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 the nitric oxide synthase (NOS) inhibitor N(omega)-nitro-L-arginine (L-NNA) on tumor blood flow compared with normal tissue blood flow was studied in anesthetized BD9 rats bearing subcutaneous P22 carcinosarcomas. Blood flow was measured by the tissue uptake of radiolabeled iodoantipyrine. The reversibility of blood flow changes was tested by subsequent administration of L-arginine, 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 2-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide and a nitric oxide scavenger. 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 pressure traces. L-NNA significantly decreased heart rate and increased MABP in a dose-dependent manner. Significant dose-dependent reductions in blood flow with L-NNA were observed in tumor, skeletal muscle, spleen, and skin overlying the tumor. No significant effect was found for normal skin, brain, heart, kidney, and small intestine. At 1 mg/kg, the effect 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 effect in any of the normal tissues. Higher doses did not produce any further reduction in tumor blood flow, presumably due to an increase in tumor perfusion pressure arising from the increase in MABP at these doses. Vascular resistance was increased to some extent in all of the tissues studied but, overall, was greatest in the tumor. At 1 mg/kg, there was a 2-2.5-fold increase in tumor vascular resistance but no significant increase in any of the normal tissues. At the highest dose used (10 mg/kg), the increases in vascular resistance in the skeletal muscle and spleen were equivalent to that in the tumor. Administration of L-arginine 15 min after L-NNA completely reversed the decrease in tumor blood flow observed for 1 mg/kg L-NNA alone. In contrast to the effect 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 inhibition of NOS may provide a means for enhancing therapeutic regimens that would benefit from a selective reduction in tumor blood flow.
Tozer
G M
GM
Tumour Microcirculation Group, Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom.
Prise
V E
VE
Chaplin
D J
DJ
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D001794:Blood Pressure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000494:pharmacology; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects*
D001565:Benzoates; D004791:Enzyme Inhibitors; D007093:Imidazoles; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; D019335:Nitroarginine; D001120:Arginine; D019001:Nitric Oxide Synthase