The comparative effects of the NOS inhibitor, Nomega-nitro-L-arginine, and the haemoxygenase inhibitor, zinc protoporphyrin IX, on tumour blood flow.
OBJECTIVE
To determine the relative effects of inhibiting nitric oxide synthase (NOS) and haemoxygenase (HO) on blood flow to the rat P22 carcinosarcoma.


METHODS
HO is the enzyme responsible for in vivo production of carbon monoxide (CO). The vascular effects of zinc protoporphyrin IX (ZnPP), a competitive inhibitor of HO, were compared with those of copper protoporphyrin IX (CuPP), a poor inhibitor of HO, in isolated ex vivo perfusions of the P22 tumour and in intact tumour-bearing rats. In ex vivo perfusions, tumour vascular resistance was calculated from measurements of perfusion pressure at a known flow rate. In intact animals, blood flow to tumour and normal tissues was calculated using a radiotracer uptake method. The effects of ZnPP were compared with those of the NOS inhibitor, N(omega)-nitro-L-arginine (L-NNA), and the combination of the two drugs.


RESULTS
HO activity in the P22 tumour was reduced by 50% following administration of either ZnPP or CuPP directly to ex vivo perfused tumours, suggesting an indirect effect on the enzyme. Enzyme inhibition was not associated with any significant vasoactive effect. Neither ZnPP nor CuPP, at a dose of 45 micromol x kg(-1) administered i.p., inhibited tumour HO in vivo. However, they did significantly decrease tumour blood flow to 60-70% of control, with similar effects in skin and brain. Skeletal muscle blood flow was increased to 150% of control. L-NNA decreased both tumour and skeletal muscle blood flow to around 40% of control. These differences suggest that the nonspecific effects of ZnPP and CuPP were not mediated by NOS inhibition. The combination of ZnPP and L-NNA improved the selective reduction in tumour blood flow achieved with either agent alone.


CONCLUSIONS
This suggests that the HO/CO pathway does not play a major vasodilatory role in this tumour. However, ZnPP and CuPP could be useful for inducing a relatively selective decrease in tumour blood flow via mechanisms unrelated to HO inhibition, especially when combined with NOS inhibition.
Tozer
G M
GM
Tumour Microcirculation Group, Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, UK.
Prise
V E
VE
Motterlini
R
R
Poole
B A
BA
Wilson
J
J
Chaplin
D J
DJ
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives*; D001794:Blood Pressure / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors*; D008297:Male; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D011524:Protoporphyrins / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012039:Regional Blood Flow / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D011524:Protoporphyrins; C092553:copper protoporphyrin IX; C017803:zinc protoporphyrin; D001120:Arginine; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing)