Activated leukocytes which are forming pseudopods and express adhesion molecules (integrins) have a high probability to become trapped in capillaries of the microcirculation. While leukocytes require to be activated in order to migrate across the endothelium during bone marrow hemopoiesis and also during emigration across peripheral microvascular endothelium, most leukocytes in the active circulation have a low level of pseudopod formation and expression of adhesion molecules. This evidence suggests that there exists a mechanism to downregulate circulating leukocytes. We have recently demonstrated that leukocytes are deactivated by plasma fluid shear stress (PNAS,94:5338,1997). Physiological fluid shear stresses (1 dyn/cm2) serve to stimulate pseudopod retraction, reduce adhesion, and increase cell deformability. This observation can be observed on all leukocyte subtypes in the circulation and without exception in a popolation of about 500 leukocytes collected by 1 g sedimentation of fresh whole blood in heparin. In the presence of inflammatory stimulators, however, leukocytes in-vivo in postcapillary venules can readily be observed to exhibit a reduced response to fluid shear stress. Individual leukocytes can be encountered which adhere to the endothelium and project pseudopods, even though there is normal flow of red cells associayed with normal physiological shear stress. Therefore we searched for a mechanism that may serve to control the shear stress response in circulating leukocytes. In vitro studies during application of a fluid shear stress on individual leukocytes shows that human leukocytes on a glass surface cease to respond to fluid shear stress after depletion of cGMP. Enhancement of cGMP increases their sensitivity to shear stress, even with inflammatory mediators. In mesentery venules, after application of stimulators, administration of a cGMP analog enhances the shear stress response by leukocytes with diminished pseudopod projection on the endothelium, thereby attenuating leukocyte attachment, spreading and transendothelial migration. The level of cGMP in leukocytes attached to the wall of flowing blood vessels with normal physiological fluid shear stress may be controlled by nitric oxide (NO) derived from the endothelium. Our results suggest, that since nitric oxide modulates cGMP, the level of endothelial NO release serve to control cGMP and the shear stress response in leukocytes attached to the endothelium. Supported by HL 43026 and NSF IBN-9512778.