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

Abstract

Abstract 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 (Pnot significant). The mean(s.d.) uptake of radiolabelled 5-FU by the tumour in the groups studied was: saline, 5·1(3·2) × 105 c.p.m. per g tissue; angiotensin II, 5·1(1·4) × 105 c.p.m. per g; endothelin 1, 15·8(14·2) × 105 c.p.m. per g; l-NAME, 3·5(1·3) × 105 c.p.m. per g; and vasopressin, 6·8(3·5) × 105 c.p.m. per g. Significant improvements in 5-FU uptake only resulted from noradrenaline infusion (22·0(9·8) × 105 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.