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Intimal Hyperplasia in Rats after Subcutaneous Injection of a Somatostatin Analog
1 Ipsen, Les Ulis, France Correspondence: Monique Y. Wells, 52, rue Lhomond, 75005 Paris, France; e-mail:mywells{at}toxpath.com. The somatostatin analog octreotide was administered to male and female Sprague-Dawley rats by subcutaneous injection for thirteen weeks at 0 (saline control), 0 (placebo control [mannitol and lactic acid; pH 4.2]), 1.25 mg/kg/day and 2.5 mg/kg/day to explore its potential effect on cutaneous vascular morphology. The placebo caused an increase in the incidence of intimal hyperplasia compared to saline controls in female rats; octreotide increased the incidence and severity of intimal hyperplasia in males and females. Intimal hyperplasia consisted of increased numbers of cells located between the endothelial cell layer and the internal elastic lamina. Severity was based on the degree of compromise of the vascular lumen (regardless of vessel size and number), with severely affected vessels having no visible lumen. Intimal hyperplasia in rats treated with octreotide was considered to be an unexpected and adverse finding, given that this compound and other somatostatin analogs have been investigated as reducers of intimal proliferation or restenosis after angioplasty in humans and that no such lesion has been reported in the literature for this class of compound to date. The induction of intimal hyperplasia by the placebo is also a notable finding; this may be because of the low pH of the formulation.
Key Words: intimal hyperplasia • subcutaneous injection • rat • somatostatin analog • octreotide Abbreviations: AAALAC, Association for Assessment and Accreditation of Laboratory Animal Care • bFGF, basic fibroblast growth factor • cAMP, cyclic adenosine monophosphate • DNA, deoxyribonucleic acid • GHIH, growth hormone inhibiting hormone • IS, injection site • mRNA, messenger ribonucleic acid • NaCl, sodium chloride • PDE, Phosphodiesterase • SD, Sprague-Dawley • SMC, smooth muscle cell(s) • SRIF, somatotropin release-inhibiting hormone • SSTR, somatostatin receptor • VEGF, vascular endothelial growth factor
This version was published on February
1, 2009 Toxicologic Pathology, Vol. 37, No. 2,
235-243 (2009) |
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