|
Sign In to gain access to subscriptions and/or personal tools.
|
Studies on Coronary Arteriopathy in Dogs Following Administration of CI-1020, an Endothelin A Receptor Antagonist
Mudher A. Albassam
Pfizer Global Research and Development, Ann Arbor, Michigan, 48105, mudher.albassam{at}pfizer.com
Alan L. Metz
Pfizer Global Research and Development, Ann Arbor, Michigan, 48105
Ronald E. Potoczak
Pfizer Global Research and Development, Ann Arbor, Michigan, 48105
Kim P. Gallagher
Pfizer Global Research and Development, Ann Arbor, Michigan, 48105
Stephen Haleen
Pfizer Global Research and Development, Ann Arbor, Michigan, 48105
Hussein Hallak
Pfizer Global Research and Development, Ann Arbor, Michigan, 48105
Edward J. Mcguire
Pfizer Global Research and Development, Ann Arbor, Michigan, 48105
A selective nonpeptide endothelin A (ETA) receptor antagonist, CI-1020, was administered to beagle dogs intravenously (iv) for 4 hours to 4 weeks. One animal/sex received CI-1020 at 1 mg/kg/hr intravenously for 4, 8, or 24 hours to investigate onset of arteriopathy. Control animals (1/sex) received the vehicle only. To determine reversibility of arteriopathy, 8 dogs/sex were given CI-1020 at 1 mg/kg/hr for 4 days. Two dogs/sex were sacrifi ced 1, 3, 8, and 29 days following cessation of infusion. Lesion development with prolonged exposure was investigated in 1 male dog. It was given CI-1020 by iv bolus at 120 mg/kg/day for 4 weeks and Monastral blue dye was administered iv to facilitate localization of vascular lesions. Coronary blood fl ow was determined in 4 dogs infused with CI-1020 at 0.3, 3, and 30 mg/kg for one hour at each dose. Macroscopically, hemorrhage or blue discoloration of Monastral blue was noted in the extramural coronary arteries along the coronary groove and atrium. Histologically, the earliest coronary changes were noted in animals sacrifi ced after 24 hours of treatment and characterized by medial hemorrhage and necrosi s with a few infi ltrating neutrophils. In the reversibility study, incidence and severity of arteriopathy was dependent on time of sacrifi ce following cessation of infusion. Acute necrotizing infl ammation of arteries was present in all animals (n = 4) on day 1 postinfusion, whereas on day 8 postinfusion, lesions characterized by medial small pockets of trapped red cells, cell debris, and adventitial thickening were seen in 1 dog/sex. By day 29 postinfusion, coronary arteries were similar to controls. In the dog given daily IV bolus injections of CI-1020 for 4 weeks, arterial infl ammatory lesions varied from acute to chronic, although most lesions were considered chronic active. Monastral blue pigments were noted in the wall of most arteries with chronic or chronic active lesions. Acute lesions were similar to those noted in day 1 postinfusion of the reversibility study. Medial smooth muscle necrosis and/or fi brosis with mixed infl ammatory cell infi ltrates characterized chronic or chronic active lesions. Smooth muscle proliferation and migration into the intima were also noted. There were no signifi cant changes in coronary blood fl ow, coronary vascular resistance, or mean arterial blood pressure following CI-1020 infusion for 3 hours. In the 24-hour infusion study, plasma endothelin 1 (ET-1) levels were mildly elevated (1.5—4 fold) during CI-1020 infusion when compared to either pretest or control values. These results indicate that administration of endothelin antagonist (CI-1020) to dogs was associated with development of coronary arteriopathy, which was completely resolved within 29 days following cessation of treatment. With prolonged (4-week) CI-1020 treatment, arterial lesions at varying stages of development (acute, chronic active, chronic) were seen, suggesting that tolerance to treatment (up to 4 weeks) does not occur.
Key Words: Endothelin A • endothelin A receptor • arteriopathy • medial necrosis • vasculitis • arteritis • endothelin receptor blockade • PD 156707 • reversibility
References
- Albassam MA, Metz AL, Gragtmans NJ, King LM, Macallum GE, Hallak H., McGuire EJ (1999). Coronary arteriopathy in monkey s following administration of CI-1020, an endotheli n A receptor antagonist. Toxicol Pathol 27: 156—164.[Abstract/Free Full Text]
- Boor PJ, Gotlieb AI, Joseph EC, Kerns WD, Roth RA, Tomaszewski KE (1995). Chemical-induced vasculature injury. Summary of the symposium presented at the 32nd annual meeting of the Society of Toxicology, New Orleans, Louisiana, March 1993. Toxicol Appl Pharmacol132: 177— 195.
- Bradbury P., Gordon K. (1977). Connective tissue and stains. In: Theory and Practice of Histological Techniques, BancroftJD, Stevens A (eds). Churchill Livingstone, New York, pp 95—112.
