Noradrenaline improves the tumour to normal blood flow ratio and drug delivery in a model of liver metastases

Background: Vasopressors administered via the hepatic artery appear to increase drug delivery to colorectal liver metastases, but are limited by a short duration of action. This study measured their effect on blood flow and drug delivery during a prolonged infusion in a model of liver metastases. Methods: In Hooded Lister rats with liver metastases, blood flow in tumour and adjacent normal liver was measured using laser Doppler flowmetry during a 30‐min hepatic arterial infusion of endothelin 1, angiotensin II, vasopressin, N ‐nitro‐ L ‐arginine methyl ester ( L ‐NAME), noradrenaline or saline ( n = 6 per group). The same agents were co‐administered with radiolabelled 5‐fluorouracil (5‐FU) ( n = 6 per group) and uptake in the tumour and normal liver was measured. Results: The mean(s.d.) duration of effect and resulting percentage changes in tumour to normal blood flow ratio of the vasopressors during this period were: noradrenaline, 2·9(0·4) min and 34(5) per cent ( P < 0·05); angiotensin II, 4·2(0·2) min and 10(2) per cent ( P < 0·05); vasopressin, 11·1(0·9) min and 7(2) per cent ( P < 0·05); endothelin 1, 21·5(2·3) min and 14(5) per cent ( P < 0·05); and L ‐NAME, 22·6(3·3) min and 2(1) per cent ( P not significant). The mean(s.d.) uptake of radiolabelled 5‐FU by the tumour in the groups studied was: saline, 5·1(3·2) × 10 5 c.p.m. per g tissue; angiotensin II, 5·1(1·4) × 10 5 c.p.m. per g; endothelin 1, 15·8(14·2) × 10 5 c.p.m. per g; L ‐NAME, 3·5(1·3) × 10 5 c.p.m. per g; and vasopressin, 6·8(3·5) × 10 5 c.p.m. per g. Significant improvements in 5‐FU uptake only resulted from noradrenaline infusion (22·0(9·8) × 10 5 c.p.m. per g; P < 0·05). Conclusion: These findings suggest that hepatic arterially infused noradrenaline might be used to improve drug delivery to liver metastases. © 1999 British Journal of Surgery Society Ltd