This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Jones, H. B. Articles by Greaves, P. Search for Related Content PubMed PubMed Citation Articles by Jones, H. B. Articles by Greaves, P. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Social Bookmarking                         What's this?

Endothelin Antagonist-Induced Coronary and Systemic Arteritis in the Beagle Dog

Safety Assessment, AstraZeneca UK Ltd, Alderley Park, Macclesfield SK10 4TG, Cheshire, United Kingdom, Huw.Jones{at}AstraZeneca.com

Allen Macpherson

Safety Assessment, AstraZeneca UK Ltd, Alderley Park, Macclesfield SK10 4TG, Cheshire, United Kingdom

Graham R. Betton

Safety Assessment, AstraZeneca UK Ltd, Alderley Park, Macclesfield SK10 4TG, Cheshire, United Kingdom

A. Stewart Davis

Animal Welfare Group, AstraZeneca UK Ltd, Alderley Park, Macclesfield SK10 4TG, Cheshire, United Kingdom

Robert Siddall

Safety Assessment, AstraZeneca UK Ltd, Alderley Park, Macclesfield SK10 4TG, Cheshire, United Kingdom

Peter Greaves

MRC Toxicology Unit, Hodgkin Building, University of Leicester, PO Box 138, Lancaster Road, Leicester LE1 9HN, United Kingdom

Two endothelin antagonists, ZD1611 (3-{4-[3-(3-methoxy-5-methylpyrazin-2-ylsulfamoyl)-2-pyridyl]phenyl }-2,2-dimethylpropanoic acid) and ZD2574 (2-(4-isobutylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide), selective for the ETA receptor and intended for use in pulmonary hypertension, were tested in Beagle dogs at various doses for periods of up to 4 weeks. These studies included in vivo telemetric hemodynamic assessment, full histopathological and ultrastructural pathological evaluation of coronary arteries. Both drugs produced arteritis in small- and medium-sized coronary arteries after single or multiple doses, some of which were at or below the ED50. The distribution of lesions was predominantly in extramural arteries over the atria and atrioventricular groove of the right side of the heart and consisted of epicardial hemorrhage and arteritis. Systemic arteritis was also present at a lower incidence than the coronary arteritis, was located at different sites and appeared inconsistently. Ultrastructural changes in coronary arteries suggested that damage was the result of mechanical factors. Although these patterns of vascular injury possessed features in common with those induced in dogs by high doses of vasodilating antihypertensive drugs and inotropic agents, they were atypical, as there was no left ventricular myocardial necrosis, papillary muscle damage, or subendocardial hemorrhage suggestive of ischaemia or excessive inotropism. Moreover, physiological monitoring showed no evidence of exaggerated systemic hypotension or reflex tachycardia at doses associated with vascular damage. Consequently, the changes might be the result of a localized pharmacological process such as intense, prolonged vasodilatation in unsupported arteries that are well endowed with endothelin receptors and particularly sensitive to endothelin antagonism.

Key Words: Arteritis • arteriopathy • vasculitis • dog • pathology • electron microscopy.

