title: Nitric oxide synthase inhibition irreversibly decreases perfusion in the R3230Ac rat mammary adenocarcinoma.
abstract: We examined the microvascular effects of competitive nitric oxide synthase (NOS) inhibition with NG-monomethyl-L-arginine (MeArg), followed by L-arginine, on R3230Ac mammary adenocarcinoma perfusion. In window preparations containing tumours, superfusion of 50 microM MeArg reduced diameters of central tumour venules by 13%, of peripheral tumour venules by 17% and of normal venules near tumours by 16% from baseline. MeArg reduced red blood cell (RBC) velocity in central tumour venules by 25%, and increased intermittent flow and stasis frequency by 20% in central tumour venules. Subsequent superfusion of 200 microM L-arginine did not restore diameters or RBC velocity of any tumour preparation venules, and decreased length density in both central tumour venules and peripheral tumour venules. In contrast, MeArg reduced control preparation venule diameter by 30% and RBC velocity by 66%, but did not decrease length density or increase intermittent flow or stasis frequency. Unlike tumour preparation venules, L-arginine restored control venule diameters and velocities. NOS inhibition reduces both tumour and control venule perfusion, but the effect is blunted in the vicinity of tumours, possibly because of increased NOS levels. Perfusion can be subsequently restored in control, but not tumour, venules with L-arginine. Tumour NOS inhibition, followed by normal tissue rescue with L-arginine, may provide a novel means to achieve the goal of selective tumour hypoxia.
authors.affiliation: Department of Anatomy, North Carolina State University College of Veterinary Medicine, Raleigh 27606, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Meyer
authors.forename: S
authors.initials: S
authors.lastname: Shan
authors.forename: J
authors.initials: J
authors.lastname: DeAngelo
authors.forename: R K
authors.initials: RK
authors.lastname: Dodge
authors.forename: J
authors.initials: J
authors.lastname: Bonaventura
authors.forename: E T
authors.initials: ET
authors.lastname: Ong
authors.forename: M W
authors.initials: MW
authors.lastname: Dewhirst
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply*; D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply*; D008833:Microcirculation / Q000187:drug effects / Q000503:physiopathology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase; D010477:Perfusion; D051381:Rats; D011916:Rats, Inbred F344; D012039:Regional Blood Flow / Q000187:drug effects; D014699:Venules / Q000187:drug effects / Q000503:physiopathology*; D019323:omega-N-Methylarginine
chemical_list: D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases