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Published on: August 14, 2017
Evaluation of plasma von Willebrand factor as a biomarker for acute arterial damage in rats
S J Newsholme1, D T Thudium, K A Gossett
1Safety Assessment, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. Stephen_J_Newsholme@sbphrd.com
Abstract:
Plasma von Willebrand factor (vWF) was evaluated as a potential biomarker of acute arterial damage in rats after a vasotoxic dose of the dopaminergic vasodilator, fenoldopam (FP). Male Sprague-Dawley rats were given FP or isotonic saline by subcutaneous injection, and plasma vWF was measured at 2, 6, and 24 hours after challenge. Mean plasma vWF values increased in FP-treated rats compared to controls at 2 hours (167 vs 122%; p < 0.05) and 6 hours postdose (172 vs 130%; p < 0.01) but were comparable to control values after 24 hours. Mesenteric arterial lesions were observed microscopically in all FP-treated rats 24 hours postdose but were not present in rats at 1, 2, 4, 6, or 8 hours after FP challenge. Further, plasma vWF concentrations increased in saline-treated rats after only the minimal perturbation of repeated venipuncture. These results indicate an early, minimal, and transient release of vWF that precedes the onset of morphologically evident vascular damage. The minimal increases in plasma vWF concentrations were of limited predictive value, may be more reflective of an acute-phase reactant response, and were not considered a reliable biomarker of acute FP-induced arterial damage in the rat.
Insights
Plasma von Willebrand factor (vWF) showed minimal, transient increases after fenoldopam (FP) in rats. These changes preceded arterial damage but were not reliable biomarkers due to limited predictive value.
Area of Science:
- Pharmacology
- Toxicology
- Vascular Biology
Background:
- Fenoldopam (FP) is a dopaminergic vasodilator with potential vasotoxic effects.
- Assessing early biomarkers for acute arterial damage is crucial in toxicology.
- Von Willebrand factor (vWF) is a known marker of endothelial activation and vascular injury.
Purpose of the Study:
- To evaluate plasma von Willebrand factor (vWF) as a potential biomarker for acute arterial damage induced by fenoldopam (FP) in rats.
- To determine the temporal relationship between vWF release and the onset of vascular lesions after FP administration.
Main Methods:
- Male Sprague-Dawley rats received subcutaneous fenoldopam (FP) or saline.
- Plasma vWF levels were measured at 2, 6, and 24 hours post-injection.
- Mesenteric arterial tissues were examined microscopically for lesions.
Main Results:
- Plasma vWF increased significantly in FP-treated rats at 2 and 6 hours compared to controls (p < 0.05 and p < 0.01, respectively).
- vWF levels returned to baseline by 24 hours post-FP.
- Microscopic arterial lesions were evident in all FP-treated rats at 24 hours, but not earlier.
- Minimal vWF increases also occurred in saline-treated rats due to venipuncture stress.
Conclusions:
- Early, transient vWF release precedes morphologically evident arterial damage after fenoldopam exposure.
- The observed vWF increases had limited predictive value and may represent an acute-phase response.
- Plasma vWF is not considered a reliable biomarker for acute fenoldopam-induced arterial damage in rats.
