Stroma-free human hemoglobin A decreases R3230Ac rat mammary adenocarcinoma blood flow and oxygen partial pressure

We examined the effect of a nitric oxide (NO) quencher, stroma-free human hemoglobin A (HbA₀; 0.01, 0.05, 0.1, 0.2 g/kg), on the blood flow measured using the Doppler flow technique, tumor oxygen pressure (pO₂) and the diameter of the arterioles using R3230Ac mammary adenocarcinoma as the tumor model. In female Fischer 344 rats with 1-cm-diameter tumors implanted in the lateral aspect of the left quadriceps, intravenous infusion of 0.1 and 0.2 g/kg HbA₀ decreased both central tumor and peripheral tumor blood flow by 20-30% (P < 0.05). Tumor pO₂ decreased 28% with 0.2 g/kg HbA₀, from 15 mm Hg (baseline) to 11 mm Hg at 10 min (P = 0.02). Although 0.2 g/kg HbA₀ increased blood flow 55% in the left quadriceps muscle proximal to the implanted tumor (P < 0.051, HbA₀ had little effect on blood flow in right quadriceps muscle with no tumor implanted, and increased right quadriceps pO₂, from 21 mm Hg (baseline) to 23 mm Hg at 10 min (P = 0.03). HbA₀ increased mean arterial pressure 5-10% in a manner that was dependent on dose while heart rate concurrently decreased 9-19%. The diameter of the arterioles supplying the tumor was rapidly reduced 10% by 0.2 g/kg HbA₀ (P = 0.037) and remained stable through 60 min of observation (P = 0.005). HbA₀ selectively reduces tumor blood flow and tumor pO₂ through vasoconstriction of the arterioles supplying the tumor. Vascular NO quenching provides an alternative to NO synthase inhibition as a means to achieve the goal of selective tumor hypoxia.