ENDOTHELIUM-DERIVED RELAXING FACTOR IS IMPORTANT IN MEDIATING THE HIGH-OUTPUT STATE IN CHRONIC SEVERE ANEMIA

Objectives. We evaluated the endothelial and vascular smooth muscle fu nction in patients with chronic severe anemia to determine whether inc reased basal nitric oxide levels contribute to the systemic vasodilati on and high cardiac output seen in these patients. Background. Patient s with chronic severe anemia have a high output state due to a low sys temic vascular resistance, However, the cause of the low vascular resi stance is unclear. Because hemoglobin is a potent inhibitor of endothe lium-derived relaxing factor, we postulated that in chronic severe ane mia, low circulating hemoglobin results in reduced inhibition of endot helium derived relaxing factor. The basal endothelium derived relaxing factor activity therefore increases, and this contributes significant ly to the low systemic vascular resistance and the hyperdynamic state seen in this condition. Methods. Hemodynamic variables and forearm blo od flow (using plethysmography) were measured in eight patients with c hronic severe anemia before (hematocrit 16 +/- 2% [mean +/- SD]) and w ithin 24 h of red blood cell transfusion (n = 6, hematocrit 30 +/- 1%) and in sis control subjects. The effect on baseline blood how of bloc king endothelium-derived relaxing factor activity with N-G-monomethyl- L-arginine was investigated. In addition, the effects of both endothel ium-dependent and endothelium-independent vasodilators on forearm bloo d flow were tested. Results. Baseline forearm blood bow was markedly i ncreased in untreated patients (6.5 +/- 1.2 ml/min per 100 ml) compare d with that in control subjects (2.8 +/- 0.7 ml/min per 100 ml, p < 0. 0001, 95% confidence interval [CI] for difference -5 to -2.5). Red blo od cell transfusion significantly reduced blood how in the anemic pati ents to 3.5 +/- 1.1 ml/min per 100 ml (p < 0.001, 95% CI for differenc e -4.9 to -1.9), which was not significantly different from that in co ntrol subjects; increased systemic vascular resistance (796 +/- 141 to 1,230 +/- 151 dynes . s . cm(-5), p < 0.001); and decreased cardiac o utput (4.9 +/- 0.6 to 3.5 +/- 0.5 liters/min per m(2), p < 0.001). N-G -monomethyl-L-arginine (16 mu mol/min), a specific inhibitor of endoth elium-derived relaxing factor, reduced forearm blood flow by an equal amount (p = 0.9, 95% CI for difference -0.7 to 0.8) in control subject s (0.98 +/- 0.39 ml/min) and treated patients (1.03 +/- 0.8 ml/min) bu t caused a threefold greater decrease in flow (2.9 +/- 0.9 ml/min) in untreated patients (p = 0.0003, 95% CI for difference between untreate d patients and control subjects 1.1 to 2.7). These findings suggest in creased basal endothelium-derived relaxing factor activity in patients with anemia. Stimulated forearm, blood flows (both endothelium depend ent and endothelium independent) were similar in all groups, confirmin g normal endothelial and smooth muscle function. Conclusions. These fi ndings support the hypothesis that enhanced basal endothelium derived relaxing factor activity makes an important contribution to the low sy stemic vascular resistance in chronic severe anemia.