the cardiovascular (CV) system of rats and mice commonly used in drug or chemical safety assessment. The standardized nomenclature presented in this document is also available electronically for society members on the internet (http://goreni.org). Accurate and precise morphologic descriptions of changes in the CV system are important for understanding the mechanisms and pathogenesis of those changes, differentiation of natural and induced injuries and their ultimate functional consequence. Challenges in nomenclature are associated with lesions or pathologic processes that may present as a temporal or pathogenic spectrum or when natural and induced injuries share indistinguishable features. Specific nomenclature recommendations are offered to provide a consistent approach.

show abstract

Section: Nomenclature Diagnostic Criteria and Differential Diagnosementioning

confidence: 99%

“…It also often accompanies medial necrosis and may be a component of medial inflammation. Arterial medial necrosis and hemorrhage is best exemplified by the arterial lesions seen in rats given intravenous infusions of the dopaminergic vasodilator fenoldopam ( Ikegami 2002 ; Yuhas et al 1985 ).…”

Section: Nomenclature Diagnostic Criteria and Differential Diagnosementioning

confidence: 99%

Non-proliferative and Proliferative Lesions of the Cardiovascular System of the Rat and Mouse

Berridge

Mowat²,

Nagai

et al. 2016

J Toxicol Pathol

View full text Add to dashboard Cite

show abstract

“…The most frequent vascular toxicity is vasculitis, which is induced by a number of drugs such as potassium channel opener 49 , 50 , adenosine agonists 51 , endothelin receptor antagonists 52 , 53 , dopaminergic agonists 54 , and quite often by PDE inhibitors 55 – 60 . An example of a subacute arteritis/periarteritis in the kidney of a rat treated with an undisclosed drug is shown in Fig.…”

Section: Examples Of Addressing Apfsmentioning

confidence: 99%

Successful Drug Development Despite Adverse Preclinical Findings Part 2: Examples

Ettlin¹,

Kuroda

Plassmann³

et al. 2010

J Toxicol Pathol

View full text Add to dashboard Cite

To illustrate the process of addressing adverse preclinical findings (APFs) as outlined in the first part of this review, a number of cases with unexpected APF in toxicity studies with drug candidates is discussed in this second part. The emphasis is on risk characterization, especially regarding the mode of action (MoA), and risk evaluation regarding relevance for man. While severe APFs such as retinal toxicity may turn out to be of little human relevance, minor findings particularly in early toxicity studies, such as vasculitis, may later pose a real problem. Rodents are imperfect models for endocrine APFs, non-rodents for human cardiac effects. Liver and kidney toxicities are frequent, but they can often be monitored in man and do not necessarily result in early termination of drug candidates. Novel findings such as the unusual lesions in the gastrointestinal tract and the bones presented in this review can be difficult to explain. It will be shown that well known issues such as phospholipidosis and carcinogenicity by agonists of peroxisome proliferator-activated receptors (PPAR) need to be evaluated on a case-by-case basis. The latter is of particular interest because the new PPAR α and dual α/γ agonists resulted in a change of the safety paradigm established with the older PPAR α agonists. General toxicologists and pathologists need some understanding of the principles of genotoxicity and reproductive toxicity testing. Both types of preclinical toxicities are major APF and clinical monitoring is difficult, generally leading to permanent use restrictions.

show abstract

“…TOXICOLOGIC PATHOLOGY Bilato and Crow (1996) note that many of the structural alterations in great vessels that are attributable to aging may also affect the arteriolar bed. Ikegami et al (2002) induced reversible endothelial cell hypertrophy and widening of the subendothelial space in the mesenteric and pancreatic arteries by a twenty-four-hour continuous infusion of the dopamine agonist and vasodilator fenoldopam in male F344 rats. Increased rough endoplasmic reticulum and enlarged nucleoli were observed in the endothelium at one and three days postinfusion, whereas amorphous, electron-dense material was seen in the subendothelial space at three days postinfusion.…”

Section: Spontaneous Vascular Pathology In the Skin Of The Rat Dorsummentioning

confidence: 99%

Histomorphology and Vascular Lesions in Dorsal Rat Skin Used as Injection Sites for a Subcutaneous Toxicity Study

Wells¹,

Voute²,

Bellingard

et al. 2010

Toxicol Pathol

View full text Add to dashboard Cite

Subcutaneous injection of pharmaceutical compounds into the dorsal skin of rats is common in preclinical and nonclinical studies. However, no detailed histologic description of this anatomic location has been published to date. Following the observation of vascular lesions in the dorsum of rats in a thirteen-week toxicity study, a complementary study was performed on untreated Sprague-Dawley rats to evaluate the normal histology of the skin and subcutis, the potential effect of chronic subcutaneous injection on the morphology of the skin and its vasculature, and the spontaneous vascular pathology in the areas used as injection sites in the principal study. This study showed that saline injection did not fundamentally alter the morphology of the injection sites used for the principal study. Skin thickness was greater in males than in females. Although acellular intimal thickening occurred spontaneously in the dorsal skin of untreated males and females, only males had a spontaneous incidence of intimal hyperplasia. No site predilection for intimal lesions was apparent for either sex. Saline injection, or the physical trauma of injection, may induce intimal hyperplasia; males appear more likely to develop the lesion than do females. It is possible that acellular intimal thickening can progress to intimal hyperplasia under appropriate conditions.

show abstract

Endothelial Hypertrophy in Acute Phase of Arteritis Induced by Fenoldopam, a Vasodilator, in Rats.

Cited by 3 publications

References 9 publications

Non-proliferative and Proliferative Lesions of the Cardiovascular System of the Rat and Mouse

Non-proliferative and Proliferative Lesions of the Cardiovascular System of the Rat and Mouse

Successful Drug Development Despite Adverse Preclinical Findings Part 2: Examples

Histomorphology and Vascular Lesions in Dorsal Rat Skin Used as Injection Sites for a Subcutaneous Toxicity Study

Contact Info

Product

Resources

About