Cortical hypoperfusion after global forebrain ischemia in rats is not caused by microvascular leukocyte plugging.

Abstract

• Background and Purpose We tested the hypothesis that cerebral hypoperfusion after experimental global cerebral ischemia is caused by plugging of the microcirculation with activated leukocytes using in vivo microscopic observation of the behavior of leukocytes in the cortical microcirculation during the transition from postischemic hyperperfusion to hypoperfusion.Methods Anesthetized and ventilated rats (n=24) were equipped with a closed cranial window. Physiological variables and cortical regional cerebral blood flow (laser-Doppler flowmetry) were measured continuously. Leukocytes were labeled intravitally with rhodamine 6G and visualized in the microcirculation of the brain surface and outer layers of the cortex with confocal laser scanning microscopy from preischemia to 4 hours after reperfusion that followed 10 minutes of global cerebral ischemia (rCBF<10% of control).Results In controls (n=8), there were no signs of leukocyte activation over the 4-hour observation period. In ischemic rats (n=16), during the transition from hyperperfusion to hypoper-S evere transient global forebrain ischemia leads to a characteristic pattern of cerebral blood flow (CBF) changes in several species: After recirculation a short period of hyperperfusion develops, followed by prolonged hypoperfusion. -2 The factors causing this blood flow pattern and its consequences for ischemic damage are not fully understood.Generally, hyperperfusion is attributed to maximal vasodilation caused by the accumulation of vasodilator metabolic products, such as H + ,K + , nitric oxide, adenosine, etc, 2 -4 although neurogenic mechanisms may be involved as well.5 It is less clear what causes hypoperfusion. The concept of a mechanical obstruction of the postischemic microcirculation with subsequent hypoperfusion 6 or "no-reflow" 7 by leukocytes ("leukocyte plugging" 8 ) has received much attention. 910 Leukocytes may be activated during ischemia, and activated leukocytes interact with the vascular endothelium, possibly resulting in microvascular obstruction. 10 In skeletal muscle, Harris and Skalak" demonstrated that even a few activated leukocytes may have a profound impact on the resistance of microvascular networks and therefore blood flow.Received April 5, 1993; final revision received October 28, 1993; accepted January 5, 1994.From the Department of Neurology, Humboldt University, Berlin, Germany.Correspondence to Dr Ulrich Dirnagl, Department of Neurology, Humboldt University, Schumannstr 20/21, 10098 Berlin, Germany.fusion there was no change in the behavior of leukocytes. Most notably, no capillary pluggers were seen. In the postischemic period only a slight increase of the number of leukocytes rolling along or sticking to the venular endothelium was seen, and very few capillaries were plugged by leukocytes. Extravasation of leukocytes into the brain tissue was observed in 8 rats beginning 2 hours after ischemia with a variable degree between animals.Conclusions Because there was only mild activation of leukocyte-endothelium interaction w...

Combined Contrast-Enhanced Ultrasound and rt-PA Treatment is Safe and Improves Impaired Microcirculation after Reperfusion of Middle Cerebral Artery Occlusion

“…reperfusion into a maximally vasodilated arterial bed (Dirnagl et al, 1994;Todd et al, 1986). In this context, it has been suggested that recovery of vascular smooth muscle tone may contribute to subsequent hypoperfusion (Todd et al, 1986).…”

“…There is still uncertainty about involved factors (Dirnagl et al, 1994). Okada et al identified fibrin deposits as one possible cause (Okada et al, 1994).…”

Platelet–Leukocyte–Endothelial Cell Interactions after Middle Cerebral Artery Occlusion and Reperfusion

“…Leukocyte-endothelial cell interactions have been previously described in porcine (Gidday et al, 1997), gerbil (Uhl et al, 2000), rat (Dirnagl et al, 1994), and murine (Ishikawa et al, 2003) models of global I/R, and after focal I/R in the rat (Ishikawa et al, 1999;Ritter et al, 2000). The present study represents the first attempt to systematically evaluate the effects of focal I/R on the…”

In vitro modeling of the microvascular occlusion and thrombosis that occur in hematologic diseases using microfluidic technology

“…stains leukocytes and platelets (28,29), revealed occasional rolling, but no prolonged adhesion, of leukocytes and little microchannel obstruction ( Figure 3, A and D, and Supplemental Video 4). Culturing the system with either HUVECs or HLMVECs showed no differences in flow patterns, leukocyte adhesion, or microchannel obstruction.…”