Protective Effects of Micronized Purified Flavonoid Fraction (MPFF) on a Novel Experimental Model of Chronic Venous Hypertension

Abstract

To assess protective effects of micronized purified flavonoid fraction (MPFF) on microcirculation in an original chronic model of hind limb venous hypertension with low blood flow in small animals. Vein ligatures were performed on male hamsters, as follows: A-right femoral vein; A+B-right femoral vein and its right branch; A+C-right femoral vein and its left branch; A+B+C-right femoral and its right and left branches; D-external right iliac vein. In sham operated groups, similar vascular dissections were performed without ligatures. Superficial (epigastric) and central (jugular) venous pressure evaluations were made during a 10 week period. Hamsters subjected to A+B+C and D ligatures were selected for leukocyte rolling and sticking, functional capillary density (FCD), and venular and arteriolar diameter observations. D ligature was selected to evaluate pharmacological treatment efficacy. MPFF (100mg/kg), concomitant active flavonoids of MPFF (diosmetin, hesperidin, linarin, and isorhoifolin) (10mg/kg), diosmin (100mg/kg) or drug vehicle were administered orally during 2 weeks before vein ligature and 6 weeks thereafter. A, A+B and A+C models maintained venous return through collaterals. From the 2nd to the 10th weeks after vein ligatures, A+B+C and D models elicited a progressive increase of superficial venous pressure (3.83±0.65 vs. 8.56±0.72mmHg, p<.001 and 4.13±0.65 vs. 9.35±0.65mmHg, p<.001, respectively) with significant changes to the microcirculation. As D model significantly increased superficial venous pressure without affecting central venous pressure, it was used to evaluate the long-term effects of treatment. Compared with vehicle, MPFF, concomitant active flavonoids of MPFF, and diosmin, significantly decreased leukocyte-endothelium interaction and prevented FCD reduction. Only MPFF significantly prevented venular enlargement as observed in the vehicle treated group. MPFF was more effective than diosmin in improving all microvascular variables. The superiority of MPFF over diosmin alone can be explained by the synergistic beneficial effects of the association between diosmin and active flavonoids of MPFF.