Vasoactive Prostaglandins in the Impending No-Reflow State

Abstract

The impending no-reflow (NRF) state was studied in the rat hindlimb to identify possible biochemical mediators producing the no-reflow phenomenon. After 5 hours of ischemia, the venous effluents draining the ischemic limb and the contralateral nonischemic limb were collected for three 30-minute time periods. Thromboxane B2 (TxB2), prostaglandin E2 (PGE2), and 6-ketoprostaglandin F1 alpha, the stable metabolite of prostacyclin (PGI2), were measured by radioimmunoassay. Venous outflow rate, distal skin perfusion assessed by dermofluorometry, and histology of muscle and skin were examined in control limbs, ischemic limbs, and limbs with impending no reflow. The no-reflow state was characterized by a significantly decreased venous outflow (less than 0.01 ml per minute), decreased skin perfusion (index of fluorescence of 15 percent in no-reflow limbs versus 70 percent in reflow limbs), and absence of thrombosis of the vasculature. The no-reflow state also was associated with 2.4 times more thromboxane B2 and 1.5 times more 6-ketoprostaglandin F1 alpha than that observed in ischemic limbs with reflow. The biosynthesis of vasodilating prostaglandin E2 in the no-reflow state, however, was only 40 percent of the prostaglandin E2 measured in limbs with reflow. We propose that the impending no-reflow state may reflect a state of global microcirculatory "agonal" vasoconstriction, most probably due to an overabundant release of the vasoconstrictor thromboxane relative to the vasodilating prostaglandin E2 and prostacyclin. The likelihood of specific biochemical mechanisms producing the no-reflow state suggests that pharmacologic agents may be able to reverse the impending no-reflow state to improve tissue survival.