References

• Albassam MA, Metz AL, Gragtmans NJ, King LM, Macallum GE, Kallak H., McGuire EJ (1999). Coronary arteriopathy in monkeys following administration of CI-1020, an endothelin A receptor antagonist. Toxicol Pathol 27: 156—164.[Abstract/Free Full Text]
• Albassam MA, Metz AL, Potoczak RE, Gallagher KP, Haleen S., Hallak H., McGuire EJ (2001). Studies on coronary arteriopathy in dogs following administration of CI-1020, an endothelin A receptor antagonist. Toxicol Pathol 29: 277—284.[Abstract/Free Full Text]
• Borges R., Von Grafenstein H., Knight DE (1989). Tissue selectivity of endothelin. Eur J Pharmacol 165: 223—231.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Brain SD, Tippins JR, Williams TJ (1988). Endothelin induces potent microvascular constriction. Br J Pharmacol 95: 1005—1010.[Web of Science][Medline] [Order article via Infotrieve]
• Carlson RG, Feenstra ES (1977). Toxicologic studies with the hypotensive agent minoxidil. Toxicol Appl Pharmacol 39: 1—11.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Cocks TM, Faulkner NL, Sudhir K., Angus J. (1989). Reactivity of endothelin-1 on human and canine large veins compared with large arteries in vitro. Eur J Pharmacol 171: 17—25.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Criteria Committee of the New York Association ( 1973). Nomenclature and Criteria for diagnosis of diseases of the heart and great vessels (7th ed). Little, Brown, Boston, p 286.
• Davenport AP, Kuc RE, Maguire JJ, Harland SP (1995). ETA receptors predominate in the human vasculature and mediate constriction. J Cardiovasc Pharmacol 26(Suppl 3): S265—S267.[Web of Science][Medline] [Order article via Infotrieve]
• Detweiler DK (1989). Spontaneous and induced arterial disease in the dog: Pathology and pathogenesis. Toxicol Pathol 17: 94—108.[Web of Science][Medline] [Order article via Infotrieve]
• Dogterom P., Zbinden G., Reznik GK (1992). Cardiotoxicity of vasodilators and positive inotropic/vasodilating drugs in dogs: An overview. Crit Revs Toxicol 22: 203—241.
• D'Orleans-Juste P., De Nucci G., Vane JR (1989). Endothelin-1 contracts isolated vessels independently of dihydropyridine-sensitive Ca2+ channel activation. Eur J Pharmacol 165: 289—295.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Douglas SA (1997). Clinical development of endothelin receptor antagonists. Trends in Pharmacological Sciences 18: 408—412.[Medline] [Order article via Infotrieve]
• Gans JH, Korson R., Cater MR, Ackerly CC (1980). Effects of short term and long term theobromine administration to male dogs. Toxicol Appl Pharmacol 53: 481—496.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Greaves P. (1998). Patterns of drug-induced cardiovascular pathology in the beagle dog: Relevance for humans. Exp Toxicol Pathol 50: 283—293.[Web of Science][Medline] [Order article via Infotrieve]
• Hartman HA (1987). Idiopathic extramural coronary arteritis in Beagle and mongrel dogs. Vet Pathol 24: 537—544.[Abstract]
• Hayes TJ, Roberts GKS, Halliwell WH (1989). An idiopathic febrile necrotising arteritis syndrome in the dog: Beagle Pain Syndrome. Toxicol Pathol 17: 129—137.[Web of Science][Medline] [Order article via Infotrieve]
• Haynes WG, Webb DJ ( 1993). The endothelin family of peptides: Local hormones with diverse roles in health and disease. Clin Sci 84: 485— 500.
• Isaacs KR, Joseph EC, Betton GR (1989). Coronary vascular lesions in dogs treated with phosphodiesterase III inhibitors. Toxicol Pathol 17: 153— 163.
• Joseph EC, Jones HB, Kerns WD (1996). Characterisation of coronary arterial lesions in the dog following administration of SK&F95654, a phosphodiesterase III inhibitor. Toxicol Pathol 24: 429—435.[Abstract/Free Full Text]
• Louden C., Nambi P., Branch C., Gossett K., Pullen M., Eustis S., Solleveld H. (1998). Coronary arterial lesions in dogs treated with an endothelial receptor antagonist. J Cardiovasc Pharmacol 31(Suppl 1): S384—S385.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Louden CS, Nambi P., Pullen MA, Thomas RA, Tierney LA, Solleveld HA, Schwartz LW (2000). Endothelin receptor subtype distribution predisposes coronary arteries to damage. Am J Pathol 157: 123—134.[Abstract/Free Full Text]
• Mesfin GM, Shawaryn GG, Higgins MJ (1987). Cardiovascular alterations in dogs treated with hydralazine. Toxicol Pathol 15: 405—430.
• Mesfin GM, Robinson FG, Higgins MJ, Zhong W-Z., DuCharme DW (1995). The pharmacologic basis of the cardiovascular toxicity of minoxidil in the dog. Toxicol Pathol 23: 498—505.[Abstract/Free Full Text]
• Mesfin GM, Higgins MJ, Robinson FG, Zhong W-Z. (1996). Relationship between serum concentrations, hemodynamic effects and cardiovascular lesions in dogs treated with minoxidil. Toxicol Appl Pharmacol 140: 337— 344.
• Metz AL, Dominick MA, Suchanek G., Gough AW (1991). Acute cardiovascular toxicity induced by an adenosine agonist-antihypertensive in beagles. Toxicol Pathol 19: 98—107.[Web of Science][Medline] [Order article via Infotrieve]
• Ruffolo RR (1995). Endothelin receptors. In: Endothelin Receptors. From the Gene to the Human, Ruffolo RR (ed). CRC Press, Boca Raton, pp 1—14.
• Schluter G. (1986). Toxicological investigations with nimodipine. Summary of relevant studies. Arzneimittelforschung 36: 1733—1735.[Medline] [Order article via Infotrieve]
• Uprichard ACG, Metz AL, Hallak H., Haleen SJ (1998). PD156707: A selective endothelin-A receptor antagonist. Cardiovasc Drug Rev 16: 89— 104.
• USA Food and Drug Administration, Center for Drug Evaluation and Research (2001). Bosentan Advisory Committee, 93rd Meeting, August 10th, 2001, Washington, DC.

Toxicologic Pathology, Vol. 31, No. 3, 263-272 (2003)
DOI: 10.1080/01926230390204298


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				C. Louden, D. Brott, A. Katein, T. Kelly, S. Gould, H. Jones, G. Betton, J.-P. Valetin, and R. J. Richardson Biomarkers and Mechanisms of Drug-Induced Vascular Injury in Non-Rodents Toxicol Pathol, January 1, 2006; 34(1): 19 - 26. [Abstract] [Full Text] [PDF]

This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Jones, H. B. Articles by Greaves, P. Search for Related Content PubMed PubMed Citation Articles by Jones, H. B. Articles by Greaves, P. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Social Bookmarking                         What's this?