Search

Hemoglobin (Hgb) and lysates of red blood cells act as vasoconstrictors in isolated vessels by a mechanism that may involve nitric oxide (NO·) scavenging. To determine if such a mechanism indeed occurs, we investigated the effects of cell-free Hgb, modified Hgb (met Hgb and cyan met Hgb), and red blood cells on the formation of NO· induced by endotoxin in rat aorta. Incubation of rat aortic rings with endotoxin induced a delayed and prolonged release of NO· that resulted in a decrease in the contractile response to phenylephrine. Hgb significantly potentiated contractions to phenylephrine in control rings and also reversed the hyporeactivity to this α₁-agonist in endotoxin-treated rings with and without endothelium. Lysed red blood cells but not whole red blood cells shifted the concentration-contraction response curves to phenylephrine significantly to the right in endotoxin-treated preparations. Neither picket-fence porphyrin-albumin (PFP-albumin) or metheme-albumin affected the contractile response to phenylephrine. Oxidation of Hgb to met Hgb did not alter the contractions to an α₁-agonist in endotoxin-treated rings. In contrast, the formation of cyan met Hgb abolished the action of Hgb on the vascular reactivity of endotoxin-treated preparations. Together, these results demonstrate that free Hgb can scavenge NO· produced in endotoxin-treated vascular tissue and that the ability to bind NO· requires a cell-free form of Hgb with an intact heme center capable of undergoing redox reactions,Copyright 1994, 1999 Academic Press, Inc.

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.