The stimulation of human neutrophil migration by angiotensin II: its dependence on Ca²⁺and the involvement of cyclic GMP

1 Angiotensin II had a bimodal effect on human neutrophil migration. Low concentrations of angiotensin II stimulated random migration. At a concentration of 10(-10) M it caused a maximal increase of migration; migration increased from 47.2 +/- 2.1 mu m in the absence of angiotensin II, to 73.1 +/- 2.2 mu m with 10(-10) M angiotensin II present in the lower compartment of the Boyden chamber (n = 5, P<0.001). Stimulation of migration by angiotensin II was partly chemotactic and partly chemokinetic. Angiotensin II concentrations of 10(-8) M and higher inhibited chemotactic peptide-stimulated chemotaxis. 2 The stimulant effect of angiotensin II on migration was completely dependent on extracellular Ca2+. In the presence of 1 mM Ca2+, angiotensin II stimulated migration to 76.1 +/- 1.7 mu m, while migration in the absence of Ca2+ was 42.2 +/- 1.9 mu m (n = 4, P<0.001). Different types of calcium channel blockers either moderately or strongly inhibited angiotensin II-activated migration. Stimulation of migration by angiotensin II in intact cells required higher concentrations of Ca2+ than in electroporated cells. This supports the view that there is an influx of Ca2+ through the plasma membrane, and a requirement of calcium for an intracellular target. 3 Angiotensin II-stimulated migration was inhibited by pertussis toxin; from 71.6 +/- 2.0 mu m in the absence, to 43.6 +/- 1.5 mu m in the presence of pertussis toxin (n = 4, P<0.001). Migration of electroporated neutrophils stimulated by angiotensin II was synergistically enhanced by GTP gamma S. This suggests that one or more G-proteins are involved in the activating effect of angiotensin II. 4 Inhibitors of soluble guanylate cyclase and antagonists of cyclic GMP-dependent kinase strongly inhibited the activating effect of angiotensin II. The results suggest that the activating effect of angiotensin II is mediated by cyclic GMP and by cyclic GMP-dependent kinase.