NITRIC-OXIDE SYNTHASE INHIBITION IRREVERSIBLY DECREASES PERFUSION IN THE R3230AC RAT MAMMARY ADENOCARCINOMA

We examined the microvascular effects of competitive nitric oxide synt hase (NOS) inhibition with N-G-monomethyl-L-arginine (MeArg), followed by L-arginine, on R3230Ac mammary adenocarcinoma perfusion. In window preparations containing tumours, superfusion of 50 mu M MeArg reduced diameters of central tumour venules by 13%, of peripheral tumour venu les by 17% and of normal venules near rumours by 16% from baseline. Me Arg reduced red blood cell (RBC) velocity in central tumour venules by 25%, and increased intermittent flow and stasis frequency by 20% in c entral tumour venules. Subsequent superfusion of 200 mu M L-arginine d id not restore diameters or RBC velocity of any tumour preparation ven ules, and decreased length density in both central tumour venules and peripheral tumour venules. In contrast, MeArg reduced control preparat ion venule diameter by 30% and RBC velocity by 66%, but did not decrea se length density or increase intermittent flow or stasis frequency. U nlike tumour preparation venules, L-arginine restored control venule d iameters and velocities. NOS inhibition reduces both tumour and contro l venule perfusion, but the effect is blunted in the vicinity of tumou rs, possibly because of increased NOS levels. Perfusion can be subsequ ently restored in control, but not tumour, venules with L-arginine. Tu mour NOS inhibition, followed by normal tissue rescue with L-arginine, may provide a novel means to achieve the goal of selective tumour hyp oxia.