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THE ROLE OF SHEAR STRESS RESPONSE GENES IN SK&F-82526-J (FENOLDOPAM) INDUCED MESENTERIC VASCULAR INJURY OF RATS. K Roland1, C Beck2 1Safety Assessment, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA,
2Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA
Select shear stress responsive genes (in vitro) were identified through a literature search and a subset was used to investigate if shear stress played a role in Fenoldopam induced mesenteric vasculature damage in rats. To address if shear stress plays a role in the development of mesenteric arterial lesions induced by Fenoldopam, endothelial and vascular smooth muscle cells were collected from the mesenteric vasculature of rats given a single subcutaneous injection of 0 or 100 mg/kg Fenoldopam and killed 1, 4 or 12 hours postdose. RNA was isolated, amplified gene expression of a number of shear stress responsive genes was determined using quantitative RT PCR analysis (TaqMan®) at each timepoint. Differential expression (> or < 2-fold from concurrent controls) was noted in 34 of 36 tested genes in EC enriched samples and 33 of 36 tested genes in VSMC enriched samples. Evaluation of data indicates that shear stress may be a contributing factor to Fenoldopam-induced lesion formation (medial necrosis and hemorrhage) first noted in samples at 12 hours postdose and that differential expression possibly due to increased shear stress can be noted as early as 1 hour postdose.
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