aprikalim and Reperfusion-Injury

We have previously shown that metabolic arrest induced with ATP-regulated potassium channel openers (PCOs) can improve lung preservation by adding Aprikalim (a PCO, Rhone-Poulene Roher) to modified Euro-Collins solution for pulmonary artery flush. Because the membrane hyperpolarizing effects of a PCO potentially competes with the depolarizing effects of a hyperkalemic solution, this study evaluated the effects of the potassium gradient on PCO-mediated lung protection.. Twenty rabbits underwent lung protection in four groups. Group 1 underwent harvest and reperfusion as a "no ischemia" control. Groups 2, 3, and 4 underwent harvest followed by 18 hours of cold ischemic storage before reperfusion. Groups 1 and 4 received Euro Collins as the pulmonary flush at induction of ischemia. Group 2 received Euro Collins plus Aprikalim (100 microM); and group 3 received lactated Ringer's plus Aprikalim. After ischemic storage, the lungs were reperfused with autologous blood for 2 hours. Every 30 minutes, the lungs were given a 10-minute 100% fractional inspired oxygen (F(i)O(2)) challenge to measure maximal gas exchange as an indication of graft function.. Repeated measures ANOVA showed Aprikalim improved graft function after 18 hours of cold ischemia (p < 0.0001). No significant differences were found when Aprikalim was used in either Euro-Collins (group 2) or lactated Ringer's (group 3) solution.. The ability of the PCO Aprikalim to preserve gas exchange in a model of hypothermic pulmonary ischemia-reperfusion injury was not affected by the plasmolemmal potassium gradient. This is consistent with recent findings in myocardial protection studies that the protective effects of PCOs may be intracellular.

Topics: Adenosine Triphosphate; Animals; Female; Hypertonic Solutions; Isotonic Solutions; Lung; Lung Transplantation; Male; Organ Preservation Solutions; Picolines; Potassium Channels; Pulmonary Gas Exchange; Pyrans; Rabbits; Reperfusion Injury; Ringer's Lactate

Ischemia-reperfusion injury continues to represent a significant challenge to successful lung transplantation. Traditional pulmonary ischemic protection is performed using hypothermic hyperkalemic depolarizing solutions to reduce the metabolic demands of the ischemic organ. Measures to further reduce the effects of ischemic injury have focused on the reperfusion period. We tested the hypothesis that novel physiologic hyperpolarizing solutions-using ATP-dependent potassium channel (K(ATP)) openers-given at the induction of ischemia, will reduce cellular injury and provide superior graft function even after prolonged periods of ischemia.. An isolated blood-perfused ventilated rabbit lung model was used to study lung injury. Airway, left atrial, and pulmonary artery pressures were measured continuously during the 2-h reperfusion period. Oxygenation, as a surrogate of graft function, was measured using intermittent blood gas analysis of paired left atrial and pulmonary artery blood samples. Graft function was measured by oxygen challenge technique (F(i)O(2) = 1.0). Wet-to-dry ratio was measured at the conclusion of the 2-h reperfusion period. Control (Group I) lungs were perfused with modified Euro-Collins solution (depolarizing) and reperfused immediately (no ischemia). Traditional protection lungs were perfused with modified Euro-Collins flush solution and stored for 4 h (Group II) or 18 h (Group III) at 4 degrees C before reperfusion. Novel protection (Group IV) lungs were protected with a hyperpolarizing solution containing 100 nM Aprikalim, a specific K(ATP) channel opener, added to the modified Euro-Collins flush solution and underwent 18 h of ischemic storage at 4 degrees C before reperfusion.. Profound graft failure was measured after 18 h of ischemic storage with traditional protection strategies (Group III). Graft function was preserved by protection with hyperpolarizing solutions even for prolonged ischemic periods (Group IV). Wet-to-dry weight ratio, airway, left atrial, and pulmonary artery pressures were not significantly different between the groups.. We have created a model of predictable lung injury. Membrane hyperpolarization with a K(ATP) channel opener (PCO) provides superior prolonged protection from ischemia-reperfusion injury in an in vitro model of pulmonary transplantation.

Topics: Animals; Blood Pressure; Female; Heart Atria; Hypertonic Solutions; In Vitro Techniques; Ion Channel Gating; Lung Transplantation; Male; Organ Preservation Solutions; Oxygen; Picolines; Potassium Channels; Pulmonary Artery; Pyrans; Rabbits; Reperfusion Injury; Solutions