INHIBITION OF NITRIC-OXIDE SYNTHASE INDUCES A SELECTIVE REDUCTION IN TUMOR BLOOD-FLOW THAT IS REVERSIBLE WITH L-ARGININE

The Effect of i.v. administration of tile nitric oxide synthase (NOS) inhibitor N-omega-nitro-L-arginine (L-NNA) on tumor blood flow compare d with normal tissue blood flow was studied in anesthetized BD9 rats b earing subcutaneous P22 carcinosarcomas. Blood flow was measured by th e tissue uptake of radiolabeled iodoantipyrine. The reversibility of b lood flow changes was tested by subsequent administration of L-arginin e, the natural substrate for NOS, The effect of L-NNA was compared to that of the imidazolineoxyl N-oxide C-PTIO, a carboxyl derivative of n yl-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide and a nitric oxide s cavenger, Drug-induced changes in mean arterial blood pressure (MABP) were monitored and used to calculate relative drug-induced changes in tissue vascular resistance. Heart rate was measured from blood pressur e traces. L-NNA significantly decreased heart rate and increased MABP in a dose-dependent manner. Significant dose-dependent reductions in b lood flow with L-NNA were observed in tumor, skeletal muscle, spleen, and skin overlying the tumor, No significant effect was found for norm al skin, brain, heart, kidney, and small intestine, At I mg/kg, the ef fect of L-NNA was selective for the tumor, with a significant decrease in tumor blood flow to 0.45 of the control level and no significant e ffect in any of the normal tissues. Higher doses did not produce any f urther reduction in tumor blood flow, presumably due to an increase in tumor perfusion pressure arising from the increase in MABP at these d oses. Vascular resistance was increased to some extent in all of the t issues studied but, overall, was greatest in the tumor, At 1 mg/kg, th ere was a 2-2.5-fold increase in tumor vascular resistance hut no sign ificant increase fn any of the normal tissues, At the highest dose use d (10 mg/kg), the increases in vascular resistance in the skeletal mus cle and spleen were equivalent to that in the tumor. Administration of L-arginine 15 min after L-NNA completely reversed the decrease in tum or blood flow observed for 1 mg/kg L-NNA alone, In contrast to the eff ect of L-NNA, constant i.v. infusion of C-PTIO had no effect on tumor or normal tissue blood flow, These results indicate that nitric oxide is important for maintaining a vasodilatory tone in tumors and that in hibition of NOS may provide a means for enhancing therapeutic regimens that would benefit from a selective reduction in tumor blood flow.