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The effect of molecular dimension of hemoglobin (Hb)-based O₂carriers on the diameter of resistance arteries (A ₀, 158 ± 21 μm) and arterial blood pressure were studied in the conscious hamster dorsal skinfold model. Cross-linked Hb (XLHb), polyethylene glycol (PEG)-conjugated Hb, hydroxyethylstarch-conjugated XLHb, polymerized XLHb, and PEG-modified Hb vesicles (PEG-HbV) were synthesized. Their molecular diameters were 7, 22, 47, 68, and 224 nm, respectively. The bolus infusion of 7 ml/kg of XLHb (5 g/dl) caused an immediate hypertension (+34 ± 13 mmHg at 3 h) with a simultaneous decrease in A ₀diameter (79 ± 8% of basal value) and a blood flow decrease throughout the microvascular network. The diameter of smaller arterioles did not change significantly. Infusion of larger O₂ carriers resulted in lesser vasoconstriction and hypertension, with PEG-HbV showing the smallest changes …