- 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]
- Haleen SJ, Cheng X-M. (1997). Cardiopulmonary indications forendothelin receptor antagonists: Review of recent effi cacy trials. Expert Opin Invest Drugs 6: 475—487.[CrossRef][Medline]
[Order article via Infotrieve]
- Hartman HA (1987). Idiopathic extramural coronary arteritis in beagle and mongrel dogs. Vet Pathol 24: 537—544.[Abstract]
- Ihara M., Noguchi K., Saeki T., Fukuroda T., Tsuchida S., Kimura S., Fukami T., Ishikawa K., Nishikibe M., Yano M. ( 1992). Biological profi les of highly potent novel endothelin antagonists selective for the ET(A) receptor. Life Sci 50: 247—255.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Isaacs KR, Joseph EC, Betton GR (1989). Coronary vascular lesions in dogs treated with phosphodiesteras e III inhibitors. Toxicol Pathol 17: 153—163.[Web of Science][Medline]
[Order article via Infotrieve]
- Joseph EC, Jones HB, Kerns WD (1996). Characterization of coronary arterial lesions in the dog following administration of SK&F 95654, a phosphodiesteras e III inhibitor. Toxicol Pathol 24: 429—435.[Abstract/Free Full Text]
- Louden C., Nambi P., Branch C., Gossett K., Pullen M., Eustis S., Solleveld HA (1998). Coronary arterial lesions in dogs treated with an endothelin 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, Piper RC, DuCharme DW, Carlson RG, Humphrey SJ, Zins GR ( 1989). Pathogenesis of cardiovascular alterations in dogs treated with minoxidil. Toxicol Pathol 17: 164—180.[Web of Science][Medline]
[Order article via Infotrieve]
- Mesfin GM, Shawaryn GG, Higgins MJ (1987). Cardiovascular alterations in dogs treated with hydralazine. Toxicol Pathol 15: 409—416.[Web of Science][Medline]
[Order article via Infotrieve]
- Metz AL, Dominick MA (1991). Acute cardiovascular toxicity induced by an adenosine agonist-antihypertensive in beagles. Toxicol Pathol 19: 98— 107.
- Miller RC, Pelton JT, Huggins JP (1993). Endothelins—From receptors to medicine. Trends Pharmacol Sci 14: 54—60.[CrossRef][Medline]
[Order article via Infotrieve]
- Newby AC, Zaltsman AB (2000). Molecular mechanisms in intimal hyperplasia. J Pathol 190: 300—309.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Reynolds EE, Keiser JA, Haleen SJ, Walker DM, Olszewski B., Schroeder RL, Taylor DG, Hwang O., Welch KM, Flynn MA, Thompson DM, Edmunds JJ, Berryman KA, Plummer M., Cheng X-M., Patt WC, Doherty AM (1995). Pharmacological characterization of PD 156707, an orally active ETA receptor antagonist. J Pharmacol Exp Ther 273: 1410— 1417.
- Rossi GL (1975). Simple apparatus for perfusion fi xation for electron microscopy. Experientia 31: 998—1000.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Sandusky GE, Means JR, Todd GC ( 1990). Comparative cardiovasculartoxicity in dogs given inotropic agents by continuous infusion. Toxicol Pathol 18: 268—278.[Web of Science][Medline]
[Order article via Infotrieve]
- Sims FH (1989). A comparison of structural features of the walls of coronary arteries from 10 different species. Pathology 21: 115—124.[Web of Science][Medline]
[Order article via Infotrieve]
- Sims FH, Gavin JB, Vanderwee MA (1989). The intima of human coronary arteries. Am Heart J 118: 32—38.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Stephan-Gueldner M., Inomata A. (2000). Coronary arterial lesions induced by endothelin antagonists. Toxicol Lett 112—113: 531—535.[CrossRef]
- Thyberg J. (1998). Phenotypic modulation of smooth muscle cells during formation of neointimal thickenings following vascular injury. Histol Histopathol 13: 871—891.[Web of Science][Medline]
[Order article via Infotrieve]
- Turk JR (1998). Physiologic and pathophysiologic effects of endothelin: Implications in cardiopulmonary disease. J Am Vet Med Assoc 212: 265— 270.
- Uprichard ACG, Metz AL, Hallak H., Haleen SJ (1998). PD 156707: A selective endothelin-A receptor antagonist. Cardiovasc Drug Rev 16: 89— 104.
- Zalewski A., Shi Y. (1997). Vascular myofi broblasts. Lessons from coronary repair and remodeling. Arterioscler Thromb Vasc Biol 17: 417—422.[Free Full Text]
Toxicologic Pathology, Vol. 29, No. 3,
277-284 (2001)
DOI: 10.1080/019262301316905228
 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]
|
|
|
|
|
|
|
H. B. Jones, A. Macpherson, G. R. Betton, A. S. Davis, R. Siddall, and P. Greaves
Endothelin Antagonist-Induced Coronary and Systemic Arteritis in the Beagle Dog
Toxicol Pathol,
April 1, 2003;
31(3):
263 - 272.
[Abstract]
[PDF]
|
|
|
|
|
