The aim of this study was to determine whether ATP-MgCl2 or isoproterenol pretreatment would attenuate the increase in canine gracilis muscle vascular resistance and permeability associated with 4 h of occlusive ischemia followed by 1 h of reperfusion. To this end, the osmotic reflection coefficient for total plasma proteins (omega), isogravimetric capillary pressure (Pci), precapillary resistance (Ra), postcapillary resistance (Rv), and total vascular resistance (Rt) were determined for the following conditions: control, ischemia, and ischemia plus pretreatment with ATP-MgCl2 or isoproterenol. Reperfusion, after ischemia, significantly reduced omega from 0.94 +/- 0.02 to 0.64 +/- 0.02, whereas Pci was decreased by 50 +/- 4%, indicating a dramatic increase in vascular permeability. Ischemia-reperfusion was also associated with an increase in Rt of 230 +/- 22%. Similar results were obtained in muscles pretreated with isoproterenol. However, in muscles pretreated with ATP-MgCl2, omega averaged 0.98 +/- 0.09, Pci was reduced by only 15 +/- 8%, and Rt was increased by just 25 +/- 12%. The effect of ATP-MgCl2 on neutrophilic oxidative metabolism was evaluated by measuring superoxide production by activated neutrophils in the presence and absence of ATP-MgCl2. Superoxide production by activated neutrophils was significantly attenuated by ATP-MgCl2. The results of these studies indicate that pretreatment with ATP-MgCl2, but not isoproterenol, is remarkably effective in attenuating the increase in skeletal muscle vascular resistance and permeability induced by ischemia-reperfusion. The protective effect of ATP-MgCl2 may be related in part to its ability to inhibit neutrophilic superoxide production.