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 incr ease drug delivery to colorectal liver metastases, but are limited by a sho rt duration of action. This study measured their effect on blood flow and d rug delivery during a prolonged infusion in a model of liver metastases. Methods: In Hooded Lister rats with liver metastases, blood how in tumour a nd adjacent normal liver was measured using laser Doppler flowmetry during a 30-min hepatic arterial infusion of endothelin 1, angiotensin II, vasopre ssin, N-nitro-L-arginine methyl ester (L-NAME), noradrenaline or saline (n = 6 per group). The same agents were co-administered with radiolabelled 5-f luorouracil (5-FU) (n = 6 per group) and uptake in the tumour and normal li ver 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 perio d were: noradrenaline, 2.9(0.4) min and 34(5) per cent (P < 0 05); angioten sin 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 signif icant). The mean(s.d.) uptake of radiolabelled 5-FU by the tumour in the gr oups studied was: saline, 5.1(3.2) x 10(5) c.p.m. per g tissue; angiotensin II, 5.1(1.4) x 10(5) c.p.m. per g; endothelin 1, 15.8(14.2) x 10(5) c.p.m. per g; L-NAME, 3.5(1.3) x 10(5) c.p.m. per g; and vasopressin, 6.8(3.5) x 10(5) c.p.m. per g. Significant improvements in 5-FU uptake only resulted f rom noradrenaline infusion (22.0(9.8) x 10(5) c.p.m. per g; P < 0.05). Conclusion: These findings suggest that hepatic arterially infused noradren aline might be used to improve drug delivery to liver metastases.