Nitric oxide–mediated increase in tumor blood flow and oxygenation of tumors implanted in muscles stimulated by electric pulses

Oxygen deficiency in tumors reduces the efficacy of nonsurgical treatment modalities. We tested the hypothesis that electrical stimulation of the sciatic nerve could modify the oxygenation status and the blood flow of tumors implanted in the thigh of mice. The sciatic nerve was electrically stimulated at 5 Hz. Local transplantable liver tumor (TLT) and fibrosarcoma (FSaII) tumor oxygen pressure (pO 2) and perfusion measurements were carried out using electron paramagnetic resonance (EPR) oximetry and the OxyLite/OxyFlo technique. The radiosensitizing effect of the protocol was assessed by irradiating FSaII tumors with X-rays. Tumor pO 2 increased from ∼3 mm Hg to ∼8 mm Hg, and relative tumor blood flow was increased by 241% and 162% for TLT and FSaII tumor models, respectively. The effect on the tumor oxygenation was inhibited by a nitric oxide synthase (NOS) inhibitor, and an increase in the tumor nitric oxide (NO) content was observed using EPR spin-trapping. The tumor oxygen consumption rate was decreased after the stimulation protocol. In addition, the electrical stimulation of the host tissue increased regrowth delays by a factor of 1.65. This increase in tumor oxygenation is due to the temporary increase in tumor blood flow, but particularly to a decrease in the tumor oxygen consumption rate (inhibition of respiration) that is mediated by a local production of NO during the protocol. Those tumor hemodynamic changes resulted in a radiosensitizing effect.