Mechanisms of contraction induced by human leukocytes in normal and atherosclerotic arteries.

Activation of leukocytes results in the release of a variety of vasoactive substances that may modulate vascular tone. We studied the effect of human polymorphonuclear (PMN) and mononuclear (MONO) leukocytes on quiescent femoral arteries in vitro. Arteries were obtained from normal and atherosclerotic cynomolgus monkeys. In normal arteries, stimulation of PMNs (3 and 5 x 10(6) cells/ml) with either thrombin (5 units/ml) or complement C5a (0.5 micrograms/ml) resulted in endothelium-independent contraction (approximately 25% of maximum contraction with 80 mM KCl). Vasocontraction was augmented in the presence of superoxide dismutase (150 units/ml) and was significantly impaired in the presence of the hydroxyl radical scavengers mannitol (20 mM) and deferoxamine (1 mM). Catalase (1,200 units/ml) or L-alanine (20 mM) did not modify this effect of PMNs. In contrast to PMNs, vasocontraction in response to MONOs was not altered by the addition of radical scavengers. Pretreatment of PMNs and MONOs with indomethacin (10 microM) or nordihydroguaiaretic acid (20 microM) did not influence vascular responses. Supernatant of thrombin-stimulated PMNs and MONOs also produced vasocontraction (approximately two thirds of the effect of intact cells). This vasocontractor factor (or factors) was heat stable (30 minutes, 95 degrees C) and had a molecular weight less than 1,000 as determined by ultrafiltration. Stimulation of MONOs or PMNs (3 and 5 x 10(6) cells/ml) produced a similar response in normal arteries. In contrast, the constrictor response in atherosclerotic arteries to MONOs (5 x 10(6) cells/ml) was significantly greater than to PMNs. We conclude that stimulated human PMNs and MONOs contract arteries in vitro by release of at least two factors. One factor appears to be heat stable, with a molecular weight less than 1,000. The vascular response to PMNs, but not to MONOs, appears to involve the generation of hydroxyl radicals. The response to MONOs is greater than the response to PMNs in atherosclerotic, but not in normal, arteries.