Pharmacological intervention of postischemic leukocyte-endothelium interaction in striated muscle

Abstract

Ischemia-reperfusion is associated with activation of leukocytes which accumulate in the postischemic tissue, adhere to the microvascular endothelium, emigrate into the perivascular space and contribute to postischemic reperfusion injury through the release of cytotoxic enzymes as well as generation of oxygen free radicals. In the following we have summarized the results of four studies in which the effects of different pharmacological agents on leukocyte-endothelium interaction after ischemia-reperfusion were tested. A 4h ischemia was induced to a thin striated muscle contained in the dorsal skin fold chamber preparation of awake hamsters. Using intravital fluorescence microscopy and a computer-assisted microcirculation analysis system, red cell velocity, vessel diameter, and leukocyte-endothelium interaction were analyzed in postcapillary venules. Drugs under investigation were infused intravenously prior to and during the early phase of reperfusion. Animals received either adenosine (110 μg kg⁻¹ min⁻¹), buflomedil (3 mg kg⁻¹ body weight), the selective leukotriene synthesis inhibitor MK-886 (20 μmol kg⁻¹ h⁻¹), or dextran 70 (5 mg kg⁻¹ body weight). In saline-treated control animals, a drastic increase of leukocyte sticking and rolling along the endothelium was observed in the early phase of reperfusion. In animals treated with adenosine, buflomedil, MK-886 or dextran 70 postischemic leukocyte-endothelium interaction was markedly reduced. Our results indicate a protective pharmacological potential of adenosine, buflomedil, MK-886 and dextran 70 on postischemic leukocyte adhesion to the endothelium of postcapillary venules.